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Originally published Sunday, September 30, 2012 at 11:18 PM

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Study: Pregnant rats pass down effects of dioxin exposure — to great-grandchildren

Washington State University researchers have found that the great-grandchildren of pregnant rats exposed to low doses of dioxin develop diseases and reproductive abnormalities — even though they did not have direct exposure. The finding challenges the traditional explanation of how traits are passed from one generation to another.

Seattle Times health reporter

Epigenome 101

University of Utah: "The Epigenome at a Glance:" learn.genetics.utah.edu/content/epigenetics/intro/

"Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations:" dx.plos.org/10.1371/journal.pone.0046249.

Michael Skinner on YouTube: youtube.com/watch?v=NecRvk6dG7k

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Washington State University researchers have found that the great-grandchildren of pregnant rats exposed to low doses of the chemical contaminant dioxin develop diseases and reproductive abnormalities — even though they were not directly exposed.

The findings are another step in the rapidly emerging field of epigenetics, which is expanding and challenging the traditional genetic explanation of how traits are passed from one generation to another.

Although the pregnant rats' DNA sequences themselves were not changed, the biochemical exposure affected how genes were turned on or off, and that modification — the epigenetic action — was inherited along with the genetic sequences, said Michael Skinner, a professor of environmental epigenetics and reproductive biology at WSU.

The field of epigenetics refines — and complicates — the standard way of thinking about inheritance and genetics, which relies heavily on the concept of mutations to explain disease processes.

"This is what you would call a new paradigm in the way we think about where disease comes from, and how environment may influence disease," Skinner said. "Previously, we've thought that genetics was running the whole show."

Skinner's research, published in the journal PLoS ONE, builds on earlier work by his team and others, drilling down to look at the ways gene expression can be modified by environmental exposures such as nutrition, chemicals and stress. He and his colleagues have also studied jet fuel and other hydrocarbon mixtures, plastics, pesticides and fungicides.

Dioxin, of interest to the Department of Defense, one of the funders of Skinner's research, is a byproduct of many types of industrial processes, including the chlorine bleaching process at pulp and paper mills or chlorination at waste and drinking-water treatment plants and municipal or industrial waste incinerators.

According to the federal Agency for Toxic Substances & Disease Registry, dioxin and its chemical cousins also are produced through the manufacture of some organic chemicals, released into the air in emissions.

Dioxin, which was contained in Agent Orange, a defoliant used during the Vietnam War, has a long half-life and is found in low levels in air, soil, water, sediment and in many types of foods.

Skinner exposed the rats during a crucial early period of pregnancy to a dose of dioxin so small it wasn't expected to have toxic effects for the mother rat.

In the research, the pregnant rats are termed the F0 generation, the offspring exposed in utero are the F1 generation; their offspring are the F2 generation, and the next generation, the "great-grandchildren," are the F3 generation.

For that F3, great-grandchild generation of rats, Skinner found the dioxin exposure to the pregnant rats caused epigenetic changes in sperm that caused kidney disease in the F3 great-grandsons and abnormalities in puberty for both male and females in that generation.

The F3 females also had greater incidence of ovarian diseases and abnormalities, including polycystic ovarian disease. Neither F3 males nor females had increased incidence of tumors or obesity.

Because dioxin bioaccumulates and can last up to a decade in humans, the researchers said, a woman becoming pregnant even 20 years after exposure "runs the risk of transmitting dioxin effects to her fetus and later generations."

At Vanderbilt University, Kevin Osteen, a professor of obstetrics and gynecology who studies reproductive issues, said the notion of inheritability of changes wrought by environmental exposures is not new.

"This is sort of a new field being rediscovered, actually," he said. "There has been evidence, all the way back to the Dutch famine during World War II that in utero environment can be impacted by various stressors such as poor nutrition, and those stressors can have consequences to offspring ... "

In part, new urgency has been created by realization that people are exposed to many chemicals used in our industrial society that aren't tested on the front end, and aren't considered harmful until proven by research, he said.

Osteen, who studies infertility, said researchers now must focus on identifying which chemicals or combinations cause changes, pinpointing the exact mechanisms and locations of those changes, and then figuring out how to mitigate the harm for current patients.

Emerging realization about the role of epigenetics — literally above or around genetics — is throwing a new wrinkle into personalized medicine, another emerging field in which drugs or treatments are tailored to a patient's particular genome, and is an important focus of research at Vanderbilt, Osteen said.

"I asked the person in charge of personalized medicine, 'What are you going to do about epigenetics?' " Osteen recalled. "He said, 'We don't know yet.' "

At this point, the work done with mice and rats are "proof of concept" studies, Osteen said, and there will be much work necessary to make the leap to humans. "Nobody is saying that this happens in humans at that level of exposure," he said. "We don't know that."

But scientists have long been concerned with dioxin, a contaminant also studied by Osteen, who calls it a "particularly bad-acting compound."

Major human exposures occurred from 1961 to 1971 during the Vietnam War, in 1976 from an industrial accident in Italy, and in 1979 from another industrial accident and food-contamination incident in Taiwan. While researchers have documented health problems in the grandchildren generation, no studies have investigated the transgenerational effects of dioxin on the great-grandchildren of people exposed, Skinner noted, in part because not enough time has passed.

Skinner, for one, believes the field will help shed light on why some diseases have become so prevalent. "There's a great deal of disease epidemiology that says many of the diseases we've looked at can't be explained by classic genetics," he said. "Epigenetics helps fill that void."

Carol M. Ostrom: 206-464-2249 or costrom@seattletimes.com. On Twitter @costrom.

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