This Just In: More Research Needed

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The question of whether prenatal environmental influences can affect patterns of disease throughout life — and whether the influence affects genes themselves or their epigenetics (the complex structures that package and protect the DNA in every cell) — continues to vex scientists, parents and regulators.

In the last few years, there has been an explosion of research confirming the broad principle that events such as maternal stress, nutritional deficits and chemical exposures in the womb can spell trouble for an organism, sometimes many years into adulthood. But how much is passed on to following generations, and for how many generations?

In 2008, Miller-McCune reported on research by molecular biologist Michael Skinner of Washington State University and his colleagues that showed prenatal chemical exposure caused reproductive and other damage through the fourth generation following maternal dosing with the fungicide vinclozolin and the insecticide methoxychlor. Vinclozolin inhibits proper functioning of male hormones, and methoxychlor does the same to female hormones.

In September, Miller-McCune.com reported that other scientists, including an Environmental Protection Agency researcher and two others who work for the manufacturers of the two chemicals, have been unable to replicate Skinner’s results and therefore challenge his claims of multigenerational transmission of environmentally induced damage.

Most researchers in the field concede that epigenetic changes can persist through at least two and probably three generations — the exposed mother, the exposed fetus and the offspring of the exposed fetus (because the eggs or sperm of the exposed fetus would also be exposed). But Skinner says he has seen reproductive problems, cancers and other diseases in the generation after that — with no direct exposure to the original toxic substance.

The stakes of the dispute over Skinner’s findings are very high. If correct, Skinner’s results will have profound implications for chemicals regulation, prenatal care, nutrition and the management of chronic diseases and disorders that appear late in life. They would also illuminate phenomena affecting inheritance and therefore shed light on evolutionary processes. If Skinner is right, a basic tenet of Mendelian genetics would be overthrown.

The critique of Skinner’s results is led by L. Earl Gray, a U.S. EPA toxicologist who has long studied vinclozolin’s and methoxychlor’s disruptive effects on reproductive hormones.

“What he’s doing doesn’t have any real obvious implications for the risk assessments on the chemical and has uncertain relevance to human or animal health,” Gray says. “And since [his results] can’t be replicated, I’m not sure they even demonstrate basic science principles.”

Naturally, this sort of scathing criticism sits poorly with Skinner, who responds, “If you’re a toxicologist at the EPA, [the epigenetic paradigm shift] scares you because it changes how you do toxicology.” Although he acknowledges that his findings could throw the reasoning behind chemical regulation and the testing protocols used to determine chemical toxicity into disarray, Skinner says this isn’t what his studies were designed to do.

His team, he says, is simply using vinclozolin to induce a change in an organism and studying the molecular mechanisms involved in that change. Studies by scientists at BASF, the manufacturer of vinclozolin, and Sumitomo, the manufacturer of methoxychlor, have not confirmed the fourth-generation effects. Both company studies differed somewhat from Skinner’s in the mode of exposure, the subspecies of rat used and the prenatal phase in which the dose was administered. Skinner believes all these factors may explain why his results were not replicated — and considers the BASF study to be “very appropriate for a risk assessment study” that does not conflict with his results.

He also believes the challenges to his work represent “industry pushback” similar to that experienced by researchers who have found harmful effects of other profitable chemicals such as bisphenol A, phthalates and atrazine.

At a July meeting of epigenetics experts sponsored by the National Academy of Sciences, Gray called attention to an apparent case of scientific fraud perpetrated by Hung-Shu Chang, one of Skinner’s postdoctoral students, in which much of the supporting data for a now-retracted 2006 Endocrinology paper was fabricated. In a prepared statement dated September 2009, Skinner notes that Chang worked only on this paper, and that there are nine other peer-reviewed and published papers from his lab on the subject. The scientific community has viewed the episode as an isolated incident that does not taint the rest of Skinner’s work, according to a Sept. 23 article by Rebecca Renner in Environmental Science & Technology.

There is one thing Skinner and Gray agree on: More research is needed. In his prepared statement, Skinner said the current conflict is “not unexpected. My hope is as this research develops we maintain a scientific objectivity and professionalism. …” Skinner has two more papers in preparation that he says will “calm things down” because they show the same results in a mouse study as he found in his rat studies.

“We just need to be careful about our science,” Gray says. “It sorts itself out over time, and I think that’s what this will do.”

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