Startling study on toxins' harm

WSU findings show that disorders can be passed on without genetic mutations

By TOM PAULSON
SEATTLE POST-INTELLIGENCER REPORTER

It's just a study involving a few rats with fertility problems in Pullman, but the findings could lead to fundamental changes in how we look at environmental toxins, cancer, heritable diseases, genetics and the basics of evolutionary biology.

If a pregnant woman is exposed to a pesticide at the wrong time, the study suggests, her children, grandchildren and the rest of her descendants could inherit the damage and diseases caused by the toxin -- even if it doesn't involve a genetic mutation.

"As so often happens in science, we just stumbled onto this," said Dr. Michael Skinner, director of the center for reproductive biology at Washington State University.

Skinner's team at WSU and colleagues from several other universities report in today's Science magazine on what they believe is the first demonstration and explanation of how a toxin-induced disorder in a pregnant female can be passed on to children and succeeding generations without changes in her genetic code, or DNA.

"We were quite surprised ... we've been sitting on this for a few years," said Skinner, who is expected to present his findings today at a scientific meeting in San Diego.

The report in Science, entitled "Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility," also sounds like an attempt to avoid attention. That's unlikely to work. The findings prompt serious and, in some cases, disturbing questions about a number of basic assumptions in biology.

The standard view of heritable disease is that for any disorder or disease to be inherited, a gene must go bad (mutate) and that gene must get passed on to the offspring.

What Skinner and his colleagues did is show that exposing a pregnant rat to high doses of a class of pesticides known as "endocrine disruptors" causes an inherited reproductive disorder in male rats that is passed on without any genetic mutation.

It's not genetic change; it's an "epigenetic" change. Epigenetics is a relatively new field of science that refers to modifying DNA without mutations in the genes.

"It's not a change in the DNA sequence," Skinner explained. "It's a chemical modification of the DNA."

Scientists have known for years about these changes to DNA that can modify genes' behavior without directly altering them.

One form of epigenetic change is natural. Every cell in the body contains the entire genetic code. But brain cells must use only the genes needed in the brain, for example, and kidney cells should activate only the genes needed for renal function.

Cells commonly switch on and off gene behavior by attaching small molecules known as methyl groups to specific sections of DNA. The attachment and detachment of methyl groups is also an important process in fetal development of the male testes and female ovaries -- which is where Skinner got started on this.

But the common wisdom has been that any artificially induced epigenetic modifications will remain as an isolated change in an individual. Because no genes get altered, the changes cannot be passed on.

"We showed that they can be," Skinner said.

The experiment got its start four years ago by accident. His lab was studying testes development in fetal rats, using a fungicide used in vineyards (vinclozin) and a common pesticide (methoxychlor) to disrupt the process. A researcher inadvertently allowed two of the exposed rats to breed, so the scientists figured they'd just see what happened.

The male in the breeding pair was born with a low sperm count and other disorders because of the mother's exposure to toxins. No surprise. But the male offspring of the pair also had these problems, as did the next two generations of male rats.

"I couldn't explain it," Skinner. This wasn't supposed to happen.

The scientists didn't tell anyone about their finding and continued, for the next two years, to confirm that it was real and to find an explanation. Eventually, they documented that a toxin-induced attachment of methyl groups to DNA in the mother rat was being passed on to offspring.

"In human terms, this would mean if your great grandmother was exposed to an environmental toxin at a critical point in her pregnancy, you may have inherited the disease," Skinner said.

While the study was focused on a heritable disorder of reproduction in rats, he said there's every reason to believe this can happen for other diseases -- such as cancer.

"There has been this speculation that the increased rates of some cancers may be due to environmental factors, but they've never been able to describe a mechanism to explain this," Skinner said.

The findings also suggest a reconsideration of one of the basic tenets of evolutionary biology -- that evolution proceeds by random genetic change.

The standard view is that the environment has no direct influence, except in how it may favor or discriminate against the creatures with the latest genetic mutations.

The WSU study, Skinner said, suggests the possibility that environmental factors such as toxins may also directly cause heritable changes in creatures. "Epigenetics may be just as important as genetics in evolution," he said.

Posted by Becca

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