Seeking Chemical Culprits for Those Deformities

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The term “endocrine disruptor” had not been coined when Rachel Carson was alive, but she was onto them.

Carson’s groundbreaking 1962 book on the dangers of synthetic pesticides, Silent Spring, was prescient in many ways. She wrote about what she termed “insecticide storage:” “There are indications that these chemicals lodge in tissues concerned with the manufacture of germ cells as well as in the cells themselves. Accumulations of insecticides have been discovered in the sex organs of a variety of birds and mammals. … Probably as an effect of such storage in the sex organs, atrophy of the testes has been observed in experimental mammals. Young rats exposed to methoxychlor had extraordinarily small testes.”

Al Gore, who wrote in the forward to zoologist Theo Colborn’s book on endocrine-disrupting compounds, Our Stolen Future, noted that Carson warned in one of her last speeches: “We are subjecting whole populations to exposure to chemicals, which animal experiments have proved to be extremely poisonous and, in many cases, cumulative in their effects. These exposures now begin at or before birth and — unless we change our methods — will continue through the lifetime of those now living. No one knows what the results will be because we have no previous experience to guide us.”

Endocrine Disruptors
Earlier this month Miller-McCune discussed the observations and practical science of a woman, Judy Hoy, sounding an alarm in western Montana. A wildlife rehabilitator, Hoy has documented malformations of genitalia of local white-tailed deer over a 13-year period in the Bitterroot Valley. She suspects the changes are caused by endocrine-disrupting compounds (or EDCs), possibly from pesticides applied to potato fields just over the border in Idaho.

Montana officials so far have discounted her hypothesis, but scientific research around the world has made similar findings — undescended and abnormally small penises and testicles, low sperm counts, genitals placed forward on the body, confused gender — in test animals and in wild populations of birds, reptiles and wildlife.

What causes these changes remains contentious. Many scientists and public health advocates point to pesticides and other environmental pollutants while others, including industry, some government agencies and more scientists, say more study is needed.

While debating mutations in deer populations is one thing, finding those changes in boy babies takes the discussion to a new level.

Results of a study released in May 2009 by the British nongovernmental organization CHEMTrust show:

• As many as 1 in 17 boys in the United Kingdom have undescended testicles, a congenital birth defect;

• Malformation of the penis (where the opening is not at the end) has increased in recent decades in several European countries, the United States, Australia and China;

• U.K. and French data show a decline in sperm count in young men as compared to their fathers; in some European countries, 1 in 5 young men has sperm counts so low that it is likely to affect their ability to father a child; and

• Testicular cancer is the most common cancer of young men, doubling in incidence in many Western countries every 25 years over the past 60 years.

The author of the report, Richard Sharpe, of the U.K.’s Medical Research Council wrote that many scientists are tying a lack of testosterone at critical times of fetal development to “testicular dysgenesis syndrome,” encompassing defects of boys’ genitals, low sperm counts and testicular cancer. He sees a link between hormone-disrupting chemicals and TDS, saying animal studies “have established beyond a doubt that certain hormone-disrupting chemicals, in particular testosterone-disrupting chemicals, can cause TDS-like disorders.”

His meta-study might be one that Rick Becker, senior toxicologist with the American Chemical Council, would caution against. Becker asks that people not leap to conclusions after reading individual reports, but look to the World Health Organization for its synthesis of studies. However, the most recent WHO report on EDCs, “Global Assessment of the State of the Science of Endocrine Disruptors,” was published in 2002.

After a lengthy review of scientific findings on the effects of the chemicals on human reproduction, the WHO report makes no firm conclusions. The authors note in a conclusions and recommendations section that “exposure data are very limited, if available at all, and in many studies exposure has only been inferred and not actually measured.” Another problem cited is that sample sizes are often small, resulting in a finding that “the currently available human data are inadequate to support a conclusion that human reproductive health has been adversely affected by exposure to EDCs.”

Still, the section concludes, “Despite these drawbacks, the biological plausibility of possible damage to human reproduction from exposure to EDCs seems strong when viewed against 1) the background of known influences of endogenous and exogenous hormones on many of the processes involved, and 2) the evidence of adverse reproductive outcomes in wildlife and laboratory animals exposed to EDCs.”

