Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder?

Abstract

Recent research on the etiology of autism spectrum disorder (ASD) has shifted in part from a singular focus on genetic causes to the involvement of environmental factors and their gene interactions. This shift in focus is a result of the rapidly increasing prevalence of ASD coupled with the incomplete penetrance of this disorder in monozygotic twins. One such area of environmentally focused research is the association of exposures to endocrine disrupting compounds (EDCs) with elevated risk for ASD. EDCs are exogenous chemicals that can alter endogenous hormone activity and homeostasis, thus potentially disrupting the action of sex and other natural hormones at all stages of human development. Inasmuch as sex hormones play a fundamental role in brain development and sexual differentiation, exposure to EDCs in utero during critical stages of development can have lasting neurological and other physiological influences on the developing fetus and, ultimately, the child as well as adult. This review will focus on the possible contributions of EDCs to autism risk and pathogenesis by first discussing the influence of endogenous sex hormones on the autistic phenotype, followed by a review of documented human exposures to EDCs and associations with behaviors relevant to ASD. Mechanistic links between EDC exposures and aberrant neurodevelopment and behaviors are then considered, with emphasis on EDC-induced transcriptional profiles derived from animal and cellular studies. Finally, this review will discuss possible mechanisms through which EDC exposure can lead to persistent changes in gene expression and phenotype, which may in turn contribute to transgenerational inheritance of ASD.

Keywords: Autism; Endocrine disrupting compounds; Epigenetics; Gene expression; Neurodevelopment; Sex hormones.

Figure 1

Schematic diagram illustrating the various ways in which endocrine disrupting compounds can impact genes and gene regulatory mechanisms (i.e., epigenetic machinery) to cause large-scale changes in gene expression (i.e., the transcriptome) as well as protein and metabolite profiles (i.e., the proteome and metabolome) that may lead to altered neural functions and pathways leading to the clinical manifestations and behaviors associated with ASD. The diagram also suggests feedback interactions between the metabolome and the gene regulatory mechanisms affecting the transcriptome and proteome.