Your Inner Fish and Womb Terrorists

The evolutionary development of males provides critically important understanding and insight into the biological vulnerabilities of males.

Book excerpt from Your Inner Fish
Shark Past: Hernias

“Our propensity for hernias near the groin, results from taking a fish body and morphing it into a mammal.

Fish have gonads that extend toward their chest, approaching their heart. Mammals don’t, and therein lies the problem. It is a good thing that our gonads are not deep in our chest and near our heart (although it might make reciting the Pledge of Allegiance a different experience). If our gonads were in our chest, we wouldn’t be able to reproduce.

Slit the belly of a shark from mouth to tail. The first thing you’ll see is liver, a lot of it. The liver of a shark is gigantic. Some zoologists believe that a large liver contributes to the buoyancy of the shark. Move the liver away and you’ll find the gonads extending up near the heart, in the “chest” area. This arrangement is typical of most fish: the gonads lie toward the front of the body.

In us, as in most mammals, this arrangement would be a disaster. Males continuously produce sperm throughout their lives. Sperm are finicky little cells that need exactly the right range of temperatures to develop correctly for the three months they live. Too hot, and sperm are malformed; too cold, and they die. Male mammals have a neat little device for controlling the temperature of the sperm-making apparatus: the scrotum. As we all know, the male gonads sit in a sac. Inside the skin of the sac are muscles that can expand and contract as the temperature changes. Muscles also can expand and contract as the temperature changes. Muscles also lie in our sperm cords. Hence, the cold shower effect: the scrotum will tuck close to the body when it is cold. The whole package rises and falls with temperature. This is all a way to optimize the production of healthy sperm.

The dangling scrotum also serves as a sexual signal in many mammals. Between the physiological advantages of having gonads outside the body wall, and the occasional benefits this provides in securing mates, there are ample advantages for our distant mammalian ancestors in having a scrotum.

The problem with this arrangement is that the plumbing that carries sperm to the penis is circuitous. Sperm travel from the testes in the scrotum through the sperm cord. The cord leaves the scrotum, travels up toward the waist, loops over the pelvis, then goes through the pelvis to travel through the penis and out. Along this complex path, the sperm gain seminal fluids from a number of glands that connect to the tube.

The reason for this absurd route lies in our development and evolutionary history. Our gonads begin in development in much the same place as the shark’s: up near our livers. As they grow and develop, our gonads descend. In females, the ovaries descend from the midsection to lie near the uterus and fallopian tubes. This ensures that the egg does not have far to travel to be fertilized. In males, the descent goes farther.

The descent of the gonads, particularly in males, creates a weak spot in the body wall. To envision what happens when the testes and spermatic cord descend to form a scrotum, imagine pushing your fist against a rubber sheet. In this example, your fist becomes equivalent to the testes and your arm to the spermatic cord. The problem is that you have created a weak space where your arm sits. Where once the rubber sheet was a simple wall, you’ve now made another space, between your arm and the rubber sheet, where things can slip. This is essentially what happens in many types of inguinal hernias in men. Some of these inguinal hernias are congenital—when a piece of the gut travels with the testes as it descends. Another kind of inguinal hernia is acquired. When we contract our abdominal muscles, our guts push against the body wall. A weakness in the body wall means that guts can escape the body cavity and be squeezed to lie next to the spermatic cord.

Females are far tougher than males, particularly in this part of the body. Because females do not have a giant tube running through it, their abdominal wall is much stronger that a man’s. This is a good thing when you think of the enormous stresses that female body walls go through during pregnancy and childbirth. A tube through the body wall just wouldn’t do. Men’s tendency to develop hernias is a trade-off between our fish ancestry and our mammal present.” – pages 193 – 196

As you can see male evolution leads to biological vulnerabilities. Hormones were critically important in the evolution of male reproductive morphology from their fish to mammal development. Those hormones played the staring role in the descent of male testicles from their abdomen to their current location. What happens when those hormones are disrupted and those testicles don’t descend?

My 12-year-old son commented, “Mom, Oscar stayed a fish!” That was his statement while we were watching, “Your Inner Fish.” (He’s a smart little bugger) I explained to him why his cousin’s health was altered when he had an undescended testicle and why the doctors should have removed it altogether. It would immediately prevent and lower his cancer risks and here’s why.

Our Stolen Future provided much understanding.

“British researchers report a doubling in the number of cases of undescended testicles in England and Wales between 1962 and 1981, and similar increases have been reported in Sweden and Hungary. Men with undescended testicles have a higher risk of testicular cancer and typically have lower sperm counts and more abnormal sperm. There also appears to be an increasing incidence of the genital defect hypospadia.

In his earlier work, Skakkebaek had slowly accumulated evidence that all these abnormalities stem from developmental errors that take place in the womb, leading him to suspect they might have a common cause. He first found signs that prenatal event might play a role in testicular cancer while exploring the causes of male infertility. Examining tissue samples taken from the testicles of infertile men, he noticed strange-looking cells resembling the fetal germ cells that evolve during normal development into the testicular cells that produce and nurture sperm in mature males. The next clue came when some of the infertile men with aberrant cells later developed testicular cancer. Then he found the same abnormal cells in a boy with undescended testicles, who also developed cancer a decade later. It appeared that the abnormal cells had given rise to the testicular cancer and that men suffering from infertility or certain genital defects were at greater risk of having such cells.

At the same time that Skakkebaek was conducting his review of sperm numbers, another researcher in Edinburgh, Scotland, was also puzzling about the increase in male reproductive problems. Richard Sharpe of the Medical Research Council’s Reproductive Biology Unit was exploring possible explanations for the increase in undescended testicles and the drop in human male sperm counts. He, too, began to suspect that prenatal events might be responsible.

When Sharpe and Skakkebaek met at a conference and discovered they were thinking along similar lines, they began collaborating. In May 1993, they published a paper in the distinguished British medical journal The Lancet, proposing that the cause of the falling sperm counts and increased reproductive abnormalities in men was increased exposure to estrogens in the womb. They cited the DES experience and laboratory studies as support for this hypothesis, noting that prenatal exposure to elevated levels of synthetic or natural estrogens resulted in reduced sperm counts and an increase in the incidence of undescended testicles, hypospadias, and possibly testicular tumors in male offspring.

Animal studies had also provided an insight into how elevated estrogen levels in the womb might limit the number of sperm a male produces in adulthood by inhibiting the multiplication of key cells in the testicles known as Sertoli cells, which orchestrate and regulate the production of sperm. Since each Sertoli cell can support only a fixed number of sperm, the number a male acquires early in life will ultimately limit the number of sperm he can produce as an adult. During male development, the pituitary gland secretes a follicle-stimulating hormone and thereby limits the growth of Sertoli cell numbers.

Of course, one has to bear in mind that many chemicals can undermine male fertility, acting not just before birth but during childhood and adulthood as well. Prenatal exposure to synthetic estrogens is just one of many assaults on male reproductive potential. As we’ve seen, U.S. Environmental Protection Agency reproductive toxicologist Earl Gray has discovered that some synthetic chemicals act as potent androgen blockers and may pose an even greater threat to males than estrogen chemicals. Nevertheless, Sharpe and Skakkebaek’s theory offers an eminently plausible explanation of how estrogens might be having a major impact of male fertility by disrupting development….

The latest sperm count studies, however, add weight to the theory that the cause of the precipitous drop in sperm counts in some prenatal event rather than later damage caused by chemical contaminants or bad habits. If sperm counts were dropping because of adult exposure to increased contamination, smoking, or alcohol or because of venereal disease, they would be dropping in older men as well as younger men. The fact that the sperm counts are lower in younger men and correlate inversely with date of birth argues that the damage was done in the womb.” – Our Stolen Future by Theo Colborn (pages 175 – 177)

And males, that’s why you should care a great deal about female health because your first home is a womb and it’s being destroyed which directly impacts your own health. Dr. Theo Colborn rightly called our ruling class industrialists “womb terrorists.” They certainly know how to manufacture many kinds of terrorists all across our globe and they cause much destruction.

Biological development is a remarkable orchestration that makes a symphony boring in comparison. The sonic hedgehog gene is responsible for building the hand. The gene is like first violin and when it gets turned on, it chemically alerts the entire string section to play so all the digits form properly. Sniper fire from an organochlorine munition like thalidomide silences the sonic hedgehog gene and many other critically important genes during development so the entire string section remains silenced and no limbs are formed.