Many studies on EDCs have been published since 2002. Sharpe’s paper references 159 papers and information sources, 101 written after the WHO report was prepared.

In June, the Endocrine Society, a nearly century-old international association of endocrinologists, issued a statement in which its position was clear. In a 50-page paper, the first scientific statement issued by the society, authors wrote: “We present evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostrate cancer, neuroendocrinology, thyroid, metabolism and obesity and cardiovascular endocrinology. Results from animal models, human clinical observations and epidemiology studies converge to implicate EDCs as a significant concern to public health.” (Breast Cancer UK recently produced a video linking EDCs to breast cancer that can be seen on YouTube.)

There has been controversy regarding various studies of sperm count decreases in men; data has varied with study and locale of men tested. One U.S. scientist known for her work in reproductive epidemiology, Shanna Swan, authored a report that appeared in Environmental Health Perspectives in 1997 that analyzed sperm-count studies and concluded that “further analysis of these studies supports a significant decline in sperm density in the United States and Europe but not in non-Western countries.” She found the studies showed that there are “large inter-area differences in sperm density.”

Swan has been studying the effects of environmental pollutants for nearly 30 years, including the effects of contaminants on various aspects of human reproduction (including fetal loss, fertility, low birth weight, birth defects, semen quality and sex hormones). She began in 1981 by studying the possible contamination of a public water supply by a toxic release from a semiconductor plant for the California Department of Health Services in 1981. Today, she is associate chair for research in the Department of Obstetrics and Gynecology at the University of Rochester School of Medicine and Dentistry, and director of the Center for Reproductive Epidemiology.

In 2005, she and other colleagues published a paper in Environmental Health Perspectives that was the first research to link human male birth defects to a known EDC, phthalates. It showed that boys born to mothers exposed to phthalates during pregnancy were likely to have smaller genitals and incomplete testicular descent. Previous studies had shown similar outcomes in rodents.

The federally financed study used levels of phthalates that are found in one-quarter of the female population in the country. Researchers also found that in the 25 percent of mothers with the highest levels of phthalate exposure, the odds were 10 times higher that their sons would have a shorter-than-expected distance between the anus and the base of the penis (the anogenital distance), which is an indicator of impacts on the reproductive system.

Those involved in the discussion of EDCs agree more studies are needed – to conclude the chemical compounds are as dangerous as some believe or to put the controversy to rest by discounting the role they play in the endocrine system.

Research of potential EDC effects is not particularly easy for many different reasons. Wildlife, obviously, are difficult to study and research, and studies of EDCs are particularly difficult to conduct on human populations (e.g., pregnant women). Sharpe noted in his report that it is not easy to find mothers who haven’t been exposed to chemicals, making it difficult to find “controls” for experiments.

A third problem is what some scientists have coined the “cocktail effect,” which postulates that individual chemicals are often not nearly as dangerous as a combination of chemicals. Studies are being conducted on the effects of various chemicals when found together, pointing to a further complication in what is already a complex, and at times confounding, science. Some researchers fear we not only carry many EDCs in our bodies, but we are exposed to new ones almost daily through our food, personal products, water and even air.

Epigenetics
One bright light at the end of the tunnel is a discovery in the field of genetics. In the past 10 years, scientists have demonstrated that epigenetic switches and markers that lie along the length of the double helix of a cell can be “dimmed” or turned off — and on. Unlike the chromosomes that make up 50 percent of our DNA, these protein molecules carry the epigenetic marks and information that regulate how a gene expresses itself.

Randy Jirtle, a professor of radiation oncology at Duke University, was one of the first researchers to delve into this realm. In a study with postdoctoral student Robert Waterland published in 2003, Jirtle found that when pregnant mice carrying the agouti gene (that made them more prone to cancer and diabetes, as well as ravenous and yellow) were fed a diet rich in methyl donors (small chemical clusters that can attach to a gene and turn it off), their offspring were slender, brown and not susceptible to cancer or diabetes. Chemical clusters in the methyl donors are found in many foods, including onions, garlic and beets, and in food supplements often given to pregnant women.

DNA methylation is important because it involves adding a methyl group to particular bases in the DNA sequence that can interfere with chemical signals, effectively silencing the gene.

Since that study, scientists have been able to show that the epigenome is sensitive to many environmental factors, including exposure to toxins and even behavioral factors such as nurturing — and that changes in genes can be passed from one generation to the next, without a change in the gene sequence.

