Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants (POPs) that continue to pose a threat to human health, despite being banned from commercial production in the US in 1979 and in most other countries in the 2000s. Initially valued for their chemical and thermal stability, these properties have contributed to their environmental persistence long after their production ceased. Furthermore, PCBs are still released as byproducts or waste in some current manufacturing processes. Research has identified that a major target of PCBs is the developing human brain, but most studies have focused on developmental neurotoxicity of individual PCB congeners or Aroclors which is concerning given that contemporary human exposures are increasingly dissimilar from these individual exposures. This raises the question of whether the developmental neurotoxicity (DNT) of a contemporary human-relevant mixture of PCBs mirrors the neurodevelopmental effects of these individual PCB exposures. The Fox River in Wisconsin, heavily contaminated by PCBs from past industrial waste, poses a particular concern as it houses a large population of game fish that constitute the primary source of protein for people in surrounding areas. Cognitive deficits have been observed following consumption of fish from this river, which has been supported by animal studies assessing adult rats, but to-date there are no in vivo studies assessing the developmental neurotoxicity potential of this mixture. This dissertation seeks to address these data gaps using a mixture of PCBs designed to mimic the congener profile in game fish from the Fox River called the Fox River PCB Mixture (FRM). In both Chapters 2 and 3, dams were exposed to FRM throughout gestation and lactation and pups were analyzed for measures of neurotoxicity, including behavioral responses in Chapter 2 and neurodevelopmental endpoints in Chapter 3. Chapter 2 demonstrates that developmental exposure to FRM results in deficits in social behaviors that are not duplicated a memory task and began addressing the potential underlying mechanisms by measuring circulating thyroid hormones. Chapter 3 deepens our understanding of the cellular and molecular responses responsible for FRM DNT by providing evidence of dose-, sex-, and timepoint-dependent alterations to astrocyte immunoreactivity, neurogenesis, and measures of dendritic arborization. Female pups showed decreased astrocytic reactivity and increased dendritic arborization whereas male pups showed altered neurogenesis and increased dendritic arborization. These findings have important implications for research moving forward as they highlight potential molecular mechanisms that are underlying the DNT of the FRM. The overlap of behavioral responses and alterations to critical neurodevelopmental endpoints strengthens the conclusion that developmental exposure to FRM results in neurotoxic outcomes. These findings also suggest that both sex and age are important biological variables that influence the effect of FRM and therefore should be measured in studies moving forward. Finally, these results do not mirror the findings of studies assessing individual PCB congeners or Aroclors, underscoring the need for further research using contemporary PCB mixtures to better understand their impact on human health. Ultimately, this dissertation provides novel evidence that the Fox River PCB Mixture (FRM) poses a risk for the developing brain.
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