Some genes like the Sox9 are triggered to play by hormones so instead of the strings playing, the trumpets belt it out and males form. Unfortunately for some males, their development is altered by munition technologies from the benzene branch and they are feminized or suffer from teeny weeny syndrome and more…

Sox9? That’s the best name they could come up with for such a critically important gene? (Poor males! That’s not going to stick in anyone’s brain! Rocket launcher gene…)

Hormones: Chemical Messengers That Work in Parts per Trillion From Our Stolen Future Theo Colborn

Hormones: Chemical Messengers That Work in Parts per Trillion

Sex determination is regulated by the Sox9 gene. During testis differentiation, this gene is directly targeted by the product of the Y chromosome–encoded gene Sry. The regulatory region of Sox9 is complex, which is typical of genes with multiple roles in development. Gonen et al. find that a single far-upstream 557–base pair element is critical for up-regulating Sox9. Without it, XY mice develop as females instead of males. The 557–base pair enhancer is conserved, likely to be relevant to human disorders of sex differentiation, and probably essential because it acts early in a time-critical process, and any failure allows ovary-specific factors to dominate.

http://discovery.ucl.ac.uk/10059532/

Sex reversal following deletion of a single distal enhancer of Sox9

https://science.sciencemag.org/content/360/6396/1469

Their technologies have hijacked and destroyed so much life and health. When will you wake up and stop attacking victims and focus on the capitalist ruling class perpetrators and their technologies destroying us all?

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How a Big Agribusiness Firm Infiltrated the EPA and Made a Mockery of Science By Kamil Ahsan for AlterNet

How a Big Agribusiness Firm Infiltrated the EPA and Made a Mockery of Science By Kamil Ahsan for AlterNet

Expensive coverups have kept a dangerous chemical in America’s water supply.

June 5, 2014

Earlier this year, in an exposé in The New Yorker, Rachel Aviv detailed the story of Syngenta, an agribusiness firm that was sued by the community water systems of six states in a class-action lawsuit over the firm’s herbicide atrazine.

Atrazine is the second most commonly used herbicide in the US and is used on more than 50% of all corn crops. It is one of Syngenta’s most profitable chemicals with sales at over $300 million a year. Banned in the EU, atrazine remains on the market in the US despite scores of scientific publications demonstrating its role in abnormal sexual development. Almost insoluble in water, atrazine contaminates drinking water supplies at 30 times the concentration demonstrated to cause severe sexual abnormalities in animal models.

Recently unsealed court documents from the lawsuit have disclosed how Syngenta launched a multimillion-dollar campaign to disrepute and suppress scientific research, and influence the US Environmental Protection Agency to prevent a ban on atrazine.

Tyrone Hayes, a professor of Integrative Biology at UC Berkeley has demonstrated in his research that atrazine leads to health problems, reproductive issues and birth defects. Hayes is a vocal proponent of legislative action to ban the dissemination of atrazine in water supplies. The court documents showed that Syngenta specifically attacked Hayes’ work with its smear campaign.

In addition to smear campaigns, Syngenta hired a private detective agency to look into the personal backgrounds of scientists on an advisory panel at the EPA, the judge presiding over the lawsuit, and Hayes. The documents also reveal a host of third-party organizations and independent “experts” who were on Syngenta’s payroll and supplied with Syngenta’s data in order to make public statements or write op-ed pieces in support of atrazine. Often, these experts were supplied directly with material that company employees edited or wrote.

Syngenta’s Coverup

It all started in 1997 when Hayes was employed by Syngenta to study atrazine, which was under review by the EPA. Hayes’ experimental research on the developmental growth of frogs began to reveal that even at levels of atrazine as low as 0.1 parts per billion (ppb), the chemical was capable of causing males to develop as hermaphrodites. Some males developed female organs and were even capable of mating with normal males and producing eggs. As reported in top peer-reviewed journals such as PNAS and Nature, at exposure to 0.1 ppb atrazine the frogs showed extremely reduced levels of testosterone and feminized voice boxes.

As Hayes amassed data, Syngenta downplayed his results, citing problems with statistics or asking him to repeat studies, often nitpicking or questioning his credibility or scientific skills.

In 2000, Hayes resigned from the panel. He continued to speak at conferences, publicizing his ongoing research in the lab. Meanwhile, Syngenta employees began to show up at conferences to publicly besmirch his data. Sporadically, the campaign turned into threats of violence. In a Democracy Now interview with Amy Goodman, Hayes said:

“Tim Pastoor, for example, before I would give a talk, would literally threaten, whisper in my ear that he could have me lynched, or he said he would send some of his ‘good ol’ boys to show me what it’s like to be gay,’ or at one point he threatened my wife and my daughter with sexual violence.”

Shockingly, even though Syngenta settled the lawsuit for $105 million in late 2012 after eight years of litigation, it still maintains that amount of atrazine present in the water is much lower than would be required to cause damage. In an article in Forbes published a week after the New Yorker story, Jon Entine criticized Hayes and claimed that “after numerous follow up studies by the EPA and a score of scientists… evidence of endocrine related problems Hayes claimed to have identified… are nowhere to be found.”

This is a patently false assertion. A mere scientific literature search shows dozens of peer-reviewed articles showing atrazine-induced defects in animal models. A number of papers on salmon and fish find similar results to those in frog: fish exposed to atrazine showed major reproductive abnormalities in both males and females, low sperm counts and low testosterone levels in males. Similar defects have been observed in reptiles. Research in rats has demonstrated decreased fertility, effects on sperm count, increased prostate disease in males and poor mammary development. A collaborative effort of an international team of scientists confirmed these studies by demonstrating feminization of male gonads across vertebrate species.

All signs point toward the same being true for humans. Said Hayes:

“A number of epidemiological studies in humans have associated atrazine with impaired reproduction and a decline in sperm count and fertility. Another study looking at increased prostrate disease in workers who are exposed to atrazine in the production plant in St. Gabriel, Louisiana. A number of studies now show birth defects in humans exposed to atrazine: gastroschisis where the intestines are on the outside of the baby when it’s born, choanal atresia, an effect where the oral cavity and the nasal cavity close up. Most recently, there’s been work showing atrazine associating with three different types of genital abnormalities in males.”

Corruption Within the EPA

Interestingly, the scientific advisory panel to the EPA recognizes this wealth of scientific data. In a memo from the 2012 review the advisory panel repeatedly calls attention to the biased methodology employed by the EPA. In fact, the advisory panel disagreed with almost every conclusion the EPA made.

Hayes explained: “The panel was only making recommendations, they don’t make decisions and so the EPA doesn’t need to listen to them. This really undermines the role of the scientific advisory panel.”

Syngenta was closely involved with the EPA’s decision. The EPA mainly considered just one study that found inconclusive effects of atrazine. This was the sole premise for the EPA’s decision. It was based on the research of a group led by Kloas Werner. Said Hayes:

“Kloas Werner was originally on the EPA scientific advisory panel that I presented my data to. He at that time was hired by Syngenta and subsequent to being on the panel he conducted a study in collaboration with the EPA and Syngenta and reported back to the panel that he was on. The panel’s conclusion was that more work needed to be done, and then he presented back to that panel. Essentially, his previous decision helped him get the money for his study. Furthermore, they selected a strain of frogs that don’t respond even to estrogen, which was acknowledged by the advisory panel which reviewed their work.”

But Syngenta wasn’t satisfied with bad science and corruption within the EPA. As Syngenta was hiring Werner, a scientific advisory panel member who could sway the EPA review process, it also held scores of closed-door meetings with panel members. As the documents reveal, Syngenta also hired a communications consultancy, the White House Writers’ Group, to set up meetings with members of Congress and Washington bigwigs to discuss upcoming EPA reviews.

The information about Syngenta’s misdeeds has had little to no effect. The fiction that Hayes is a scientific hack continues to pervade the work of pro-Syngenta writers like Entine. These columnists, who write from corporation-apologist perspectives, bolster the fiction by glossing over critiques of the EPA and pretending like its conclusions represent uncontroversial scientific consensus.

Time and time again, these “third-party allies” of Syngenta hyperbolically talk about the “scientific method,” and suggest that science is science, regardless of the angle of the investigator (none have much to say about Werner’s estrogen-insensitive frogs). For them, it seems, there is no conceivable way Syngenta employed techniques that would furnish them with results to protect its multimillion-dollar profits.

In other words, for them, “conflict of interest” means nothing. Scientific publishing is uncompromising about this: journals require the disclosure of conflicts of interest in publications. Obviously, political and financial incentives are sufficient criteria to change scientific results because they deeply influence the way experimenters do science.

Unsurprisingly, the Kloas paper failed to declare any conflict of interest.

“How can you declare no conflict of interest when clearly the manufacturer benefits from the conclusions drawn by that paper as well as benefits from the decisions made by the EPA advisory panel?” Hayes said. “Especially when the member was both on the panel and was paid by Syngenta.”

Corporation v. Science

Syngenta frequently alleges that Hayes never made his data on atrazine publicly available, a damning indictment that makes it seem like his data could have been fabricated. Hayes said this is not the case.

“The work that I did for Syngenta, Syngenta owns all that raw data,” he said. “This includes the generated raw data, the transcribed typed data, and really everything. The EPA actually visited my lab. Members of the EPA actually were in my laboratory, they observed all of our processes and data collection. Mary Frankenberry, a statistician, actually analyzed the data herself.”

Syngenta and its supporters also rely heavily on the vitriol that Hayes hardly seems like a disinterested, objective scientist. Rich criticism from a company that hires people to obtain the scientific results it wants.

