CD4+ T cell-mediated neurotoxicity with continuous trichloroethylene exposure

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DESCRIPTION (provided by applicant) Trichloroethylene (TCE) is an industrial solvent and Superfund chemical that can be detected at low levels in groundwater and drinking water supplies across the U.S. due to inappropriate disposal. Several epidemiological studies have documented neurologic and behavioral disorders in children exposed to TCE in utero or in early life through maternal exposure. Using the investigators' mouse model, studies in their laboratory have shown that low level early life- only or gestational-only exposure promotes oxidative stress in association with abnormal behavior similar to children with attention-deficit hyperactivity disorder. The investigators do no know how TCE exposure mediates neurotoxicity and adverse behavior. This K02 independent Scientist Development Award application will enable the candidate to develop a program of research whose goal is to test the hypothesis that continuous developmental exposure occurring throughout gestation and early life to even lower levels of TCE than used previously alters neuroprotective factors in the brain leading to oxidative stress and adverse behavior over that of gestational-or early life-exposure only (aim 1). Because they have shown that CD4+ T cells are early-life targets of TCE developmental toxicity, the investigators will test the novel hypothesis that dysregulated CD4+ T cells contribute to adverse neurologic outcome observed in our model (aim 2). Adoptive transfer experiments using CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to promote adverse neurobehavior following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice generated in their laboratory. This K02 will help foster the candidate's ability to achieve these research goals by providing her with protected time to be more fully engaged in her NIH-funded R01 funded project designed to examine whether developmental exposure to TCE accelerates the development of autoimmunity in MRL+/+ mice. It will also allow her to focus on her career goals to examine the interaction between CD4+ T cells and neurological outcome. The candidate's Career Development Plan involving intense training in neurobehavioral techniques and analysis in both experimental models and in children will enhance her knowledge and skills in this area. The K02 will be of critical value to expand the candidate's research program with the potential to discover unknown mechanisms of action of TCE neurotoxicity that may pave the way to nutritional or anti- oxidant support therapies in TCE-exposed children.