The Convergence of Early-Life Stress and Autism Spectrum Disorder on the Epigenetics of Genes Key to the HPA Axis

Autism spectrum disorder (ASD) arises from complex genetic and environmental influences. Despite its prevalence and being the focus of study for several decades, its causes and their underlying mechanisms are still not fully understood. However, one consistent causal mechanism of interest is epigenetic modification. While some risk factors, such as maternal stress, nutrition, and environmental toxins, have a more established epigenetic connection, early-life stress (ELS) in the postnatal years is less studied but may be just as impactful in terms of phenotypic outcomes. A major intermediary between ELS and ASD is likely the hypothalamic-pituitary-adrenal axis (HPA axis), which has been shown to be epigenetically modified by ELS and whose genes and dysfunction overlap with ASD genes and symptoms. In this narrative review, we synthesize human and animal evidence to examine the relationships between ELS and ASD through epigenetic regulation of a non-exhaustive list of autism candidate genes involved in the HPA axis, including <i>NR3C1</i>, <i>FKBP5</i>, <i>MECP2</i>, <i>GAD1</i>, <i>RELN</i>, <i>SHANK3</i>, <i>OXTR</i>, and <i>BDNF</i>. We discuss how ELS-induced epigenetics may modulate HPA axis negative feedback, and how epigenetic alterations in this pathway and associated genes could affect ASD phenotypes.