Hayes has spoken widely, set up a website AtrazineLovers.com and rapped about Syngenta’s powerful lobbying to keep atrazine on the market. There is, however, a fundamental distinction between a company lobbying to get its favored scientific result, and a scientist who vocally defends his scientific results. Hayes’ response isn’t surprising or unusual. Scientists often claim ownership over their results and will doggedly defend them at conferences.

The actions of big corporations like Syngenta, especially when dealing with highly profitable products, reveal a broader truth about the nature of corporate power. There is a dangerous trend in which corporate fiat is used to call scientific research into question and sway governmental policy. This trend puts millions of lives at risk as hazardous products avoid regulation and remain on the market.

One wonders why the burden isn’t on Syngenta for proving without a doubt that atrazine has no effects before plying the entire population with a highly dangerous chemical. Even if it wasn’t a near-certainty that atrazine causes birth defects, why wouldn’t we require regulatory bodies such as the EPA to err on the side of caution?

Today, atrazine remains legal and in the water supplies of millions of Americans, despite evidence from scores of labs outside Tyrone Hayes’ showing it to be hazardous.

“In the 15 plus years that I’ve had experience with the EPA, I don’t really have a lot of faith that we’re going to get an objective review that’s really going to focus on environmental health and public health with regards to atrazine, or any other chemical for that matter,” Hayes said.

Who can blame him?

http://www.alternet.org/personal-health/how-big-agribusiness-firm-infiltrated-epa-and-made-mockery-science?paging=off&current_page=1#bookmark

The Expose

http://www.newyorker.com/reporting/2014/02/10/140210fa_fact_aviv?currentPage=all

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“Our Stolen Future,” by Theo Colborn, Dianne Dumanoski, and John Peterson Myers. Hand-Me-Down Poisons Excerpt

“Our Stolen Future,” by Theo Colborn, Dianne Dumanoski, and John Peterson Myers.
Hand-Me-Down Poisons Excerpt

Gilbertson had given Colborn complete access to his meticulously organized collection of material on each animal species that breeds in the Great Lakes basin–data that he had gathered over the years and arranged in chronological order in three-ring binders. Colborn was awed by the elegance of the effort and by the years of dedication and scholarly consideration that it reflected. With a sense of history, Gilbertson had gone to great lengths to collect papers and studies dating back a half century or more–literature documenting that the problems seen today in the birds and wildlife along the lakes had not been reported before World War II. In the bald eagle file, she found evidence of parallel declines in the postwar period in the bald eagle in North America and in its European cousin, the white-tailed sea eagle, along with a collection of reports detailing the concentrations of synthetic chemical contaminants found in both species. Photocopies from Gilbertson’s archive had greatly enriched Colborn’s files, but their conversations, during which Gilbertson generously shared his broad experience, had proven even more valuable.

Over lunch in the Canadian Wildlife Service cafeteria, Colborn, Gilbertson, and Fox had discussed the wildlife evidence contradicting the frequent claims that the lakes had been cleaned up. The two Canadians shared the conviction the wildlife work had likely implications for human health and constituted a warning humans ought to heed. In her survey of the scientific literature, Colborn had been fascinated by some of Fox’s work, which reported evidence of behavioral changes in wildlife as well as signs of physical damage.

In herring gull colonies, particularly in highly polluted areas of Lakes Ontario and Michigan, Fox and his colleagues had found nests with twice the normal number of eggs–a sign that the birds occupying the nests were two females instead of the expected male-female pair. The phenomenon, which persisted in some areas, had been particularly prevalent in the mid to late 1970s. During this period, Fox had collected and preserved seventeen near-term embryos and newly hatched chicks from the affected colonies in hopes that he might eventually discover what was causing this unusual behavior and other reproduction problems.

A few years later, Fox encountered a scientist who might help him find the answer. Michael Fry, a wildlife toxicologist at the University of California at Davis, had investigated how the pesticide DDT and other synthetic chemicals disrupt the sexual development of birds after hearing reports of nests with female pairs in western gull colonies in southern California. While some looked for an evolutionary explanation for the phenomenon, Fry had suspected contamination. Reports in scientific literature indicated that a number of synthetic chemicals, including the pesticide DDT, could somehow act like the female hormone estrogen.

To test his theory, Fry had injected eggs taken from western gull and California gull colonies in relatively uncontaminated areas with four substances–two forms of DDT; DDE, the breakdown product of DDT; and methoxychlor, another synthetic pesticide that had also been reported to act like the hormone estrogen. The experiment showed that the levels of DDT reported in contaminated areas would disrupt the sexual development of male birds. Fry noted a feminization of the males’ reproductive tracts, evident by the presence of typically female cell types in the testicles or, in cases of higher doses, by the presence of an oviduct, the egg-laying canal normally found in females. Despite all this internal disruption, the chicks had no visible defects and looked completely normal.

As soon as he could make arrangements, Fox shipped the preserved embryos and chicks off to Fry in California. In his examination of the birds’ reproductive tracts, Fry found that five of the seven males were significantly feminized and two had visibly abnormal sex organs. Five of the nine females showed significant signs of disrupted development as well, including the presence of two egg-laying canals instead of the one that is normal in gulls. Such disruption, Fry noted, could indicate that the birds had been exposed to chemicals that acted like the female hormone estrogen.

Earlier experiments by other researchers had shown that exposing male birds to estrogen during development affects the brain as well as the reproductive tract and permanently suppresses sexual behavior. When chicken and Japanese quail eggs received estrogen injections, the males that hatched never crowed, strutted, or exhibited mating behavior as adults.

Taken together, the evidence in the Great Lakes suggested that the females were nesting together because of a shortage of males, which might be absent because they were disinterested in mating or incapable of reproducing. Though most eggs in these same sex nests were infertile, these females sometimes managed to mate with an already paired male and hatch a chick. The female pairs appeared to be an effort to make the best of a bad situation.

Fox and others had noticed other behavioral abnormalities as well, particularly in birds that had high levels of chemical contamination. In Lake Ontario colonies, the birds showed aberrant parental behavior, including less inclination to defend their nests or sit on their eggs. In unsuccessful nests, the incubating eggs were unattended for three times as long as in the nests where birds successfully produced offspring. A study comparing reproduction in Forster’s terns nesting in clean and contaminated areas reported that nest abandonment and egg disappearance, often due to theft by predators, was substantial in the contaminated area on Lake Michigan but virtually nonexistent in the clean colony on a smaller lake in Wisconsin. Parental inattentiveness clearly diminished the chances that the eggs would hatch and the chicks would survive.

What Colborn remembered afterward about the conversation was how cautious they had all been. Despite the shared view that wildlife findings had implications for humans, no one wanted to acknowledge the unspoken question hanging in the air. No one dared ask whether synthetic chemicals might be having similar disrupting effects on human behavior. Those were treacherous waters they all preferred to avoid.

pages 20 – 22

For additional information – http://www.ourstolenfuture.org/

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The Toxins That Affected Your Great-Grandparents Could Be In Your Genes. Biologist Michael Skinner has enraged the chemical community and shocked his peers with his breakthrough research by By Jeneen Interlandi for Smithsonian magazine, December 2013

“The Toxins That Affected Your Great-Grandparents Could Be In Your Genes”

Biologist Michael Skinner has enraged the chemical community and shocked his peers with his breakthrough research

By Jeneen Interlandi for Smithsonian magazine, December 2013

Michael Skinner’s biggest discovery began, as often happens in science stories like this one, with a brilliant failure. Back in 2005, when he was still a traditional developmental biologist and the accolades and attacks were still in the future, a distraught research fellow went to his office to apologize for taking an experiment one step too far. In his laboratories at Washington State University, she and Skinner had exposed pregnant rats to an endocrine disruptor—a chemical known to interfere with fetal development—in the hope of disturbing (and thereby gaining more insight into) the process by which an unborn fetus becomes either male or female. But the chemical they used, an agricultural fungicide called vinclozolin, had not affected sexual differentiation after all. The scientists did find lower sperm counts and decreased fertility when the male offspring reached adulthood, but that was no surprise. The study seemed like a bust.

By accident, though, Skinner’s colleague had bred the grandchildren of those exposed rats, creating a fourth generation, or the great-grandchildren of the original subjects. “It’s OK,” Skinner told her. “You might as well analyze them.” If nothing else, he thought, the exercise might take her mind off her mistake. So she went ahead and studied the rats’ testes under a microscope.

What they found would not only change the direction of Skinner’s research but also challenge a bedrock principle of modern biology. And Skinner would become the forerunner of a new way of thinking about the possible long-term health consequences of exposure to environmental chemicals.

His discoveries touch on the basic question of how biological instructions are transmitted from one generation to the next. For half a century it has been common knowledge that the genetic material DNA controls this process; the “letters” in the DNA strand spell out messages that are passed from parent to offspring and so on. The messages come in the form of genes, the molecular equivalent of sentences, but they are not permanent. A change in a letter, a result of a random mutation, for example, can alter a gene’s message. The altered message can then be transmitted instead.

