Behavioral Obesogenics: Environmental EDC effects on behavioral processes promoting obesity.

Abstract The prevalence of both obesity and cognitive disorders has increased over the past decades, a period during which the number of environmental endocrine-disrupting chemicals (EDCs) has also grown. EDCs are associated with increased metabolic problems and obesity. EDCs also have links to cognitive disorders such as attention-deficit/hyperactivity disorder (ADHD). The fact that obesity and behavioral problems often co-exist in individuals suggests the heretofore unexplored possibility that EDCs play a role in their co-morbidity. This project aims to explore how EDCs disrupt cognitive and food reward processes in the brain, with a focus on dopamine (DA) pathways, which are critical for regulating both cognitive function and motivated eating behavior in the brain reward system. Using a curated EDC mixture, NeuroMix (NMX), which comprises environmentally relevant EDCs below the no observed adverse effect level with known obesogenic and neurodevelopmental impacts, this research will investigate how exposure to EDCs lead to neuromolecular reprogramming of the brain’s reward system and impacts related behaviors. Specifically, in an established rat model, I will examine how NMX impacts food reward, motivation, and cognitive flexibility, and whether these effects are sex-specific. Additionally, the study will investigate the intergenerational effects of EDC exposure on motivated eating and cognitive behavior, as previous findings suggest that some EDCs cause epigenetic reprogramming of neuromolecular processes, leading to new or worsened behavioral and physiological disruptions to emerge in later generations. To achieve these objectives, I will leverage advanced molecular techniques, including single nucleus RNA sequencing (snRNA-seq) and bisulfite sequencing, to analyze DA-specific gene expression and epigenetic modifications throughout the brain’s reward system. By linking molecular disruptions with behavioral outcomes, this study seeks to define the mechanisms by which EDCs drive the convergence of obesity and cognitive disorders, providing a comprehensive model of behavioral obesogenics. The findings from this project will offer novel insights into the role of environmental chemicals in the comorbid development of obesity and neurodevelopmental disorders like ADHD, with implications for public health strategies aimed at mitigating the multiplicative risks associated with EDC exposure. These goals meet the NIEHS’ strategic goal to “investigate the effects of the environment on genome structure and function”, including epigenetic regulation of biological processes, while including sex as a biological variable.