Mice genetically engineered to be susceptible to autism-like behaviors that were exposed to a common flame retardant were less fertile and their offspring were smaller, less sociable and demonstrated marked deficits in learning and long-term memory when compared with the offspring of normal unexposed mice, a study by researchers at UC Davis has found. The researchers said the study is the first to link genetics and epigenetics with exposure to a flame retardant chemical.
The research was published online February 16 in the journal Human Molecular Genetics. It will be presented during a symposium on Feb. 18, at the annual meeting of the American Association for the Advancement of Science (AAAS) by Janine LaSalle, a professor in the Department of Medical Microbiology and Immunology in the UC Davis School of Medicine and the UC Davis Genome Center.
"This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants," said Janine LaSalle, the study's senior author and a researcher affiliated with the UC Davis MIND Institute. "Our experiments with wild-type and mutant mice indicate that exposure to flame retardants presents an independent risk of neurodevelopmental deficits associated with reduced sociability and learning."
Epigenetics describes the heritable changes in gene expression caused by mechanisms other than those in the DNA sequence. One such mechanism is DNA methylation, in which genes are silenced when their activation no longer is required. DNA methylation is essential for normal development. The researchers chose a mouse that was genetically and epigenetically susceptible to social behavioral deficits in order to understand the potential effect of this environmental pollutant on genetically susceptible humans.
LaSalle and her colleagues examined the effects of the chemical BDE-47 (Tetrabromodiphenl ether), a member of the class of flame retardants called polybrominated diphenylethers, or PBDEs. PBDEs have been used in a wide range of products, including electronics, bedding, carpeting and furniture. They have been shown to persist in the environment and accumulate in living organisms, and toxicological testing has found that they may cause liver toxicity, thyroid toxicity and neurodevelopmental toxicity, according to the U.S. Environmental Protection Agency. BDE-47 is the PBDE found at highest concentrations in human blood and breast milk, raising concerns about its potential neurotoxic effects during pregnancy and neonatal development.
The research was conducted in the offspring of mice genetically engineered for the autism phenotype found in Rett syndrome, a disorder that occurs primarily in females and causes regression in expressive language, motor skills and social reciprocity in late infancy. The condition affects about 1 in 10,000 children.
Autism spectrum disorders are a group of neurodevelopmental disabilities that can cause significant social, communication and behavioral deficits. The U.S. Centers for Disease Control and Prevention estimates that an average of 1 in 110 children born in the United States today will be diagnosed with an autism spectrum disorder.
Rett syndrome is causally linked to defects in the methyl-CpG-binding protein 2 gene MECP2 situated on the X chromosome. Mutations in MECP2 result in a nonfunctional MeCP2 protein, which is required for normal brain development. The researchers evaluated the effects of exposure to BDE-47 on mice genetically engineered to have mutations in MECP2 and their offspring, or pups. The genetically engineered Mecp2 mother mice, or dams, were bred with non-mutant wild-type males. The dams were monitored for 10 weeks -- for four weeks prior to conception, three weeks during gestation and three weeks of lactation. They were then compared with a control group of normal, unexposed dams and pups over several generations and hundreds of mice.
The study found that that the weights of the pups of the lactating BDE-47-exposed dams were diminished when compared with the controls, as were their survival rates. To assess the effects of the flame retardant exposure on the pups and their genotypes, the researchers placed them through more than 10 cognitive, social and physical tests.
Female offspring of dams exposed with BDE-47 spent half as much time interacting with another mouse in a 10-minute sociability test compared to controls. The reduced sociability in BDE-47 exposed females corresponded to reduced DNA methylation in females regardless of genotype. In addition, genetic and environmental interaction effects in this study were specifically observed in females.
In a short-term memory test of social novelty, although all mice showed the expected preference for interacting with a novel over a familiar mouse, BDE-47-exposed mutant female mice spent about half as much time interacting with the familiar mouse than their non-mutant littermates. In a long-term memory test of swimming to reach a hidden platform in a cloudy pool, female mice who were both mutant and BDE-47 exposed did not learn to reach the platform faster after fourdays of training. These behavioral changes in social and cognitive learning specifically in the interaction group corresponded to changes in a known epigenetic regulator of DNA methylation in brain, DNA methyltransferase 3a (Dnmt3a).
LaSalle said that the study results are important because better understanding of the epigenetic pathways implicated in social behavior and cognition may lead to improved treatments for autism spectrum disorders.
"While the obvious preventative step is to limit the use and accumulation of PBDEs in our environment, this would likely be a long-term solution," LaSalle said. "These pollutants are going to be hard to get rid of tomorrow. However, one important preventative that all women could do tomorrow is to start taking prenatal vitamins before becoming pregnant, as these may counteract the toxins in our environment through DNA methylation," she said.
A study by researchers at UC Davis conducted in 2011 found that women who reported not taking a daily prenatal vitamin immediately before and during the first month of pregnancy were nearly twice as likely to have a child with an autism spectrum disorder as women who did take the supplements -- and the associated risk rose to seven times as great when combined with a high-risk genetic make-up.
Other authors of the research are Rima Woods, Roxanne O. Vallero, Mari Golub, Joanne K. Suarez, Tram Anh Ta, Dag H. Yasui, Lai-Har Chi, Isaac N. Pessah and Robert F. Berman, all of UC Davis, and Paul J. Kostyniak of the Toxicology Research Center, University at Buffalo, the State University of New York.
The research was funded by grants from the National Institutes of Health and the American Recovery and Reinvestment Act, the National Institutes of Environmental Health Sciences/Environmental Protection Agency Center for Children's Environmental Health, and the U.S. Environmental Protection Agency Science to Achieve Results (STAR) program.
- Rima Woods, Roxanne O. Vallero, Mari Golub, Joanne K Suarez, Tram Anh Ta, Dag H. Yasui, Lai-Har Chi, Paul J. Kostyniak, Isaac N. Pessah, Robert F. Berman, and Janine M. LaSalle. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Human Molecular Genetics, 2012 DOI: 10.1093/hmg/dds046
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