The strange thing about Skinner’s lab rats was that three generations after the pregnant mothers were exposed to the fungicide, the animals had abnormally low sperm counts—but not because of a change in their inherited DNA sequence. Puzzled, Skinner and his team repeated the experiments—once, twice, 15 times—and found the same sperm defects. So they bred more rats, and tested more chemicals, including substances that lead to diseases in the prostate, kidney, ovaries and immune system. Again and again, these diseases also showed up in the fourth- and fifth-generation offspring of mothers exposed to a chemical.

“In essence,” Skinner explains, “what your great-grandmother was exposed to could cause disease in you and your grandchildren.”

And, startlingly, whatever disease pathway a chemical was opening in the rats’ fur-covered bodies, it did not begin or end at a mutation in the genetic code. Skinner and his team found instead that as the toxins flooded in, they altered the pattern of simple molecules called methyl groups that latch onto DNA in the fetus’ germ-line cells, which would eventually become its eggs or sperm. Like burrs stuck to a knit sweater, these methyl molecules interfered with the functioning of the DNA and rode it down through future generations, opening each new one to the same diseases. These burrs, known to be involved in development, persisted for generations. The phenomenon was so unexpected that it has given rise to a new field, with Skinner an acknowledged leader, named transgenerational epigenetics, or the study of inherited changes that can’t be explained by traditional genetics.

A study by Skinner and colleagues published last year in the journal PLOS One has upped the ante considerably. The burrs were not just haphazardly attached, Skinner found. Instead, they fastened themselves in particular arrangements. When he bathed the insides of his pregnant rats in bug spray, jet fuel and BPA, the plastics component recently banned from baby bottles, each exposure left a distinct pattern of methyl group attachments that persisted in the great-grandchildren of exposed rats.

Not only is your great-grandmother’s environment affecting your health, Skinner concluded, but the chemicals she was exposed to may have left a fingerprint that scientists can actually trace.

The findings point to potentially new medical diagnostics. In the future, you may even go to your doctor’s office to have your methylation patterns screened. Exposure of lab rats to the chemical DDT can lead to obesity in subsequent generations—a link Skinner’s team reported in October. Hypothetically, a doctor might someday look at your methylation patterns early in life to determine your risk for obesity later. What’s more, toxicologists may need to reconsider how they study chemical exposures, especially those occurring during pregnancy. The work raises implications for monitoring the environment, for determining the safety of certain chemicals, perhaps even for establishing liability in legal cases involving health risks of chemical exposure.

These possibilities have not been lost on regulators, industries, scientists and others who have a stake in such matters. “There are two forces working against me,” Skinner says. “On one side, you have moneyed interests refusing to accept data that might force stronger regulations of their most profitable chemicals. On the other side, you have genetic determinists clinging to an old paradigm.”

Michael Skinner wears a gray Stetson with a tan strap, and leans back easily in his chair in his office on the Pullman campus. His fly-fishing rod stands in the corner, and a colossal northern pike is mounted on the wall. An avid fly fisherman, Skinner, age 57, was born and raised on the Umatilla Indian Reservation in eastern Oregon. The Skinners are not of Indian descent, but his parents owned a family farm there—“a good cultural experience,” he says. His father worked in insurance, and he and his four brothers grew up just as five generations of Skinners had before them—hunting and fishing and cowboying, learning a way of life that would sustain them into adulthood.

He loved the outdoors, and his fascination with how nature worked prompted a school guidance counselor’s suggestion that a career in science might be just the thing. He was about 12, and true to form he stuck with it. In high school and then at Reed College he wrestled competitively, and today his supporters and critics alike may detect a bit of his old grappling self in how he approaches a problem—head-on. “It probably taught me how to confront, rather than avoid challenges,” he says now. The sport also led him to his future wife, Roberta McMaster, or Bobbie, who served as his high-school wrestling team’s scorekeeper. “I was fascinated that someone so young knew exactly what he wanted to do with his life,” Bobbie recalls. He proposed marriage before heading for college, and the two have been together ever since and have two grown children.

He attended Washington State University for his PhD in biochemistry, and during that time he and Bobbie often lived on game that he’d hunted. It was not unheard of to find a freshly killed deer hanging in the carport of their student housing. “They were lean years,” Bobbie says. “But they were good ones.”

After positions at Vanderbilt and the University of California, San Francisco, Skinner returned to Washington State University. “I wanted a big research college in a rural town,” he says. He spent the next decade studying how genes turn on and off in ovaries and testes, and how those organs’ cells interact. He wasn’t aiming to take on the central idea in biology for much of the 20th century: genetic determinism, the belief that DNA is the sole blueprint for traits from hair and eye color to athletic ability, personality type and disease risk.

In some sense this interpretation of genetic determinism was always oversimplified. Scientists have long understood that environments shape us in mysterious ways, that nature and nurture are not opposing forces so much as collaborators in the great art of human-making. The environment, for example, can ramp up and pull back on gene activity through methyl groups, as well as a host of other molecules that modify and mark up a person’s full complement of DNA, called the genome. But only changes in the DNA sequence itself were normally passed to offspring.

So certain was everyone of this basic principle that President Bill Clinton praised the effort to complete the first full reading of the human genome, saying in June 2000 that this achievement would “revolutionize the diagnosis, prevention and treatment of most, if not all human diseases.” When stacked against such enthusiasm, Skinner’s findings have felt like heresy. And for a while, at least, he was criticized accordingly.

***

Critics of the Skinner-led research pointed out that the doses of vinclozolin in his rat studies were way too high to be relevant to human exposure, and injecting the rats as opposed to administering the toxins through their food exaggerated the effects. “What he’s doing doesn’t have any real obvious implications for the risk assessments on the chemical,” EPA toxicologist L. Earl Gray was quoted telling Pacific Standard magazine back in 2009. Until the results are replicated, “I’m not sure they even demonstrate basic science principles.”

Skinner responds to assaults on his data by saying that risk assessment, of the type that toxicologists do, has not been his goal. Rather, he’s interested in uncovering new biological mechanisms that control growth, development and inheritance. “My approach is basically to hit it with a hammer and see what kind of response we get,” he says. He remains calm, even when called on to defend that approach. “Conflicts with individuals solve very little,” he says. “The best way to handle these things is to let the science speak for itself.”

That science has received a lot of attention (the vinclozolin study has been cited in the scientific literature more than 800 times). Recently, the journal Nature Reviews Genetics asked five leading researchers to share their views on the importance of epigenetic inheritance. A “mixture of excitement and caution,” is how the editors described the responses, with one researcher arguing that the phenomenon was “the best candidate” for explaining at least some transgenerational effects, and another noting that it might, if fully documented, have “profound implications for how we consider inheritance, for mechanisms underlying diseases and for phenotypes that are regulated by gene-environment interactions.”

Though most of Skinner’s critics have been reassured by new data from his lab and others, he says he still feels embattled. “I really try to be a scientist first and foremost,” he says. “I’m not a toxicologist, or even an environmentalist. I didn’t come to this as an advocate for or against any particular chemical or policy. I found something in the data, and I pursued it along a logical path, the way any basic researcher would.”

Read more: http://www.smithsonianmag.com/ideas-innovations/The-Toxins-That-Affected-Your-Great-Grandparents-Could-Be-In-Your-Genes-231152741.html#ixzz2mIaKLsRH
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“Some women actually have men on the brain,” By Melissa Healy, Los Angeles Times 9/27/2012

Some women actually have men on the brain By Melissa Healy, Los Angeles Times
http://www.latimes.com/health/boostershots/la-heb-women-brain-microchimerism-20120926,0,6446716.story
For the Booster Shots Blog
September 27, 2012

For decades after a woman has carried a male child in her womb or shared her mother’s womb with a brother, she carries a faint but unmistakable echo of that intimate bond: male fetal DNA that lodges itself in the far recesses of her brain.

That astonishing finding, published Wednesday in the journal Public Library of Science One (PLoS One), suggests that the act of having a child is no mere one-way transmission of genetic material and all that goes with it: There is an exchange of DNA that passes into the part of us that makes us who we are. That, in turn, may alter a woman’s health prospects in ways her own DNA never intended.

In the study, researchers from the Fred Hutchinson Cancer Research Center and the University of Washington examined, post-mortem, the brains of 59 women. In 63% of the brains, they found fetal DNA that could only have come from a male. While scattered throughout the brain, the genetic traces of this other individual were clustered heavily in the brain’s hippocampus — a region crucial to the consolidation of memories — and in the parietal and temporal lobes of the brain’s prefrontal cortex, areas that play roles in sensation, perception, sensory integration and language comprehension.

When a person takes on the DNA of another, as happens, for instance, in bone marrow transfusions, she is called a “chimera” — in mythology, a beast that is the fusion of two or more creatures. The discovery that a person can carry the fetal DNA of another person has given rise to a variant: This is dubbed microchimerism.

