OR13-07 Epigenetic and transcriptional changes associated with early-life exposure to a mixture of endocrine-disrupting chemicals: obesogenic effects in the brain reward system

Abstract Disclosure: E.N. Hilz: None. N.R. Gonzalez: None. C. McAdams: None. L. Giorgberidze: None. L. Thompson: None. A.C. Gore: None. Humans are widely exposed to a variety of endocrine-disrupting chemicals (EDCs), some of which, termed ‘obesogens’, contribute to metabolic dysfunction and obesity. While obesogens are well-studied for their effects on adipogenesis, their neurodisruptive properties, particularly within the brain reward system controlling food intake, remain underexplored. This system may mediate obesogenic effects by altering the valuation and motivation for calorie-dense foods, creating a behavioral basis for EDC-mediated obesity. In the current study, male and female rats were exposed perinatally to a mixture of obesogenic and neurodevelopmentally disruptive EDCs termed “NeuroMix” (NMX). Developmental measures were tracked throughout life, and in adulthood, rats underwent a battery of behavioral tests to assess preference for highly rewarding foods including high-fat diet and sucrose solution. NMX exposure transiently increased sucrose preference in males and high-fat food preference, intake, and subsequent weight gain in females, without affecting bodyweight over development. Testosterone was reduced in NMX-exposed males, while estradiol in females remained unchanged. Targeted 3’ RNA sequencing (TAGseq) was then performed in the brain reward system. NMX induced sex-specific changes in gene expression across regions of the brain that support reward processing and feeding behavior; using Gene Ontology (GO), the functional significance of these changes related primarily to processes involved in epigenetic regulation (e.g., chromatin remodeling, histone modification, and DNA methylation) and transcriptional activity. These processes were downregulated in the lateral hypothalamus and ventral tegmental area of NMX-exposed males, and upregulated in the nucleus accumbens of both sexes. Weighted gene co-expression analysis (WGCNA) was used to correlate neuromolecular changes with behavioral outcomes, suggesting that molecular disruptions in the brain reward and metabolic systems drive obesogenic EDC effects. This research provides novel evidence for the role of epigenetic processes in brain-reward pathways as a potential mechanism through which early-life EDC exposures drive sex-specific vulnerabilities to long-term metabolic and behavioral health risks. Grant funding: F32 ES034257 (ENH), R35 ES035024 (ACG) Presentation: Sunday, July 13, 2025