ORF51-05 - The Brain Reward System as a Critical Substrate through Which Environmental Endocrine Disruptors Promote Obesogenic Eating.

Humans are widely exposed to a variety of endocrine-disrupting chemicals (EDCs), some of which, termed ‘obesogens’, contribute to metabolic dysfunction and obesity risk. Obesogens are best understood through their effects on fat storage and metabolic hormone signaling; far less attention has been given to how EDCs, particularly environmentally relevant mixtures, affect food choice and the related appetitive-reward components of the central control of energy balance. In the presented studies, male and female rats were exposed perinatally or via the germline to a low-dose mixture of common obesogenic and neurodevelopmentally disruptive EDCs termed ‘NeuroMix’ (n = 14-15/group). Behavioral indices of palatable food preference and motivation were examined across generations to identify behavioral, endocrinological, and neuromolecular contributors to obesogenic eating and reward valuation. Female rats perinatally exposed to EDCs demonstrated robust preference for high-fat foods, accompanied by appreciable weight gain and selective transcriptomic remodeling of the nucleus accumbens (NAc) – a region of the brain critical for reward responsivity and motivation. Enrichment of ribonucleoprotein complexes within the NAc, particularly spliceosomal complexes, consistently predicted EDC-mediated fatty food preference, with splicing factors Luc7l3 and Sf3a3/Sf3b2 showing coordinated differential expression within the behavioral-transcriptomic framework. We provide further exploratory analyses of alternative splicing in the NAc. Fatty food preference persisted across generations in the absence of continued EDC exposure and reflected altered reward valuation rather than impaired satiety signaling. Finally, appetite-regulating hormones and the single-cell transcriptomic landscape of the NAc were profiled using combined snRNA- and ATAC-seq to explore potential endocrinological and epigenetic mechanisms underlying persistent alterations in reward valuation that promote obesogenic eating. This research provides novel evidence for the role of brain-reward pathways as a substrate through which EDC exposures drive multigenerational vulnerability to metabolic and behavioral health risks.

Grant funding: K99 ES037720 (ENH), R35 ES035024 (ACG)