This line of research, says rheumatologist J. Lee Nelson, coauthor of the study, “suggests we need a new paradigm of the biological self” and how it is formed. We think of ourselves as the product of two biological parents and a one-time roll of the genetic dice. That, says Nelson, appears to be wrong: In the womb, we may also pick up the DNA of older siblings left over from their stay, or of a fetal twin who never made it to daylight. In the course of our lives, we may take on the DNA of the sons we bear, or even of the sons we conceived and miscarried. And that DNA can stay with us long after our big brothers have moved on and our sons have grown up and moved away.

The sources of our DNA “are much more diverse than we know,” said Nelson in an interview. And these exchanges of DNA may play an evolutionary role far greater than we have ever imagined, she added. Walt Whitman once wrote, “I contain multitudes,” and Nelson says she and her colleagues now glean new meanings from the observation.

The new study shows that this evolutionary X-factor is also at work in the brain.

It hasn’t been many years since scientists first learned that a baby’s DNA could cross the placental barrier from baby to mother and lodge itself in her blood and organs. The current study finds that it can also penetrate the vaunted “blood-brain barrier,” which is thought to protect the brain from toxins and foreign invaders.

Once there, Nelson said, the DNA of another person may alter a woman’s propensity to certain brain diseases — conferring protection in some cases and vulnerability in others. It may carry the switches that turn brain cancers on — or off. It may harden the brain against trauma or psychiatric disease — or make it less resilient. Future research will need to determine how, say, carrying a male fetus may influence a mother’s likelihood of developing Alzheimer’s disease or auto-immune diseases such as multiple sclerosis.

http://www.latimes.com/health/boostershots/la-heb-women-brain-microchimerism-20120926,0,6446716.story

Male Microchimerism in the Human Female Brain
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045592

William F. N. Chan1¤*, Cécile Gurnot1, Thomas J. Montine2, Joshua A. Sonnen2, Katherine A. Guthrie1, J. Lee Nelson1,3
1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Department of Pathology, University of Washington, Seattle, Washington, United States of America, 3 Division of Rheumatology, University of Washington, Seattle, Washington, United States of America

Abstract

In humans, naturally acquired microchimerism has been observed in many tissues and organs. Fetal microchimerism, however, has not been investigated in the human brain. Microchimerism of fetal as well as maternal origin has recently been reported in the mouse brain. In this study, we quantified male DNA in the human female brain as a marker for microchimerism of fetal origin (i.e. acquisition of male DNA by a woman while bearing a male fetus). Targeting the Y-chromosome-specific DYS14 gene, we performed real-time quantitative PCR in autopsied brain from women without clinical or pathologic evidence of neurologic disease (n = 26), or women who had Alzheimer’s disease (n = 33). We report that 63% of the females (37 of 59) tested harbored male microchimerism in the brain. Male microchimerism was present in multiple brain regions. Results also suggested lower prevalence (p = 0.03) and concentration (p = 0.06) of male microchimerism in the brains of women with Alzheimer’s disease than the brains of women without neurologic disease. In conclusion, male microchimerism is frequent and widely distributed in the human female brain.

Introduction

During pregnancy, genetic material and cells are bi-directionally exchanged between the fetus and mother [1], following which there can be persistence of the foreign cells and/or DNA in the recipient [2], [3]. This naturally acquired microchimerism (Mc) may impart beneficial or adverse effects on human health. Fetal Mc, which describes the persistence of cells and/or DNA of fetal origin in the mother acquired during pregnancy, has been associated with several different autoimmune diseases as well as implicated in tissue repair and immunosurveillance [4]–[6].

Although there is a broad anatomical distribution of Mc in humans that varies in prevalence and quantity [7]–[13], whether the human brain harbors fetal Mc and with what frequency is not known. Fetal Mc has recently been described in the mouse brain [14], [15]. In limited studies, maternal Mc was described in the human fetal brain [9].

In this study, we performed real-time quantitative PCR (qPCR) to detect and quantify male DNA in multiple brain regions of women, targeting the Y-chromosome-specific DYS14 gene sequence as a marker for Mc of fetal origin. Deceased female subjects had no clinical or pathologic evidence of neurologic disease. We also tested brain specimens from women with Alzheimer’s disease (AD) for Mc. This is because AD has been reported as more prevalent in parous vs. nulliparous women [16], [17], increasing with higher number of pregnancies that also correlated with a younger age of AD onset [17], [18].

Methods

Subjects and Specimens

This study was approved by the institutional review board of the Fred Hutchinson Cancer Research Center (Number 5369; Protocol 1707). Subjects of the study were women without neurologic disease or with AD, totaling 59 deceased individuals. Twenty-six women had no neurologic disease. Thirty-three women had AD (Table 1). Brain autopsy specimens from these women came from one of two institutions: the Department of Pathology at the University of Washington in Seattle, Washington, or the Harvard Brain Tissue Resource Center established at McLean Hospital in Belmont, Massachusetts. Specimens from the University of Washington were obtained from adult women who had no clinical history of neurologic disease within two years of death and whose brain histology showed no evidence of disease, and from women who were diagnosed with probable AD during life [19] and met the National Institute on Aging-Reagan Institute consensus criteria for a neuropathologic diagnosis of AD [20]. Similarly, specimens from the Harvard Brain Tissue Resource Center were obtained from adult women without neurologic disease or who met clinical and pathologic criteria for AD. Age at death ranged from 32 to 101 (Table 1). Age at disease onset was known for subjects with AD from the University of Washington (median: 77 years; range: 64–93 years). Following autopsy, brain specimens were either formalin fixed or frozen in liquid nitrogen. Depending on availability, samples from two to twelve brain regions were obtained from each subject. Brain regions investigated included frontal lobe, parietal lobe, temporal lobe, occipital lobe, cingulate gyrus, hippocampus, amygdala, caudate, putamen, globus pallidus, thalamus, medulla, pons, cerebellum, and spinal cord. Subjects with AD contributed more specimens per person than subjects without neurologic disease, but this was not statistically significant (means: 3.6 vs. 2.5, respectively; p = 0.05). Combining subjects from both institutions, subjects with AD were significantly older at death (p<0.001); the post-mortem intervals (PMIs) were not significantly different (p = 0.06; Table 1). The most likely source of male Mc in female brain is a woman’s acquisition of male DNA from pregnancy with a male fetus. Limited pregnancy history was available on the subjects; pregnancy history on most subjects was unknown. Nine women were known to have at least one son, eight with AD and one without neurologic disease. Two women were known to have no history of having sons, one with AD and one without neurologic disease.

DNA Extraction

Genomic DNA was extracted from brain tissues using the QIAamp® DNA Mini Kit (QIAGEN, Valencia, CA) according to the manufacturer’s tissue protocol.

Real-time qPCR

Male DNA was quantified in female brain tissues by amplifying the Y chromosome-specific sequence DYS14 (GenBank Accession X06325) [21] using the TaqMan® assay and the ABI Prism® 7000 Sequence Detection System (Applied Biosystems, Foster City, CA). Primer and probe sequences for quantifying DYS14 [22], as well as preparation of standard curves, composition of the qPCR mixture and thermal profile [23] have all been described previously. Square of the correlation coefficient for all standard curves was always greater than 0.99. Every experiment included no template controls to test for male DNA contamination during plate setup and all controls were negative. A minimum of six wells was tested for each specimen. Mean Ct was 36, with a range between 30 and 39 for all specimens except those of B6388, which was between 26 and 29. A representative amplification plot is provided in (Figure S1). Only wells in which amplification occurred at Ct0.5 gEq/105. Thus, estimates of male Mc might be lower than the true values. On the other hand, since detection of male DNA did not account for Mc potentially contributed by female fetuses, this could result in underestimation of the overall Mc in the brain. HLA-specific qPCR, as previously reported [25], [26], is another approach to Mc detection that is not sex-dependent. It requires participation of family members which was not possible for the current studies. As a supplementary study, we tested autopsied brain from a female systemic sclerosis patient by HLA-specific qPCR for whom we had familial HLA genotyping, targeting the child’s paternally transmitted HLA as previously described [26], [27]. These data are provided in (Tables S1 and S2). All qPCR data were analyzed using the 7000 System Sequence Detection Software.

Statistics

Subject and Mc measurement characteristics were compared across groups by Chi-squared test for categorical data and t-test for continuous data. Mc prevalence and concentrations were analyzed according to disease status. A logistic regression model was used to estimate the association between Mc prevalence and disease status, with adjustment for total gEq tested, age at death, and PMI. The estimates were also adjusted for possible correlation between repeated measures from the same subject via generalized estimating equations. Association was reported as an odds ratio (OR) along with p value to indicate significance. As an example, OR of 0.30 could be interpreted to say that the odds of having AD for a subject who tested positive for Mc was 70% lower than the odds for a subject who tested negative. We also analyzed Mc concentrations as the outcome in Poisson log-linear regression models, assuming that the number of gEq detected as Mc was directly proportional to the number of total gEq tested. By definition, Mc occurs rarely, thus the data distribution is skewed to the right. We utilized negative-binomial models to account for the high degree of over-dispersion in the data; interpretation of the resulting estimates is identical to those of a Poisson model. Adjustments for potential confounders and for possible correlation between repeated measures were made as described above. The rate ratio (RR), along with p value to indicate significance, was used to compare the observed rates of Mc detection in the two groups. As an example, RR of 0.30 could be interpreted to say that the rate of Mc detection in subjects with AD was 70% lower than the rate of Mc detection in subjects without neurological disease. Secondary analysis was conducted to determine whether disease status was associated with Mc prevalence or concentration in a subset of samples from brain regions thought to be most affected by AD. Furthermore, we investigated whether Mc prevalence or concentration correlated with the Braak stage, which describes the extent of neurofibrillary tangles in subjects with AD [28], or with HLA-DRB1*1501, a human leukocyte antigen allele that has been reported in association with AD [29]. Two-sided p-values from regression models were derived from the Wald test. Analyses were performed on SAS software version 9 (SAS Institute, Inc., Cary, NC).

