Developmental exposure to organophosphorus pesticide to evaluate airway hyperreactivity Epidemiological studies have linked organophosphorus pesticide (OP) exposure to increased risk of asthma in children and adults, yet preclinical evidence supporting this causal link is limited. Dr. Grodzki’s previous work has shown that the OP chlorpyrifos causes airway hyperreactivity (AHR) at low doses that do not inhibit acetylcholinesterase. However, current understanding of the mechanisms involved in OP-induced AHR is incomplete and the question of whether developmental OP exposure could lead to asthmatic symptoms has not been addressed in preclinical models. Dr. Grodzki is investigating the effects of developmental chlorpyrifos exposures on AHR using physiological measurements of lung function and markers of neurogenic inflammation in animal models.
In vitro model of developmental endocrine disruption The contribution of the pesticide DDT and its metabolite DDE to breast cancer risk is controversial, where a recent report by the World Health Organization noted the importance of early-life exposure to DDT remains unresolved. We recently demonstrated that prenatal DDT exposure is associated with nearly four-fold higher incidence of breast cancer among adult daughters born at the Oakland Kaiser Permanente hospital in the 1960s. In parallel we exposed mice to DDT while they were in the womb and found they also had nearly four-fold higher mammary tumors. Based on our preliminary research, we suggest that a daughter’s prenatal DDT exposure increases breast cancer risk through altered metabolism that increases tumor growth. The best system to rigorously evaluate this mechanistic hypothesis is cell culture but dosing standard mammary cell lines with DDT would not model prenatal DDT exposure or endocrine carcinogenesis. We seek to establish a plausible mechanism of our striking human and mouse observations by evaluating tumor cells of mice exposed to DDT prenatally. We will characterize the growth and metabolism of these cells and whole mouse tumors.