7321 A Mixture Of PCBs Induces Sex-Specific Disruptions To Cognitive And Neuromolecular Endpoints In Grandchildren Of Exposed Rats

Abstract Disclosure: E.N. Hilz: None. E. Morales-Ledesma: None. J. Deka: None. S. Bhamidipati: None. L. Thompson: None. D.C. Wiley: None. A.C. Gore: None. Polychlorinated biphenyls (PCBs) are a weakly estrogenic class of ubiquitous environmental endocrine-disrupting chemicals that affect a range of sex-specific neuroendocrine and reproductive outcomes. Furthermore, these effects can extend intergenerationally via epigenetic changes carried down the germline. In humans, PCBs are associated with sexually dimorphic and hormone sensitive neurobehavioral disorders including attention deficit hyperactivity disorder (ADHD) and depression; however, little preclinical work has modeled these cognitive changes in rats and none has determined if they extend intergenerationally via endocrine-mediated changes to the brain. In the current work, pregnant and nursing Sprague-Dawley rats were exposed to the PCB mixture Aroclor 1221 (A1221). Male and female grandchildren of these rats, exposed preconceptionally to A1221 via the germline, underwent a battery of behavioral tasks to assess attentional phenotype, cognitive flexibility, and reward preference followed by targeted 3’ RNA sequencing (TAGseq) to assess neuromolecular changes in brain regions that support these behaviors. Results revealed that A1221 exposure had sex-specific effects. In germline-exposed females, A1221 decreased conditioned orienting suggestive of a hyporesponsive attentional phenotype and impaired attentional set-shifting suggestive of reduced cognitive flexibility; in both males and females, germline exposure to A1221 increased preference for sucrose solution indicating potential hypersensitivity to rewarding substances. From these animals, dopamine (DA) cell numbers in the midbrain significantly and negatively correlated with behavioral changes. TAGseq in regions of the brain DA system (including the prelimbic region of the prefrontal cortex, core of the nucleus accumbens, and substantia nigra and ventral tegmental area of the midbrain), revealed that molecular disruptions of A1221 were most apparent along the male germline: in the core of the nucleus accumbens, A1221 downregulated genes involved in myelination and upregulated genes involved in synaptic signaling compared to controls. Using gene ontology (GO), it was determined that GO sets involved in these processes were differentially affected throughout regions of the DA system of exposed animals in both males and females. These data show that the PCB mixture A1221 impairs different aspects of cognitive behavior between the sexes in a manner that emerges over generations, and may be mediated by both structural and molecular changes in the brain DA system. Supported by 1F32-ES034257-01A1 and R01 ES028464. Presentation: 6/3/2024