Results

Mc Prevalence and Concentration According to Brain Regions

he median number of specimens tested per subject was three, with a range of one to 12. Table 2 summarizes the specimen-level prevalence of male Mc according to brain region for all subjects. Per brain region, between two and 35 specimens were tested for male DNA. Although there were few specimens available, we did not detect male DNA in the frontal lobe and the putamen, and found the highest prevalence in the medulla. Considering all subjects together, Mc concentrations ranged from 0–512.5 gEq/105, with a median value of 0.2 and a 90th percentile of 3.7 gEq/105 (Figure 1). One subject from the Harvard Brain Tissue Resource Center who was without neurologic disease (coded as B6388; age of death 69 years) had three specimens with the highest concentration values in our dataset (296.1, 481.8, and 512.5 gEq/105 in the temporal lobe, cingulate gyrus, and pons, respectively). Using fluorescence in situ hybridization, we indeed found rare male cells in the brain of B6388 (Figure S2). The remaining concentration values in the dataset were 29.4 gEq/105 or less. Regarding the relationship between pregnancy history and Mc prevalence, five of nine subjects who were known to have at least one son harbored male Mc in at least one of their brain regions (Table S3). All positive individuals had AD; among the negatives were three with AD and one without neurologic disease. One of two women without history of having sons was also positive for male Mc in her brain and without neurologic disease; the negative individual had AD.

Prevalence and Concentration of Male Mc in Human Brain: Women without Neurologic Disease or with AD

Of 183 specimens, 64 (35%) tested positive for Mc (Table 2). Eighteen of 26 subjects without neurologic disease (69%) had at least one positive value, with 30 positive results in 65 specimens (46%). Nineteen of 33 subjects with AD (58%) had at least one positive value, with 34 positive results in 118 specimens (29%). The estimated OR from a univariate model was 0.47 (95% confidence interval (CI) 0.21–1.08, p = 0.08). After adjustment for total gEq tested, age at death, and PMI, AD was significantly associated with lower Mc prevalence: OR 0.40 (95% CI 0.17–0.93, p = 0.03). Thus, the odds of having AD for a subject who tested positive for Mc was 60% lower than the odds for a subject who tested negative. When Mc concentrations were analyzed according to whether subjects had no neurologic disease or had AD, the estimated RR from an adjusted model was 0.05 (95% CI 0.01–0.39, p = 0.004). However, exclusion of brain specimens from subject B6388, who was without neurologic disease and whose level of male Mc was 10-fold greater than the next highest concentration from a different subject, changed the estimate dramatically: RR 0.41 (95% CI 0.16–1.05, p = 0.06). Thus, the rate of Mc detection in subjects with AD was 59% lower than the rate of Mc detection in subjects without neurological disease, but was not statistically significant. Age at death was also not statistically significantly associated with Mc prevalence, either in univariate or adjusted models (adjustments for disease status and total gEq tested; p = 0.79). However, any relationship between age at death and male Mc from prior pregnancies with a male fetus could not be evaluated because pregnancy history and the time interval from pregnancies to death were generally unknown from our subjects.

Prevalence and Concentration of Male Mc in Brain Regions Affected by AD

We conducted a secondary analysis considering specimens only from the five brain regions thought to be most affected by AD: amygdala, hippocampus, frontal lobe, parietal lobe, and temporal lobe [30], [31]. Considering only these regions, 12 of 24 subjects without neurologic disease (50%) had at least one positive value, with 12 positive results in 24 specimens (50%). Thirteen of 33 subjects with AD (39%) had at least one positive value, with 15 positive results in 44 specimens (34%). The adjusted OR describing the association of Mc prevalence and disease status was 0.48 (95% CI 0.14–1.62, p = 0.23). Therefore, the odds of having AD for a subject who tested positive for Mc in brain regions most affected by this disease was 52% lower than the odds for a subject who tested negative, but was not statistically significant. However, none of the subjects without neurologic disease contributed specimens of the amygdala or the frontal lobe. Comparing Mc concentrations across groups, excluding one specimen from subject B6388, the adjusted RR was 0.27 (95% CI 0.13–0.56, p<0.001). Thus, the proportion of positive specimens was not significantly different between groups, but Mc concentrations in this subset of brain specimens from subjects with AD tended to have lower values than those found in subjects without neurologic disease. In other analyses, there was no significant association between Mc prevalence or concentration and the Braak stage (Table 1; p = 0.99 and 0.93, respectively), and no significant association between Mc prevalence and HLA-DRB1*1501 (8 of 11 DR15-bearing subjects positive for Mc (73%) vs. 16 of 31 subjects without DR15 who also had Mc (52%); p = 0.13).

Discussion

n this study, we provide the first description of male Mc in female human brain and specific brain regions. Collectively with data showing the presence of male DNA in the cerebrospinal fluid [32], our results indicate that fetal DNA and likely cells can cross the human blood-brain barrier (BBB) and reside in the brain. Changes in BBB permeability occur during pregnancy [33] and may therefore provide a unique opportunity for the establishment of Mc in the brain. Also unique to our study are the findings that male Mc in the human female brain is relatively frequent (positive in 63% of subjects) and distributed in multiple brain regions, and is potentially persistent across the human lifespan (the oldest female in whom male DNA was detected in the brain was 94 years).

That Mc can penetrate the human BBB and reside in the brain was first indicated by murine studies that showed the presence of both foreign cells and DNA in mouse brains [14], [15]. However, prevalence of brain Mc in mice has not been well defined, as the frequency reported varies depending on the study [14], [15], [34]–[36], and in one investigation, Mc was not observed [37]. Similar to mouse data, our study of humans found that brain Mc was not present in all individuals tested. Even in those who showed positivity overall, not all of their brain regions had Mc. Mc concentration also showed considerable variability. Overall, our data complement and extend on other reports describing Mc in the general human population, in peripheral blood and at the level of the tissue/organ studied within and between subjects [9]–[13]. It is currently not possible to meaningfully compare Mc prevalence or concentration in human brain to other tissues because other tissues were not available from our subjects. Moreover, prior studies that evaluated Mc in other organs used diverse methods, some of which were not quantitative.

The most likely source of male Mc in female brain is acquisition of fetal Mc from pregnancy with a male fetus. In women without sons, male DNA can also be acquired from an abortion or a miscarriage [22], [23], [38]–[40]. The pregnancy history was unknown for all but a few subjects in the current studies, thus male Mc in female brain could not be evaluated according to specific prior pregnancy history. In addition to prior pregnancies, male Mc could be acquired by a female from a recognized or vanished male twin [41]–[43], an older male sibling, or through non-irradiated blood transfusion [44].

Because AD is more prevalent in women than men and an increased risk has been reported in parous vs. nulliparous women and correlated with younger age of onset [16]–[18], we also investigated male Mc in women with AD. AD is a neurodegenerative disease characterized by elevated levels of amyloid plaques, cerebrovascular amyloidosis, and neurofibrillary tangle [30]. Our results suggesting women with AD have a lower prevalence of male Mc in the brain and lower concentrations in regions most affected by AD were unexpected. However, the number of subjects tested was modest and, as discussed previously, pregnancy history was largely unknown. The explanation for decreased Mc in AD, should this observation be replicated in a larger study, is not obvious. In other diseases, both beneficial and detrimental effects of Mc of fetal origin have been described depending on several factors including the specific type and source of Mc [6]. A significant limitation of the current study was the inability to distinguish the type and source of male Mc, and further studies that distinguish genetically normal from abnormal Mc would be of potential interest.

At present, the biological significance of harboring Mc in the human brain requires further investigation. Mc appears to persist in the blood, bone, and bone marrow for decades [2], [45] and is present among different hematopoietic lineages [46]. Moreover, Mc appears to integrate and generate specific cell types in tissues [10], [11], [47]–[49]. In murine studies, fetal Mc in the maternal brain has been observed to resemble perivascular macrophages, neurons, astrocytes, and oligodendrocytes both morphologically and phenotypically and occupy the respective niches [15], [36]. Thus, it is possible that Mc in the brain is able to differentiate into various mature phenotypes or undergoes fusion with pre-existing cells and acquires a new phenotype, as suggested by murine and human studies in which bone marrow-derived cells circulated to the brain and generated neuronal cells by differentiation, or fused with pre-existing neurons [50]–[53]. Lastly, a few studies have reported an association between parity and decreased risk of brain cancer, raising the possibility that Mc could contribute to immunosurveillance against tumorigenic cells as has been suggested for some other types of malignancy [6], [54]–[56].

