Flame retardant linked to autism risk
UC DAVIS (US) — Exposure to flame retardant is linked to smaller offspring with social and learning issues, according to a study with mice.
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, the researchers report.
The University of California, Davis researchers say the study, published in the journal Human Molecular Genetics, is the first to link genetics and epigenetics with exposure to a flame retardant chemical.
“This study highlights the interaction between epigenetics and the effects of early exposure to flame retardants,” says 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, which raises 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.
Lower weight, survival rates
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 that were both mutant and BDE-47 exposed did not learn to reach the platform faster after four days 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 says 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 says. “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 says.
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.
Additional authors contributed to the study from UC Davis, and the Toxicology Research Center, University at Buffalo, the State University of New York.
The research was funded by the National Institutes of Health, 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.
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