UC Davis

Exposure to environmental pollutants can leave a lasting imprint on organisms and potentially impact future generations. Polybrominated diphenyl ethers (PBDEs), persistent flame retardants, disrupt early development and pose ongoing risks despite reduction in use. However, their potential for multigenerational toxicity and the influence of exposure route on long-term neurotoxic effects remain poorly understood. This dissertation investigates whether exposures to 2,2’,4,4’5-pentaBDE (BDE-99), a predominant PBDE congener, induce neurobehavioral and molecular effects that persist into adulthood and across generations using Atlantic killifish (Fundulus heteroclitus) as a vertebrate model. To assess how exposure route influences outcomes, I conducted two complementary multigenerational experiments. In the progenitor exposure experiment, adult fish were exposed to BDE-99 through diet for 64 days during the breeding season, leading to maternal transfer into F1 eggs. In the direct embryonic exposure experiment, embryos from unexposed parents were exposed to BDE-99 via water for six days post-fertilization, achieving comparable embryonic doses. Developmentally exposed fish from both experiments were reared in clean conditions until adulthood and spawned to produce the next generation. I evaluated a suite of endpoints across generations, including developmental morphology, hatch success, larval survival, larval photomotor responses (light/dark assay), juvenile anxiety-like behavior (novel tank diving test), and whole-brain gene expression. To assess the persistence of effects into adulthood, I also performed novel tank diving tests and whole-brain transcriptomic analyses in adult fish that had experienced early-life exposure over two years earlier. Maternal transfer of BDE-99 into eggs led to early-stage F1 exposure, altering larval and juvenile behavior, including photomotor and anxiety-like responses, as well as changes in juvenile brain gene expression. Notably, direct embryonic exposure did not affect F0 larvae or juveniles but caused behavioral alterations in their F1 descendants, despite the brevity of exposure. No behavioral or molecular effects persisted into the F2 generation, suggesting that maternal transfer influences neurobehavioral outcomes, but stable transgenerational inheritance of exposure-induced effects was not supported by the data. Behavioral effects followed a non-monotonic dose-response pattern, with greater impacts at low-to-intermediate doses but diminished effects at the highest dose. Additionally, exposure-induced behavioral perturbations were not consistently correlated with transcriptional changes, indicating that multiple independent molecular and cellular mechanisms may underlie BDE-99-induced neurodevelopmental effects. Both maternal and direct embryonic exposure resulted in long-term hyperactivity and reduced anxiety-like behavior, though outcomes varied by dose, sex, and exposure route. Progenitor exposure altered behavior in F1 males (females untested) and induced persistent changes in male brain gene expression, while direct embryonic exposure affected behavior only in females and did not induce detectable transcriptomic shifts. These differences suggest that maternal factors in addition to direct chemical transfer, such as chemical metabolites, altered lipid provisioning, small molecules, and epigenetic imprinting, contribute to exposure outcomes. This research demonstrates the complexity of BDE-99-induced neurobehavioral effects, showing that early-life exposures result in effects that persist into adulthood and across one generation but may not extend further. Although chemical transfer from progenitor to descendant contributes to intergenerational effects, it does not fully account for the observed impacts. Distinct behavioral outcomes between maternal transfer and direct embryonic exposure, despite comparable doses, reinforce the role of maternal influences beyond chemical deposition. I conclude that maternal factors significantly modify the persistent and multigenerational impacts of early-life exposure, emphasizing the need to consider exposure route when assessing risks from persistent pollutants. Given that maternal and environmental exposures co-occur in nature, future studies should incorporate combined exposure scenarios to better predict real-world risks. These findings underscore the importance of accounting for early-life exposures, maternal transfer, long-term behavioral consequences, and potential multigenerational effects in toxicological assessments of bioaccumulative pollutants.