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news “mom on a mission,” continued... was Michael Skinner, a professor in the School of Molecular Biosciences at Washington State University. Skinner laid out the shift in thinking that is setting off waves of disagreement among geneticists. For more than a century, scientists believed that only alterations in the actual DNA sequence of genes could be passed on to subsequent generations. But now scientists believe that molecules called the “epigenome” modify a person’s instruction-giving genome in a way that tells it what to do, and where and when to do it. And the epigenome is much more easily influenced by environmental factors than the genome. Skinner explained it to Escher this way: “Think of the genome as the computer, and the epigenome as the software.” The hypothesis is that if the germ cells are affected in the fetus, disruptions in signals can be transmitted to subsequent generations without affecting the DNA sequence. If at least three generations of offspring are affected, Skinner calls it “transgenerational.”

“I had given up trying to find out. I felt I would die never knowing what happened to my children.” “In essence, what your grandmother was exposed to when she was pregnant may cause disease in you and your grandchildren. Therefore, the potential hazard of environmental toxicants is dramatically increased, in particular for pregnant women in mid-gestation, six to 18 weeks,” Skinner said at a symposium on epigenetics and autism at UC Davis in March, partly supported by a grant from the Escher Fund for Autism. In lab animals, Skinner and other scientists have linked a dozen chemicals, including phthalate plasticizers, the insecticide DEET and a fungicide, to transgenerational epigenetic changes that have led to tumors, prostate disease, reproductive problems and other problems in at least three generations of offspring. Environmental epigenetics may have an important role in the origins of autism, Skinner said. “The majority of brain disease has been shown not to be genetically based, and autism is likely environmentally

an unexplained explosion U.S. children diagnosed with autism per thousand

11.3

9.0 8.0 6.6

2002

induced during some period of development,” he said.

more research needed

Possible links between autism and multigenerational effects of environmental exposures are in the early stages, and they remain a topic of debate among scientists. “So far there are only a handful of gene mutations that are found in the human autism population. For the majority of patients we know something else is going on, and that might be epigenetic changes,” said Emilie Rissman, professor of biochemistry and molecular genetics at the University of Virginia School of Medicine. Many diseases have increased faster than can be explained by normal genetic mechanisms. The epigenetic phenomenon could be a reason. “If environmental factors influence gene expression, the risk of someone having autism could increase,” said UC Davis’ Amaral. But Amaral said more basic science is needed to figure out the possible effects of environmental toxicants and pharmaceuticals. “Not enough is being done,” he said. “There are many pieces of information learned from more than a decade of study that need to be connected before any conclusion can be made about autism,” said Andrea Gore, professor of pharmacology and toxicology at the University of Texas at Austin. Gore was one of the first researchers to show in lab animals that prenatal exposure to hormone-like chemicals interfered with development of the neurological and reproductive systems, leading to abnormalities, including social and neurobehavioral disorders. “It’s too soon to make a direct connection between exposure to synthetic reproductive hormones and autism,” Gore said. “We think most behavioral disorders are a combination of genetic predisposition, natural differences in reproductive hormones and differences in environmental

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exposures.” University of California, Davis, autism researcher Janine M. LaSalle said human studies over many generations would be needed to determine whether genomes and epigenomes may be increasingly susceptible to autism due to a multitude of environmental factors. With lab animals, Gore and her colleagues will conduct transgenerational studies of hormone-mimicking chemicals to try to understand molecular changes in the brain and the connection between nerve cells and behavior. “The caveat is that animals don’t get autism spectrum disorders. All we can do is look at perturbations of normal behavior in ways that we believe may mimic some aspects of autism,” she said.

family histories

Last summer, Escher, along with Alycia Halladay of the national nonprofit Autism Speaks, presented the germ line disruption hypothesis to a committee of the National Institute of Mental Health, which is congressionally mandated to deal with the autism crisis. The National Institutes of Health has begun funding some epigenetics studies related to autism and prescription drugs. A large study in Europe, led by the Mount Sinai School of Medicine, is looking at medications taken by mothers and the health of their offspring. UC Davis researchers are examining links between exposure to air pollution and pesticides, epigenetic changes and increased risk of autism. Johns Hopkins University researchers are testing for epigenetic changes in autistic children associated with prenatal exposures to environmental chemicals. The National Institute of Mental Health is financing some studies on pharmaceuticals, including an investigation of whether antidepressants are causing epigenetic changes. And an ambitious, first-of-its-kind study of 8,000 people in Denmark, partially paid

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Inhealth October 2013  
Inhealth October 2013