SIR–In his recent review, James provocatively extends the Baron–Cohen theory of autism to suggest that excess maternal testosterone exposure, rather than fetal testosterone exposure, is a potential unifying biological mechanism behind many of the risk factors for autism.1 While James’ extension of the Baron–Cohen hypothesis may oversimplify some aspects of the complex genetic and environmental etiology of autism, I applaud this bold approach. In the face of a growing body of research suggesting that autism has fetal origins, environmental risk factors, and less genetic heritability than previously estimated, such bold theories will be necessary to drive the science forward and identify modifiable risk factors for autism.
While the list of potential risk factors discussed by James was quite comprehensive, I propose expanding it to include endocrine disrupting compounds (EDCs) as a set of exposures that may affect the development of autism by disrupting the in utero hormonal milieu directly or changing maternal hormone metabolism or action.
I believe there are several reasons to pursue this line of research. First, epidemiological studies have observed that maternal exposure to environmental chemicals during pregnancy, including air pollution, EDCs, and metals has been associated with attention-deficit–hyperactivity disorder (ADHD) and ADHD-like behaviors, autism and autistic-like behaviors, and pervasive developmental disorder–not otherwise specified.2 Second, the developing brain is susceptible to environmental insults and the fetus/child is less efficient at detoxifying environmental chemicals than adults. This implies that the developing fetus/child may be particularly vulnerable to exposures that would be less harmful to an adult. Third, pregnant women are exposed to multiple environmental chemicals, including EDCs.3 Very little is known about the cumulative or synergistic effects of these chemicals on human health. Finally, environmental chemicals may be a modifiable risk factor that would be amenable to public health interventions that could reduce the burden of autism.
Phthalates are one illustrative example of an EDC that plausibly fits into the Baron–Cohen hypothesis of autism. Phthalates are a class of chemicals used to retain scents in personal care/beauty products and impart flexibility in polyvinyl chloride plastics. Exposure to phthalates is ubiquitous among persons in industrialized countries and some phthalates have anti-androgenic activity.4 More importantly, the fetus seems to be uniquely sensitive to the anti-androgenic effects of phthalates. Given their anti-androgenic properties, one could hypothesize that phthalate exposures might reduce the risk of autism since higher phthalate exposures could counteract the effect of excess androgen exposure. However, one group of investigators observed increased ADHD-like and autistic-like behaviors in children born to women with higher levels of phthalate exposures.5,6 These results suggest that EDC action may not act via simplistic agonist-antagonist pathways. Furthermore, the relationship between phthalate exposure (or other environmental chemicals) and child behavior may be modified by child sex, which might be one possible explanation for the excess number of male children with autism.
With tens of thousands of chemicals being used in commerce, a single letter to the editor could never do justice to the research being conducted on any one chemical. However, the above example suggesting a potential role for phthalates in the development of autism illustrates why EDCs deserve inclusion in the growing list of potential autism risk factors enumerated by James. Even at the risk of proving James’ hypothesis wrong, the relationships between EDCs, maternal and fetal hormones, and autism deserves further attention.