Airborne PCBs and their Metabolites: Risk Factors for Adverse Neurodevelopmental Outcomes in Adolescence
Project 1’s long-term goal is to characterize the contribution of airborne PCBs and their metabolites to PCB neurotoxicity following exposure to airborne PCB congeners detected in indoor air of U.S. schools and, as a consequence, in school children and adolescents. The objective of this project is to inform future risk assessment by defining the link between neurotoxic PCB metabolites present in the brain and neurotoxic outcomes following adolescent exposure. We will accomplish our objective by:
1) Identifying cellular sites and targets of airborne PCB metabolites vs. parent compounds responsible for neurotoxicity in vitro. Based on preliminary findings demonstrating that airborne PCBs affect neurotransmitter homeostasis in cells in culture producing toxic species, we hypothesize that, like the parent compounds, airborne PCB metabolites: a) elicit toxic responses (i.e.., neuroinflammation, oxidative stress and dysfunction of neurotransmitter metabolism and trafficking); and b) cause the production of reactive oxygen species and toxic neurotransmitter metabolites in cultured neurons and astrocytes.
Aim 1 will utilize isolated primary neurons and astrocytes to determine the molecular targets of PCB metabolites and measure toxic products formed by altered dopamine homeostasis. To determine the cellular response to PCBs and metabolites, cells grown to confluence will be exposed to a range of concentrations (1 nM to 10 mM) with negative control (vehicle; no PCB).
2) Characterizing the region-specific biotransformation of PCBs and PCB metabolites with in vitro models and in the adolescent rat brain in vivo. We have demonstrated that PCB metabolites are formed in the liver and distributed to the rodent brain, where they undergo further metabolism to neurotoxic metabolites. Building on these findings, we will test the hypothesis that metabolism of PCBs in neurons and/or astrocytes results in the local formation of neurotoxic metabolites of airborne PCBs.
3) Determining the effects of human metabolites of airborne PCB on biochemical markers of PCB neurotoxicity and behavioral outcomes in rats exposed throughout adolescence in vivo. Because our inhalation studies implicate PCBs in adverse neurobehavioral outcomes, we will test the hypothesis that exposure of adolescent rats to human metabolites of airborne PCBs affects neurotoxic outcomes, including adverse behavioral responses related to attention/working memory, executive functioning/impulse control, and motor control, in a dose- and sex-dependent manner. Endpoints to be assessed include PCB metabolite profiles (PCB metabolome), oxidative stress, neurotransmitter metabolism, and neuroinflammation.
Project Leader: Hans-Joachim Lehmler, PhD
Dr. Lehmler is a Professor in the Department of Occupational and Environmental Health at the University of Iowa (UI). He earned his PhD in synthetic organic chemistry from the University of Bonn, Germany, and received training in chemical and analytical toxicology at the University of Kentucky and the UI. He has extensive experience with assessment of the toxicity of environmental contaminants and their metabolites in vitro and in vivo. He serves as Director of the Environmental Health Sciences Research Center (EHSRC) and as Leader of the Synthesis Core of the Iowa Superfund Research Program (ISRP) since 2006. Together with Jonathan Doorn, he directs the Oxidative Stress and Metabolism Thematic Area of the EHSRC.
Jonathan Doorn, PhD, Co-Investigator
Dr. Doorn is an Associate Professor in the Division of Medicinal and Natural Products Chemistry, College of Pharmacy at the UI. He earned a PhD in Toxicology from the University of Michigan and received postdoctoral training in pharmacology/toxicology at the University of Colorado Health Sciences Center. He has much experience studying the role of neurotransmitter (dopamine) metabolism in neurotoxicity and disease and the involvement of pesticides.
Michael W. Duffel, PhD, Co-Investigator
Dr. Duffel is a Professor in the Division of Medicinal and Natural Products Chemistry, College of Pharmacy at the UI. He has extensive expertise in theenzymology of sulfation and sulfotransferases and in the oxidation and subsequent further metabolism of lower-chlorinated PCBs. This includes experience with a range of approaches from in vitro biochemical methods to quantitative structure activity relationships and studies with in vivo models. He will be directly involved in experimental design and interpretation of those aspects of Aims 1 and 2 relevant to metabolism of PCBs and interconversion of those metabolites.