Environmental risk factors for autism: Do they help cause de novo genetic mutations that contribute to the disorder?

Genetics Laboratory, McLean Hospital, 115 Mill St, Belmont, MA 02478, USA.
Medical Hypotheses (Impact Factor: 1.07). 09/2009; 74(1):102-6. DOI: 10.1016/j.mehy.2009.07.052
Source: PubMed


Recent research has discovered that a number of genetic risk factors for autism are de novo mutations. Advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations. We investigated the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations. A survey of the research literature identified 9 environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of these factors--mercury, cadmium, nickel, trichloroethylene, and vinyl chloride--are established mutagens. Another four--including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation--are associated with decreased sun exposure and increased risk for vitamin D deficiency. Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress--a key cause of DNA damage. Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA. We note how de novo mutations may also help explain why the concordance rate for autism is so markedly higher in monozygotic than dizygotic twins. De novo mutations may also explain in part why the prevalence of autism is so remarkably high, given the evidence for a strong role of genetic factors and the low fertility of individuals with autism--and resultant selection pressure against autism susceptibility genes. These several lines of evidence provide support for the hypothesis, and warrant new research approaches--which we suggest--to address limitations in existing studies. The hypothesis has implications for understanding possible etiologic roles of de novo mutations in autism, and it suggests possible approaches to primary prevention of the disorder, such as addressing widespread vitamin D deficiency and exposure to known mutagens.

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    • "). In addition to the strong genetic background, environmental influences, gene 9 environment interaction, epigenetic factors, and pre-perinatal complications also play an important role in susceptibility to ASD (Gardener et al. 2009, 2011; Dietert et al. 2011; Kinney et al. 2010; Wong et al. 2014). Multiple causal pathways may thus underlie the same clinical profiles , and, at the same time, the complex etiology may result in highly heterogeneous clinical profiles. "
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    Journal of Autism and Developmental Disorders 09/2015; DOI:10.1007/s10803-015-2572-9 · 3.06 Impact Factor
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    • "Based on previous European studies our hypothesis was that the offspring of non-European parents would have an increased risk of childhood autism. In particular, we hypothesized that offspring of mothers with dark skin would have the highest risk, based on a suggested association between lower levels of vitamin D and increased risk of autism in offspring [8,23-25]. "
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    • "U.S. EPA reviews have indicated that all of these pollutants have established or suspected effects on the nervous system and on the developing fetus from human or animal studies, except for nickel, which has no known effects on the nervous system, and quinoline, for which possible developmental effects have not been studied (U.S. EPA 2010). Arsenic, cad­ mium, chromium, mercury, methylene chlo­ ride, nickel, styrene, trichloroethylene, and vinyl chloride are also known or suspected mutagens (Agency for Toxic Substances and Disease Registry 2011), and de novo DNA mutations have been implicated in ASD etiology (Kinney et al. 2010; Sebat et al. 2007; Smith et al. 2009). Therefore, we focused on these pollutants a priori. "
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