UC Davis

Polychlorinated biphenyls (PCBs) were historically synthesized from the 1930s to the early 2000s for a wide variety of commercial and industrial purposes because of their high chemical stability, high heat dissipation and low flammability. The production of PCBs was banned in 1979 in the United States due to rising concerns about their environmental persistence and detrimental effects on human health. PCBs that were a synthesized as the original commercial mixtures are referred to as “legacy” PCBs. Legacy PCBs are ubiquitous in the environment and remain environmental pollutants of concern despite the trend of decreasing levels in various environmental matrices and human tissues. However, there is mounting evidence that humans worldwide are increasingly exposed to another group of “contemporary” PCBs represented predominantly of lower-chlorinated (LC) PCBs. LC-PCBs were not synthesized in the original PCB mixtures but rather are inadvertent byproducts of modern pigment making processes. To support risk assessments and regulations to reduce harmful PCB exposures, it is important to understand the mechanisms by which PCBs cause adverse health effects. The target organ of concern for PCBs is the developing brain and there is increasing data linking PCBs to increased risk for neurodevelopmental disorders (NDDs). A subset of legacy PCBs have been shown to alter dendritic arborization of hippocampal and cortical neurons in primary neuron-glia co-cultures and in vivo. A reproducible observation from studies of PCB-induced dendritic growth is a non-monotonic dose-response relationship in which higher PCB levels have no effect on dendritic arborization. This inverted U-shaped dose-response curve has prompted some to question whether PCB developmental neurotoxicity is a legitimate concern. Identifying a mechanism to explain why the dendrite-promoting activity of PCBs disappears at higher levels is needed to not only instill confidence in the data but also inform risk assessment. Another key data gap in the field is the limited information available regarding the potential developmental neurotoxicity of the contemporary LC-PCBs. This dissertation aims to address these knowledge gaps using a primary neuron-glia co-culture model and in vivo developmental PCB-exposure paradigm. Chapter 2 explores multiple mechanisms hypothesized to cause the non-monotonic dose-related effects of legacy PCBs on dendritic arborization. The data identify a potential role for the transcription factor UBE3A in blocking PCB 95-induced dendritic growth in cortical but not hippocampal neuron-glia cell cultures. UBE3A is critical for regulating dendrite remodeling during development, and mutations in UBE3A have been implicated in NDDs, suggesting a potential gene X environment interaction that influences individual risk for NDDs. Chapter 3 describes data suggesting that developmental exposure to LC-PCB 11 in the maternal diet throughout gestation and lactation increases the dendritic complexity of cortical, but not hippocampal, neurons of postnatal day 2 (P21) mouse pups. In contrast, developmental exposure to PCB 11 exposure had no significant effect on caspase-3 activity in P4 cortical or hippocampal mouse tissues. These findings have critical implications for understanding the neurotoxic risks of legacy as well as contemporary LC-PCBs. These data indicate that legacy NDL PCB congeners like PCB 95 may modulate multiple signaling pathways involved in regulating dendritic growth during development. A question that is raised by these findings is how do the cumulative cellular effects of PCB 95 contribute to NDDs? These data also highlight that LC-PCBs warrant further studies to investigate the cellular and molecular mechanisms by which LC-PCBs exert their effects on a developing brain. These data also raise several important questions: other than dendrite arborization, do LC-PCBs influence any other neurodevelopmental processes in the brain? How do the effects of LC-PCBs on neurodevelopmental processes, such as dendritogenesis, influence neurobehavior? How does developmental exposure to LC-PCBs affect the prognosis of NDDs in individuals with genetic predispositions for abnormal development of the brain? Do the effects of LC-PCBs on dendrite growth in a developing brain persist into adulthood? In summary, the data indicate that both legacy and contemporary PCBs are likely risk factors for adverse neurodevelopmental outcomes.