In conclusion, male Mc is frequent and widely distributed in the human female brain. Although the relationship between brain Mc and health versus disease requires further study, our findings suggest that Mc of fetal origin could impact maternal health and potentially be of evolutionary significance.

For more on this important study http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045592

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Unnatural selection: How humans are driving evolution by Michael Le Page

Unnatural selection: How humans are driving evolution by Michael Le Page
New Scientist – 27 April 2011

Humans are not only causing a mass extinction – we are also the biggest force in the evolution of the species that will survive

THE Zoque people of Mexico hold a ceremony every year during which they grind up a poisonous plant and pour the mixture into a river running through a cave (pictured below). Any of the river’s molly fish that float to the surface are seen as a gift from the gods. The gods seem to be on the side of the fish, though – the fish in the poisoned parts of the river are becoming resistant to the plant’s active ingredient, rotenone.

If fish can evolve in response to a small religious ceremony, just imagine the effects of all the other changes we are making to the planet. We are turning grassland and forests into fields and cities, while polluting the air and water. We are hunting species to the brink of extinction and beyond, as well as introducing new pests and diseases to just about every part of the world. And that’s not to mention drastically altering the climate of the entire planet.

It is no secret that many – perhaps even most – species living today are likely to be wiped out over the next century or two as a result of this multiple onslaught. What is now becoming clear is that few of the species that survive will live on unchanged.

Far from being a slow process, evolution can occur extremely rapidly when the environment changes (New Scientist, 2 April, p 32). So, as we alter the planet ever faster and more drastically, we are becoming the main force driving evolution. “The intensity of the ecological effect of man is pretty obvious,” says Stephen Palumbi of Stanford University in California. “There is an amazing amount of evolutionary change as a result.”

Some of the fastest rates of evolution ever measured in the wild are in plants and animals harvested by humans. The few populations for which we have data are, on average, evolving three times as fast as populations subject only to natural pressures, for example.

Over the following pages, we look at the many ways in which plants and animals are already evolving in response to human pressures. Some of these changes, such as animals evolving to survive in highly polluted areas, can be seen as a positive thing. Others are bad from our point of view, such as animals we hunt losing the traits we value most in them, or pests becoming immune to poisons. What is clear is that whether the issue is growing enough food, conserving wild animals or keeping our beds bug-free, human-driven evolution is a factor we can no longer afford to ignore.

Unnatural selection: Hunting down elephants’ tusks

Most predators target the young or the weak. We are different, targeting the biggest and best, or those with characteristics we desire, such as large antlers. Combine this with our ability to kill in great number and the result is extremely rapid evolution of our prey.

The first clear evidence was published in 1942, and since then many examples have emerged of how hunting can transform the hunted. The targeting of large animals has resulted in a fall in the average size of caribou in some areas, for instance, while trophy hunting has led to bighorn sheep in Canada and mouflon in France evolving smaller horns.

Perhaps the most dramatic example is the shrinking of tusks in elephants, or even their complete loss. In eastern Zambia, the proportion of tuskless female elephants shot up from 10 per cent in 1969 to nearly 40 per cent in 1989 as a result of poaching (African Journal of Ecology, vol 33, p 230). Less dramatic rises in tusklessness have been reported in many other parts of Africa, with some bull elephants losing tusks too.

Humans have had an even bigger impact in Asia. Only male Asian elephants have tusks, and the proportion of tuskless bulls has soared in many areas. In Sri Lanka, where there has been a lot of poaching, under 5 per cent of males now have tusks, says Raman Sukumar of the Indian Institute of Science in Bangalore, who studies Asian elephants. Simulations by Ralph Tiedemann of the University of Potsdam in Germany and colleagues suggest that female elephants’ preference for tuskers has partly counteracted the effect of hunting. However, even if all poaching stopped, it would take a very long time for the percentage of tuskers to rise again.

It’s not just animals that are being shaped by human preferences: the harvesting of wild plants can have a similar effect to hunting and fishing. In Tibet, for example, the height of the snow lotus at flowering has nearly halved over the past century as a result of the flowers being picked for use in traditional medicine (Proceedings of the National Academy of Sciences, vol 102, p 10218).

To even the balance, some biologists are now promoting the idea of counteracting the evolutionary pressures of hunting through “compensatory culling” – killing animals with undesirable traits. This has actually long been done in some places. In Germany and Poland, for instance, there is a tradition of shooting yearling deer with poor antlers to prevent a decrease in the antler size of mature stags.

Private reserves in countries such as Zimbabwe have a similar policy. They typically charge hunters a smaller “trophy fee” for shooting tuskless elephants – $3000 versus at least $12,500 for a tusker, for example. This is partly because tuskless animals are less valuable, but it is also a deliberate attempt to eliminate the trait.

Unnatural selection: The race against climate change

In Finland, the tawny owl used to be mainly grey. But since the 1960s, the proportion of a brown subtype has risen fast. “The frequency averaged around 12 per cent in the early 60s and has increased steadily to over 40 per cent nationwide,” says Patrik Karell of the University of Helsinki, whose findings were published earlier this year (Nature Communications, DOI: 10.1038/ncomms1213).

His team found that grey owls (pictured above right) have an advantage over brown ones only when there is lots of snow. As winters have become milder, the brown subtype has thrived. It is possible that this is because brown owls are better camouflaged when there is less snow, but it could also be because brown coloration is linked to another characteristic, such as higher energy needs.

There are countless examples of how global warming is affecting life, from plants flowering earlier in spring, to species spreading to areas that were once too cold for them to survive, to birds becoming smaller. The vast majority of these changes are not genetic but due to plasticity: organisms’ built-in ability to change their bodies and behaviour in response to whatever the environment throws at them. At least a few species, however, like the owls of Finland, are already changing genetically – evolving – in response to climate change.

In North America, for instance, pitcher plant mosquitoes lay their eggs in pitcher plants and the larvae enter a state of dormancy in the winter months before resuming development in spring. Dormancy is genetically programmed, triggered not by falling temperature but by the shortening days. As the growing season has lengthened, mutant mosquitoes that keep feeding and growing for longer have thrived. Northern populations now go dormant more than a week later than in 1972, when studies began.

The earlier breeding of red squirrels in North America is also thought to be partly a result of genetic changes. Some families emerge earlier in spring, and they are doing better as the climate shifts.

Plants are changing too. When seed collected from field mustard plants (Brassica rapa) in California in 1997 and 2004 were grown in identical conditions, the 2004 strains flowered 9 days earlier on average (Proceedings of the National Academy of Sciences, vol 104, p 1278). The change was a result of drought – the plants have evolved to reproduce before they run out of water.

Rapid evolution is thus already helping some species adapt to a warming world, but it is no “Get out of jail free” card. For instance, so far pied flycatchers in the UK seem unable to shift to laying eggs earlier in spring. And according to one model that specifically takes rapid evolution into account, global warming will kill off 20 per cent of all lizard species by 2080. The problem for lizards is that as the climate warms, they have to spend more time in the shade and less time feeding.

Organisms with long generation times and slow reproductive rates are the least able to evolve, says Stephen Palumbi at Stanford University. “And they are the ones that are already threatened. It’s a double whammy.”

Even species whose evolution has kept pace with the slight warming so far will not necessarily keep up as the global temperature soars by another 4 °C or more. Rapid evolution generally depends on the existing variation within a population, rather than on new mutations. “It is limited to the kind of changes that can happen quickly,” Palumbi says.

In fact, there is a catch-22 to very rapid evolution – the faster organisms evolve, the less able they are to evolve further. This is because fast change occurs when only a small proportion of each generation manages to reproduce, resulting in a dramatic loss of genetic diversity – the fuel for further evolution. In many cases, the size of populations will also plummet, rendering them vulnerable to extinction. “You could evolve really fast but just not make it,” says Michael Kinnison of the University of Maine in Orono.

Unnatural selection: Living with pollution

Between 1947 and 1976, two factories released half a billion kilograms of chemicals called polychlorinated biphenyls (PCBs) into the Hudson river, in the north-east US. The effects on wildlife weren’t studied at the time, but today some species seem to be thriving despite levels of PCBs, many of which are toxic, remaining high.

At least one species, the Atlantic tomcod – an ordinary-looking fish about 10 centimetres long – has evolved resistance. “We could blast them with PCBs and dioxins with no effect,” says Isaac Wirgin of New York University School of Medicine.

Many of the ill effects of PCBs and dioxins are caused by them binding to a protein called the hydrocarbon receptor (Science, vol 331, p 1322). The Hudson tomcod all have a mutation in the receptor that stops PCBs binding to it, Wirgin and colleagues reported earlier this year. The mutation is present in other tomcod populations too, Wirgin says, but at low levels.

