Airborne PCBs and Their Metabolites: Risk Factors for Adverse Neurodevelopmental Outcomes in Adolescence

University Of Iowa, Iowa City IA

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Abstract

PROJECT SUMMARY: PROJECT 1 – PCB NEUROTOXICITY IN ADOLESCENTS Previous work by the Iowa Superfund Research Program demonstrated that indoor air, especially in U.S. schools, is contaminated with polychlorinated biphenyls (PCBs). Such exposure represents a current public health concern for U.S. adolescents considering recent data indicating PCBs interfere with neurodevelopment. In addition, findings from Project 1 have implicated astrocytes as a target for PCBs with a putative mechanism involving mitochondrial dysfunction. Despite such evidence, there is a gap in scientific knowledge regarding the mechanism of neurotoxicity via which airborne PCBs, such as the School and Superfund Air Mixture (SSAM), target the developing brain, and in addition, the role of SSAM metabolites compared to the parent compound. Therefore, a critical need exists to establish how SSAM PCBs affect neurotoxic outcomes in adolescents and elucidate mechanisms by which human metabolites of these PCBs cause neurotoxicity. The long-term goal of this project is to assess and prevent neurotoxicity outcomes following exposure to PCB congener profiles detected in the air of U.S. schools and at PCB-contaminated Superfund sites. Our central hypothesis is that adolescent exposure to airborne PCBs, and their metabolites formed in vivo, is mechanistically linked to altered neurodevelopmental outcomes through oxidative stress and mitochondrial dysfunction in astrocytes. We propose that SSAM PCBs, and especially their metabolites, target mitochondrial astrocytes and cause disruption of neighboring cells, including microglia and neurons, yielding neuroinflammation and cell injury, respectively. This hypothesis is based on strong preliminary studies showing that metabolites of SSAM PCBs: a) are present in the rodent brain; b) cause oxidative stress in vitro and in vivo; c) target astrocyte mitochondria causing a change in form/structure and rapid disruption of bioenergetics. Guided by these preliminary data, the novel hypothesis will be tested by: 1) determining the effects of an inhaled PCB mixture on biochemical markers and behavioral outcomes indicative of neurotoxicity in mice (collaboration with Project 2); 2) characterizing the role of astrocytes and interactions with other cell types in PCB-mediated neurotoxicity in cells in culture; and in addition: 2.1) identifying mechanistic targets of PCBs in primary mouse astrocyte cultures in vitro; and 2.2) assessing the contribution of astrocyte interactions with other cell types (microglia and neurons) from mice on the adverse outcomes of PCBs in vitro. The proposed research is conceptually and technically innovative as it seeks to elucidate a mechanism of airborne PCB neurotoxicity stemming from mitochondrial dysfunction in astrocytes via PCB metabolites and utilizes novel cell culture methods. The outcomes of these studies will pinpoint novel mechanisms by which PCBs elicit neurotoxic responses. Completing this research will impact public health by providing fundamental, mechanistic insights needed to advance the human risk assessment of exposure to PCBs to inform strategies to prevent or mitigate adverse outcomes following PCB inhalation.