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

## TL;DR

This review explores how early-life stress and autism may be linked through epigenetic changes in genes related to the body's stress response.

## Contribution

The paper identifies specific genes where early-life stress causes epigenetic changes overlapping with autism-related genes.

## Key findings

- Early-life stress can cause epigenetic changes in genes like NR3C1 and FKBP5, which are also linked to autism.
- Epigenetic modifications in HPA axis genes may disrupt stress regulation and contribute to autism symptoms.
- Understanding these epigenetic overlaps could help identify at-risk children and guide new treatments.

## Abstract

Autism spectrum disorder is a complex condition whose causes are not fully understood, though both genetic and environmental factors play a role. This review explores how stressful experiences during early childhood, such as abuse, neglect, parental loss, or poverty, may contribute to autism through changes in how genes are turned on or off, a process called epigenetics. These changes do not alter the genetic code itself but can affect brain development and behavior. This review focuses specifically on genes involved in the body’s stress response system, which releases hormones like cortisol to help us cope with challenges. When this system becomes dysregulated, it can lead to chronic stress and developmental problems. By examining research from both human and animal studies, this review identifies several genes where early stress appears to cause epigenetic changes that overlap with genes that are already implicated in autism. This suggests that people already at risk for increased early-life stress and emotional dysregulation are subject to epigenetic changes that exacerbate the body’s physical response to stress. Understanding these connections is valuable because it may reveal biological markers that help identify at-risk children earlier and point toward new treatment approaches.

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 NR3C1, FKBP5, MECP2, GAD1, RELN, SHANK3, OXTR, and BDNF. 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.