Prenatal exposure to synthetic chemicals in relation to HPA axis activity: A systematic review of the epidemiological literature

Abstract

Background: Pregnant people are widely exposed to numerous synthetic chemicals with known endocrine-disrupting properties (e.g., phthalates, phenols, per- and poly-fluoroalkyl substances (PFAS)). To date, most epidemiological research on how endocrine-disrupting chemicals (EDCs) disrupt hormone pathways has focused on estrogens, androgens, and thyroid hormones. Far less research has examined the impact of EDCs on the hypothalamic-pituitary-adrenal (HPA) axis, despite its central role in the physiologic stress response and metabolic function.

Objective: To systematically review the epidemiological literature on prenatal synthetic EDC exposures in relation to HPA axis hormones (e.g., corticotropin-releasing hormone, adrenocorticotropic hormone, cortisol, cortisone) in pregnant people and their offspring.

Methods: A literature search of PubMed, Scopus, and Embase was conducted. Primary research studies were selected for inclusion by two independent reviewers and risk of bias was assessed using the Office of Health Assessment and Translation guidelines established by the National Toxicology Program with customization for the specific research topic. Data were extracted from each study and included in a qualitative synthesis.

Results: 22 published studies met the inclusion criteria. Phthalates were the most prevalent EDC studied, followed by PFAS, phenols, and parabens, with fewer studies considering other synthetic chemicals. Offspring glucocorticoids were the most commonly considered outcome, followed by maternal glucocorticoids and placental corticotropin-releasing hormone. There was considerable heterogeneity in methods across studies, particularly in HPA axis outcome measures and matrices, making cross-study comparisons challenging. Numerous studies suggested disruption of HPA axis hormones and sex differences in association, but results varied considerably across studies and EDC classes.

Conclusions: The limited literature to date suggests the HPA axis may be vulnerable to disruption by synthetic EDCs. Carefully designed studies that prioritize biospecimen collection specific to HPA axis hormones are needed along with greater standardization of biospecimen collection and analysis protocols to facilitate cross-study comparisons and interpretation.

Keywords: Corticotropin-releasing hormone; Cortisol; Endocrine-disrupting chemical; Hypothalamic-pituitary-adrenal axis; Pregnancy; Systematic review.