The most famous example of evolution in action was a response to pollution: as the industrial revolution got under way, cream-coloured peppered moths in northern Britain turned black to stay hidden on trees stained by soot. As the tomcod shows, though, most evolutionary changes in response to pollution are invisible.

The spoil heaps of many old mines, for instance, are covered in plants that appear normal, but are in fact growing in soil containing high levels of metals such as copper, zinc, lead and arsenic that would be toxic to most specimens of these and other species. The evolution of tolerance has occurred extremely rapidly in some cases, sometimes within just a few years of the soil being contaminated.

With very widespread pollutants, it is much harder to show that organisms are evolving in response, because all populations change at once. The comparison has been done with a common weed called plantain (Plantago major), though. Ground-level ozone, produced when sunlight strikes car exhaust fumes, greatly impairs the growth of plants. When researchers grew plantain seeds collected in 1985 and 1991 from a site in northern England where ozone pollution reached very high levels in 1989 and 1990, they found that the plants from the 1985 batch grew nearly a third more slowly when exposed to ozone, whereas the growth of those from 1991 fell by only a tenth (New Phytologist, vol 131, p 337).

Since even the remotest parts of the planet are now polluted in one way or another, it is likely that many plants and animal populations have evolved some degree of tolerance, even though few cases have been documented. “Nobody looks for resistance,” says Wirgin. “My guess is that if you look you will find a lot of it.” His own discovery was entirely accidental: the team had set out to study liver cancers, and they only noticed the tomcod’s resistance when blasting the fish with PCBs failed to produce any tumours.

However, there are obviously limits to what evolution can achieve. This is especially true for small populations that reproduce slowly and have few offspring, such as the Yangtze river dolphin. Pollution is thought to have contributed to its extinction.

What’s more, pollution resistance in one species can have unexpected consequences for others. The tomcod’s tolerance allows it to accumulate extraordinarily high levels of PCBs in its body, for instance, which are a threat to animals higher up the food chain – such as humans with a taste for these reportedly delicious fish.

Unnatural selection: Spreading sickness

Perch in Lake Windermere in the UK used to live to a ripe old age. While the average age of fish caught and released by researchers was around 5 years, a few individuals were as old as 20. Then in 1976, an unidentified disease wiped out 99 per cent of adult fish and continued to preferentially kill older fish for years afterwards. Since then, no fish older than 7 have been caught.

According to Jan Ohlberger of the University of Oslo, Norway, the perch (Perca fluviatilis) evolved very quickly in response. They now become sexually mature at an earlier age, which increases their chances of breeding before they get killed by the disease (Proceedings of the Royal Society B, vol 278, p 35).

While the disease is thought to have spread naturally in the lake, Ohlberger points out that many devastating disease outbreaks in plants and animals are a result of human activity. To mention just a few: Dutch elm disease was caused by fungi introduced from Asia; lions were hard hit by canine distemper spread by village dogs, and corals are far more susceptible to diseases when water temperatures are abnormally high, which is happening often as a result of climate change.

Anything that kills a significant proportion of a population has the potential to bring about very fast evolution. In frogs there is now some evidence of this: last year several research groups reported that some populations appear to be becoming resistant to a fungus that has decimated many amphibian species. It is also clear that human populations have sometimes evolved rapidly in response to diseases such as kuru, which attacks the nervous system.

So it seems plausible that by spreading diseases or creating the conditions in which they thrive, humans are indirectly forcing many organisms to evolve. “I think this is a common phenomenon and has not yet been described because it is simply hard to prove,” says Ohlberger. He points out that the long-running capture-and-release programme at Lake Windermere, which began in 1943 and just happened to coincide with the disease outbreak in perch, is pretty unique. In most cases we know too little about what populations were like before disease outbreaks to be able to tell if and how they have evolved in response.

Unnatural selection: The arms race against pests

Had any strange itchy bites or rashes recently? You might have fallen victim to bedbugs. The little bloodsuckers are back in a big way, thanks in part to the fact that, like head lice and human fleas, they have evolved resistance to many common pesticides.

Whatever their drawbacks, there is no doubt that pesticides have made a huge difference to our lives. They have helped eliminate diseases like malaria from some areas and made possible the switch to intensive farming. As soon as we started using them, though, resistance began to evolve.

“Insects that succumb readily to kerosene in the Atlantic states defy it absolutely in Colorado [and] washes that easily destroy the San José scale [insect] in California are ridiculously ineffective in the Atlantic states,” wrote entomologist John Smith in 1897 – the first known report of insecticide resistance.

The use of synthetic pesticides like DDT took off in the 1940s. Resistant houseflies were discovered in 1946. By 1948, resistance had been reported in 12 insect species. In 1966, James Crow of the University of Wisconsin-Madison reported that the count had exceeded 165 species. “No more convincing examples of Darwinian evolution could be found than those provided by the development of resistance in one species after another,” he noted at the time.

It’s not just bugs. Rats and mice around the world have become resistant to the poison warfarin, and in Europe some have even become resistant to warfarin’s replacement, superwarfarin (Journal of Toxicological Studies, vol 33, p 283). In Australia, meanwhile, rabbits are becoming resistant to the poison used to control their numbers, called Compound 1080.

Because of its economic importance, pesticide resistance has been studied far more closely than other kinds of ongoing evolution. In many cases we know which mutations are involved, how they make organisms resistant and sometimes even how the mutations spread through populations.

Resistance often arises due to mutations that alter the shape of proteins and thus prevent insecticides binding to their targets. For instance, DDT and pyrethroid compounds kill insects by opening sodium ion channels in nerve cells, but in the malaria-carrying mosquito Anopheles gambiae, variants of the channels that cannot be opened this way have evolved on at least four separate occasions (PLoS One, vol 2, p e1243).

The other main mechanism of resistance involves enzymes that inactivate pesticides before they can kill. Some resistant strains of A. gambiae, for instance, produce large quantities of an enzyme called CYP6Z1 that can inactivate DDT.

Pesticide resistance is becoming such a serious problem that strategies for preventing it evolving in the first place are taken increasingly seriously. One approach is to alternate the type of pesticide applied, to try to avoid applying sustained selective pressure in one direction.

At present, though, the pests seem to be evolving faster than we can develop new pesticides. In one region of Burkina Faso, A. gambiae has become resistant to all four classes of insecticides used for malaria control.

Unnatural selection: Introducing invaders

In 1935, the South American cane toad was introduced to Australia to control pests feeding on sugar cane. The cane fields were not to the toad’s liking, but the rest of the countryside was. The toad has spread rapidly at the expense of many native species.

The highly poisonous animals are having a big effect on predators. Some, such as the Australian black snake, are developing resistance to cane toad toxins. Others, such as the red-bellied black snake and green tree snake, are changing in a more surprising way – their mouths are getting smaller. The reason is simple: snakes with big mouths can eat large toads that contain enough toxin to kill them.

The toads themselves are also changing. Some are now colonising regions that were too hot for the founder population, suggesting that they are evolving tolerance to more extreme conditions. What’s more, the toads leading the invasion are becoming better colonisers: they have bigger front legs and stronger back legs than toads living in the areas already colonised. Radio tagging has confirmed that these “super-invader” toads can travel faster, as you might expect. They are probably evolving because the first toads to reach new areas benefit from more food and less competition, and thus have more offspring. The changes are likely to be transient, though – once the toads stop spreading, the “super-invader” traits will gradually be lost.

Ships and planes have turned the natural trickle of species spreading to new islands or continents into a raging torrent, and the new arrivals sometimes have a dramatic effect. In areas of the US that have been invaded by fire ants, for instance, native fence lizards have evolved longer legs. They need them: given the opportunity, a dozen fire ants can kill a lizard in minutes.

Rather than simply study the results of invasions, Michael Kinnison of the University of Maine in Orono and colleagues have been actively experimenting. In one experiment, his team moved juvenile chinook salmon from one river in New Zealand to another. The salmon were introduced to the country around a century ago, and Kinnison wanted to assess the extent to which they had adapted to conditions in individual rivers. He found drastic differences in survival, even though the fish appear identical (Canadian Journal of Fisheries and Aquatic Sciences, vol 60, p 1). “When a population was locally adapted, it performed twice as well,” he says.

Kinnison suspects that lots of small changes can add up to make a huge difference to a population’s success. “Contemporary evolution may be relatively modest on a trait-by-trait basis, but its overall contribution to the performance of populations may be immense,” he says.

Such findings help explain why there is often a lag between the introduction of new species and their rapid spread. A newly arrived species is likely to find itself in an environment that is not quite ideal, and its population may be very small, meaning there is little genetic diversity. In these circumstances, a species will spread only slowly, if at all.

As the population begins to adapt to local conditions, though – perhaps via invisible changes such as mutations in immune genes – it is likely to start to grow and spread. Because more mutations occur in larger populations, it will then evolve faster, enabling it to spread quicker and further. If this turns out to be common, it is bad news. It suggests that many introduced species that seem to be behaving themselves could yet start spreading explosively and cause serious problems.

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Unnatural selection: How humans are driving evolution by Michael Le Page

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