Sex- and Lineage-Dependent Transgenerational Effects of Vinclozolin and Flutamide on Rat Development and Behavior

Vinclozolin (VIN) is an agricultural fungicide that acts as an endocrine-disrupting chemical (EDC), primarily through its anti-androgenic actions. Developmental exposure to VIN is linked with reproductive and neurodevelopmental alterations; furthermore, VIN was the first EDC identified as causing heritable epigenetic transmission across generations. The present study provides a more detailed and comprehensive look into the developmental and transgenerational behavioral effects of VIN exposure in rats, with the experiment designed to investigate the influence of sex differences and parental lineage (maternal, paternal). Specifically, dams were exposed to either the vehicle (DMSO; negative control), VIN (100 mg/kg), or flutamide (FLUT; 1 mg/kg), the latter an anti-androgenic compound used as a positive control for the anti-androgenic effects of VIN. Developmental measures, anxiety, and social tests were conducted on males and females from the F1 (direct prenatal exposure) and F3 (ancestral exposure through epigenetic inheritance) generations. Generally, effects were sexually dimorphic, lineage-specific, and differed between FLUT and VIN, pointing to different mechanisms of the chemicals. More behavioral effects of VIN emerged at the F3 generation's paternal lineage compared to the F1 generation. Overall, this study provides more detailed insight into the transgenerational effects of a high dose of VIN exposure and suggests future inquiry into the mechanisms of action of the EDC, specifically as it pertains to its differences from FLUT and its differing effects on lineage, sex, and generation.