The WSU study is the first to show that a toxin-induced change in methylation can promote a disease state and be passed to subsequent generations.
Funny thing about scientific breakthroughs. You can’t tell where the next one will come from. There you are, doing an ordinary experiment. Next thing you know, you’ve got a result that changes our basic understanding of how nature works.
Ask Mike Skinner, director of Washington State University’s Center for Reproductive Biology, and his colleagues Matthew Anway, Andrea Cupp, and Mehmet Uzumcu. They started out looking at how environmental toxins affect testis development. They ended up showing that genes-DNA sequences-are not the only source of inherited information. Perhaps equally important are small chemicals that attach to the DNA.
Skinner says their findings raise fundamental questions about inheritance, ranging from what diseases we are prone to get, to why some species adapt to new conditions while others become extinct.
The Skinner team did a straightforward experiment: inject pregnant rats with a synthetic toxin known as an endocrine disruptor, and see if the offspring develop normal sex organs. After the rat pups were born, the males were found to have normal-looking testes but reduced numbers of sperm. When they grew up and were mated with normal females, their male offspring also had lower fertility. So did their grandsons and their great-grandsons.
The drop in fertility probably wasn’t due to a genetic mutation, or change in the DNA sequence. Instead, Skinner’s group found it was related to changes in chemicals called methyl groups that were attached to the DNA. Such changes are called “epigenetic,” meaning “around the genes.”
Depending on where on the DNA they attach, methyl groups can turn genes on or off. Some methylation is normal, helping to control which genes get turned on in which cells. Over the past several years, abnormal methylation has been implicated in several kinds of leukemia and in the premature aging of cloned animals such as Dolly the sheep.
The WSU study is the first to show that a toxin-induced change in methylation can promote a disease state and be passed to subsequent generations. It suggests that epigenetic effects can be even more influential than genes. Mutated genes don’t get passed to all of an animal’s offspring, so over several generations, they tend to occur less often in the population. The epigenetic changes Skinner observed were inherited by almost all of the male offspring, through four generations.
“I think this concept that epigenetics is going to play a really important role in biology is just now being appreciated,” says Skinner. “It probably is a big piece of the puzzle which we didn’t really have before”-a puzzle Skinner and his team weren’t even trying to solve. In fact, if they had stuck to their experimental plan, they’d have missed it completely.
”We stumbled onto all of this,” says Skinner.
Well, it wasn’t entirely an accident. Luck and error did play roles in the discovery. But so did the researchers’ willingness to take a closer look at their mistake rather than ignoring it or pitching it out.
First came the luck. They exposed mother rats to the toxin during a time when the male fetuses were going through a critical stage of sex development. What nobody knew then was that it was also the one time in their fetal life when the methylation pattern of their DNA can be re-programmed in a way that will be passed to their descendents.
Next came the mistake, and what Skinner and his crew did about it. After the exposed rats grew up, post-doctoral researcher Andrea Cupp accidentally bred some of them. She hadn’t planned to, because there was no reason to think the next generation would show the effects of the toxin.
“She came into the office one day and she was upset,” recalls Skinner. “She said, ‘I’m really sorry, I got this breeding.’ And I said that’s fine, go ahead and look” at the pups born in the next generation.
That was a crucial decision. Several months later, says Skinner, she came back and said the male offspring had the same sperm deficit as their fathers.
“I said, ‘I don’t believe it.'”
Was he excited about it? “I was confused, because I couldn’t explain it. It was just weird.”
So weird, that even after finding that the results persisted through two more generations, Skinner didn’t publish the work. Then, a couple of years later, another lab described the methylation programming that occurs in the cells destined to become sperm. Click. Skinner’s group did the experiment again, this time looking at the methylation pattern of the affected rats’ DNA. Sure enough, the toxin had changed it. Skinner had his explanation-and the world of biology got a new way of looking at how traits are inherited.
Skinner says he’s still amazed at their results.
“There’s no way I would have predicted up front that this was going on, because it’s really outside the paradigm of how we think about genetics.”
Now other biologists are adjusting their views to take Skinner’s work into account.
And there’s no mistake about that.