Jirtle exhibited the patience and communication skills inherent in a good teacher in a recent interview with Miller-McCune. He described the difference between the genome and epigenome in this way: “I always think of the genome as comparable to the hardware of your computer and the epigenome as the software that tells that computer when, where and how to work. That’s why you can have one set of genetic information in your cell, but you’ll have some cells that give rise to skin cells, liver cells, eye cells. That’s because they’re programmed differently. It’s the same thing as the same computer running Word, Excel and Photoshop.”

In the case of the agouti mice, methylation was reversed, altering the epigenome without changing the DNA. Thus, Jirtle and Waterland were able to demonstrate that genetic alteration can occur through programming of the epigenome. In a more recent study Jirtle and others showed that bisphenol-A in mice caused DNA methylation, which altered the epigenome. As interesting, and obviously, promising, is the finding that these epigenetic switches can be reversed, in the case of these mice, by dietary supplements.

Jirtle said recent breakthroughs in the mapping of the epigenome (which is different for each species) will play a role in determining what EDCs might be affecting species and when. “The problem with altering these programs very early is that every cell in your body now has that inappropriate information,” he said, “so they’re altering the programming, which can increase susceptibility to cancer, neurological disorders, the kinds of things potentially that are being seen in these deer (referring to Hoy’s findings). All of that stuff could be happening because you’re altering the programming by these endocrine-disrupting agents.”

He said recent findings in epigenetics will likely bring the studies of toxicology and genetics closer together, adding that to date “the focus at the National Toxicology Program has been on whether a compound causes mutations to the genome – changing the computer rather than altering the software.” He said it’s important that scientists research epigenetic change, which he believes is linked to susceptibility to many diseases that researchers have assumed are the result of genome mutation.

“This is a big issue,” he said. “There are possibly a number of compounds out there that are endocrine disruptors that are not being looked at.”

In 2007, Jirtle published a paper with Michael Skinner, a molecular biologist at Washington State University, that suggests that environmental exposures early in development have a role in susceptibility to disease later in life and that they can be passed down. Skinner is known in the field for his research of trans-generational epigenetic change.

Jirtle said Skinner’s research suggests that, even if there is no pollutant now affecting the deer in the Bitterroot Valley, a toxic exposure at the right time generations ago could be seen in their offspring today — without any further exposure.

He said Skinner “has seen a trans-generational inheritance that’s gone on for four or five generations. If you mess the system up enough, you can propagate this for a long period of time without being exposed to it again. There’s no residual of the compound whatsoever, but you’ve now put an epigenetic legacy in the sperm and/or the egg that gets passed forward like a mutation. But it’s almost acting as a dominant rather than just a recessor (where you need to have two come together). Now, you only need one. ”

As with all science, there is a need for more studies — many more. And they may or may not address what, if anything, is happening in the Bitterroot Valley in western Montana. But scientists like Jirtle are excited by what they see as a new frontier in both genetics and toxicology.

“The thing that is going to be ultimately important is when the National Toxicology Program gets on board with looking at the effects that compounds can have on the epigenome rather than looking at effects on the genome,” he said.

Today he is studying “imprinted” genes, which play a major role in brain development and may determine susceptibility to asthma, cancer, diabetes, obesity and many behavioral and developmental disorders. One of his studies is on epigenetic changes in the brains of schizophrenics. Asked if he thinks mental disease can be reversed through epigenetic “switches,” Jirtle said, “We already know that [the switches] can be reversed. We know meditation changes the structure of the brain. There has to be some process doing that.”

Hoy has corresponded with him, presenting her findings on malformations in white-tailed deer. Jirtle said he would like to see studies done in the valley — on ungulate species as well as humans. “Data [are] what’s needed to move this field forward,” he said.

But he’s clearly energized by what is happening in epigenetics, referring to the field as “the Wild, Wild West.”

“This stuff will be sorted out,” he said. “There’s a lot of momentum now. Money is starting to flow into the field because people are interested in epigenetics from a lot of different angles. I see that these types of issues will be resolved at some point — not that distant a future either. Things happen fast now. We have the tools now, and we can do things a lot faster than ever before.”

No doubt Hoy will be watching.

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