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.

Download full-text


Available from: Kerim Munir
    • "). 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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Children with an autism spectrum disorder (ASD) and their unaffected siblings from 54 simplex (SPX, one individual in the family affected) and 59 multiplex (MPX, two or more individuals affected) families, and 124 controls were assessed on intelligence, social cognition and executive functions. SPX and MPX ASD probands displayed similar cognitive profiles, but within-family contrasts were highest in SPX families, suggesting SPX-MPX stratification may help parse etiological heterogeneity of ASD. Unaffected siblings (regardless SPX or MPX) were mostly unimpaired, suggesting that cognitive problems may be part of the defining features of ASD, rather than being an endophenotypic trait. Except for affective prosody, which appeared to be the most sensitive cognitive marker for detecting familial risk for ASD.
    No preview · Article · Sep 2015 · Journal of Autism and Developmental Disorders
    • "To maintain intracellular balance and protect against oxidative stress, cells produce glutathione. Mercury, cadmium and nickel are toxic because they reduce intracellular glutathione and bind to proteins used for DNA packing (Valko et al., 2005), leaving the DNA vulnerable to mutagenic effects of reactive oxygen species (Kinney et al., 2010). The defects mentioned above are related to two key elements for ASD determinism: a) Synaptic development and functioning and intracellular Ca 2+ signaling (Levitt and Campbell, 2009); b) Epigenetic regulation of gene functioning. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders that affect an individual’s ability to communicate and socialize, often associated with repetitive movements or behaviors. Frequently patients associate intellectual disability or digestive problems. Autism is more common in males and affects 1 in 88 children in USA. The mechanism that leads to ASD is very complex, involving genetic, epigenetic, immune and environmental factors that could act in different proportions, at different developmental stages (prenatal, perinatal or postnatal) and on different pathways. The general prototype consists in an initial systemic dysfunction, such as immune dysregulation, inflammation, impaired detoxification or oxidative stress in an individual with genetic predisposition. In this context, ASD may arise due to the harmful action of environmental factors that lead to neuroinflammation and abnormal brain development. Environmental factors involved in autism determinism could be very diverse and include classical extrinsic factors (toxicants, environmental pollutants, medications, food additives, electromagnetic fields and even social influences), maternal disorders or lifestyle factors, as well as intrinsic factors (hormones, inflammatory mediators, microbiota and other biological molecules that make up the microenvironment around the developing fetal or neonatal brain). The aim of the present review is to discuss actual theories concerning genetic, epigenetic, immunologic and environmental factors interplay in ASD determinism, to present a practical and global approach of this complex problem, as well as to point some of the new directions for ASD prevention and therapy.
    No preview · Article · Apr 2015 · Environmental engineering and management journal
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studying second-generation immigrants can help in identifying genetic or environmental risk factors for childhood autism. Most previous studies have focused on maternal region of birth and showed inconsistent results. No previous study has been conducted in Finland. The study was a nested case--control study based on a national birth cohort. Children born in 1987--2005 and diagnosed with childhood autism by the year 2007 were identified from the Finnish Hospital Discharge Register. Controls were selected from the Finnish Medical Birth Register. Information on maternal and paternal country of birth and mother tongue was collected from the Finnish Central Population Register. There were 1132 cases and 4515 matched controls. The statistical test used was conditional logistic regression analysis. Compared with children with two Finnish parents, the risk of childhood autism was increased for those whose parents are both immigrants (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.2--2.7) and for those with only an immigrant mother (aOR 1.8, 95% CI 1.2--2.7), but not for those with only an immigrant father. The risk was increased for those with a mother born in the former Soviet Union or Yugoslavia and for those with a mother or a father born in Asia. Specific parental countries of birth associated with an increased risk were the former Soviet Union, the former Yugoslavia and Vietnam. In Finland, children who are born to immigrant mothers with or without an immigrant partner, have an increased risk of childhood autism. The risk varies with immigrant parents' region of birth. The findings may help in identifying possible risk factors, which can be examined in future studies.
    Full-text · Article · Oct 2013 · BMC Pediatrics
Show more