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Rats Harmed by Great-Grandmothers' Exposure to Dioxin

Pregnant rats exposed to an industrial pollutant passed on a variety of diseases to three generations of descendants
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Pregnant rats exposed to an industrial pollutant passed on a variety of diseases to their unexposed great-grandkids, according to a study published Wednesday.

Washington State University scientists found that third-generation offspring of pregnant rats exposed to dioxin had high rates of kidney and ovarian diseases as well as early onset of puberty. They also found changes in the great-grandsons' sperm.

The great-grandkids – the first generation not directly exposed to dioxin – inherited their health conditions through cellular changes controlling how their genes were turned on and off, the researchers reported.

The findings add to a body of research suggesting that the health consequences of exposure to environmental chemicals might be passed to future generations.

“Not only does the individual exposed get the disease, but it’s transmitted to great-grandchildren with no exposure,” said Michael Skinner of Washington State University, who is the senior author of the study, which was published in the journal PLoS One. Skinner is a pioneer in epigenetics – the study of inherited changes in gene expression.

Dioxins, which have been linked to cancer, reproductive disorders and other health problems, are industrial byproducts created by waste incinerators and other processes.

The dioxin doses used in the study were low for lab rats, but are higher than most people’s exposures from the environment. The study raises questions that won’t be easy to answer about people exposed to dioxins from food and industrial sources.

“The study is a nice demonstration of the large scope of damage from a low-dose dioxin,” said Jennifer Wolstenholme, a biochemist who specializes in epigenetics at the University of Virginia. She was not involved with the research.

One of the most interesting findings, she said, was that multiple organ systems were affected in the rats.

Dioxins have declined in food and the environment over the past few decades because emissions from many industries, including pulp and paper mills, smelters and waste incinerators, have been regulated.

The new study focused on a specific dioxin, known as TCDD, a component of the herbicide Agent Orange that was used during the Vietnam War.

Among Vietnamese people exposed to Agent Orange, a high rate of cancers has been found, and their children have had many birth defects and other health problems, too. Vietnam veterans from the United States also were highly exposed, and the U.S. government has determined that certain cancers and other disorders are “presumptive diseases” in veterans who handled Agent Orange.

The new study examined how dioxin exposure affects a person’s epigenome – a road map of chemical changes to DNA and associated proteins. As a fetus develops, its epigenome is reprogrammed, and it can be permanently altered by exposures. The epigenome is then passed down through generations – along with susceptibility to adult-onset disease.

“The cause of the higher rates of disease in these [third generation] animals was not due to direct exposure, but rather through transmission of changes in the code that regulates gene expression,” said Abby Benninghoff, who specializes in epigenetics at Utah State University. She was not involved with the study.

Scientists have long known that environmental exposures can cause genetic mutations. But now epigenetics experts are finding that some exposures seem capable of changing how genes are expressed, or turned on and off, without actually damaging the genes. These changes then can be inherited by future generations.

The findings are not directly applicable to humans, researchers said. The way the animals were dosed is not the same way people are exposed to dioxins, and the moms were dosed for a few days – roughly similar to the first trimester – which does not mimic typical human exposure that is low and gradual but builds over time, Wolstenholme said. Humans and rats also clear dioxin from their bodies differently, she said.

“We cannot know from these studies if people are similarly at increased risk for these same diseases,” Wolstenholme said.

Still, the researchers wrote that their findings “have implications for the human populations that are exposed to dioxin and are experiencing declines in fertility and increases in adult onset disease, with a potential to transmit them to later generations.”

Dioxin builds up in the body and has up to a decade-long half-life in humans, so scientists say a woman who becomes pregnant even 20 years after exposure is at risk of transmitting the consequences of her exposure to later generations.

Most human studies of dioxins have focused on the direct exposure in adults and fetuses. A study of a 1976 industrial accident in Anshu Seveso, Italy, documented health defects in the grandchildren of women that conceived as long as 25 years after exposure to dioxin. No human studies have investigated how a person’s dioxin exposure will affect their great grandkids.

“Although transgenerational studies in humans are challenging, it will be very interesting for future epidemiologic research to investigate some of these populations, such as Vietnam veterans or the Seveso cohort, to evaluate whether similar increases incidence of kidney and ovarian disease are found,” said Carrie Breton, an environmental epidemiologist at the University of Southern California.

Earlier this year, Skinner’s research group found that pregnant rats exposed to high doses of dioxin and other chemicals passed down the negative health effects to their great-granddaughters, who developed cysts and other ovarian problems during puberty, even though they were not directly exposed.

In 2011, researchers found a decline in fertility in the third generation following dioxin exposure to pregnant mice.

In the new study, the rats were allowed to live longer so researchers could examine a wide variety of diseases and study how a legacy of dioxin exposure is recorded in sperm over generations.

“These findings are an example of environmentally induced epigenetic transgenerational inheritance of adult-onset disease,” the researchers wrote.

Previous studies with dioxin used high doses. The new study used a small percentage of the lethal oral dose for TCDD to avoid any acutely toxic effects from the exposure. The dose used is not comparable to people’s exposure from the environment. Due to bioaccumulation of dioxins, however, the dose in some people can get very high, Skinner said.

The researchers wrote that the purpose of the dosage was “not to assess environmental risk of exposure to dioxin,” but rather to “to investigate if exposure to TCDD could promote epigenetic transgenerational inheritance of disease.” The data could now be used to assess the environmental risk of exposure to dioxin.

In the study, pregnant rats were exposed to dioxin when their fetuses were 8 and 14 days old. Damage to the testes, prostate, kidney and ovaries were measured in the children and great-grandchildren after they were a year old.

The first generation offspring had more prostate disease and two types of ovarian disease, compared to control groups. Kidney disease, changes in puberty and ovarian disease were more prevalent in the great-grandkids than the control rats.

“Some of this damage persists into future generations, even without further dioxin exposure,” Wolstenholme said.

Abnormalities in puberty were nearly eight times higher in the third generation of female rats exposed to dioxin, compared to a control group. Forty-seven percent of third generation females had early puberty. Six percent in the control group had puberty abnormalities, with the majority being early onset.

“That is a profound observation,” Benninghoff said.

Third generation female rats also showed an increase in ovarian disease, which is consistent with previous studies.

For male rats, kidney disease was significantly higher in the third generation rats whose ancestors were exposed to dioxin, the first time such a finding has been reported. Twenty-seven percent of the third generation male rats had signs of kidney damage, compared to about 9 percent of the control group.

Third generation female rats also had a higher incidence of multiple diseases or abnormalities per rat.

Complicating matters, the rats directly exposed to dioxin had different disease profiles than later generations, so “one cannot necessarily predict possible disease outcomes in future generations by observing individuals that were directly exposed,” Benninghoff said.

Sperm from the great-grandkids – the first generation without direct dioxin exposure – had telltale modifications in gene expression in 50 regions of DNA as a result of their ancestors’ dioxin exposure, Skinner said. These regions can be used as “biomarkers for ancestral exposures and disease,” he said. That means researchers could use these regions as a road map to trace dioxin exposure through generations.

The study focused on TCDD, but Skinner speculated that all dioxins would behave the same way, but that remains to be studied.

Other environmental chemicals also have transgenerational effects in lab animals, including BPA, phthalates, the pesticides permethrins, vinclozolin and methoxychlor and the insect repellent DEET.

The American Chemistry Council, which represents chemical companies, did not return a request for comment.

This article originally ran at Environmental Health News, a news source published by Environmental Health Sciences, a nonprofit media company.

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