Diversity Supplement to Molecular and Cellular Basis of PCB Developmental Neurotoxicity (Mendieta)

PROJECT SUMMARY Lower-chlorinated polychlorinated biphenyls (LC-PCBs) are increasingly recognized as a significant risk to human health, and a primary target of concern is the developing brain. LC-PCBs are the predominant PCB congener type detected in the serum of pregnant women at increased risk of having a child with a

neurodevelopmental disorder (NDD), and they are widely detected in not only school air but also the serum of schoolchildren and teachers. The parent grant investigates how CYP-mediated metabolism influences the in vitro and in vivo effects of LC-PCBs on CREB-dependent neurodevelopmental processes using state-of-the-art

mouse models that express human CYP2A6 or CYP2B6 but not mouse Cyp2a, 2b, 2f2, 2g1, and 2s1 proteins (Cyp2abfgs-null mice). Preliminary data generated under the parent grant suggests that the LC-PCB, PCB 28, interferes with axonal and dendritic growth in primary rat cortical neuron-glia co-cultures. This diversity

supplement leverages and extends findings from the parent grant to address the following questions: (1) Does exposure to PCB 28 cause developmental neurotoxicity (DNT) in vivo, and (2) To what extent does the route of exposure influence the in vivo DNT of PCB 28, e.g., are different neurotoxic outcomes observed in pups born to

dams exposed to PCB 28 via diet vs. inhalation? To address these questions, the diversity supplement will use Sprague Dawley rat dams exposed to varying doses of PCB 28 in the diet vs. the air to test the hypothesis that maternal exposure to PCB 28 causes neurodevelopmental deficits in weanling pups and that the profile of

developmental neurotoxicity differs between inhalation and dietary exposure. This hypothesis will be tested by addressing the following aims: 1) Characterize the disposition of PCB 28 and metabolites in dams and pups following inhalational vs. dietary exposure; (2) Determine whether maternal exposure to PCB 28 via inhalation

vs ingestion differentially impacts neurobehavioral outcomes in juvenile rats; and (3) Evaluate the effects of maternal exposure to PCB 28 via inhalation vs. diet on neurodevelopmental endpoints. The anticipated outcomes of these research studies include the identification of LC-PCBs as a new class of environmental contaminants

that interfere with neurodevelopment and novel mechanistic data regarding how the route of exposure impacts PCB DNT. Together with findings from the parent grant, this research will impact public health by providing critical mechanistic insights regarding risk that LC-PCBs pose to the developing brain and strategies for

mitigating DNT risk in vulnerable subpopulations. The training goals of this Diversity supplement include: (1) developing the trainee’s knowledge and technical skill set to enable them to successfully conduct research on environmental influences on neurodevelopmental outcomes; (2) guiding the trainee’s research activity to ensure

the generation of data needed to support their preparation of a competitive F31 application and advance to candidacy; (3) enhancing the trainee’s professional skills; and (4) actively working with the trainee to build their professional networks to enhance their success in transitioning to an independent career in research.