Fetal growth restriction (FGR) is a critical disease that contributes significantly to infant mortality and morbidity. Although the etiology of FGR is poorly understood, environmental and occupational exposures have been implicated in its pathogenesis. Measurable levels of the environmental toxicant cadmium (Cd) have been found in >99% of pregnant women. This widespread exposure is important as Cd has been shown to induce FGR in rodents and linked to FGR in human epidemiological studies. Cd targets key functions of the placenta that lead to FGR. Under healthy conditions, the placenta critically regulates nutrient exchange between the maternal and fetal circulation while at the same time restricts the transfer of toxicants. Efflux pumps, including the breast cancer resistance protein (human BCRP/rodent Bcrp), are highly expressed on the maternal-facing membrane of placentas and thus aid in fetal protection by lowering placental (and fetal) xenobiotic concentrations. Our laboratory has demonstrated that in vitro overexpression of the human BCRP gene lowers intracellular Cd concentrations and confers resistance against Cd cellular stress and toxicity. However, it is unknown whether Bcrp in the placenta can regulate Cd toxicity in vivo. To begin to address this question, I have developed a model of Cd-induced FGR in wild-type mice. Preliminary data reveal a decrease in fetal weights that is accompanied by a decline in fetal glucose levels following administration of CdCl2 to pregnant mice. These data align with prior studies suggesting that nutrient transporters are molecular targets of Cd-induced FGR. My central hypothesis is that placentas with a complete loss or reduction in Bcrp transporter function are at a heightened risk of Cd accumulation which leads to impaired glucose transfer and utilization and severe fetal growth restriction. I will utilize two transgenic mouse lines to test this hypothesis: 1) Bcrp-/- mice that have no Bcrp expression and 2) Bcrp-Q140K mice, a CRISPR model that is orthologous to the human loss-of-function Q141K variant and recapitulates the reduced functioning of BCRP observed clinically. I anticipate that placentas from Bcrp-/- and Bcrp-Q140K mice will be more sensitive to Cd accumulation and toxicity compared to wild-type (Bcrp+/+) mice which will be tested in two specific aims. For this fellowship, I will complete a series of training in rodent and clinical anatomic pathology of the placenta, coursework and workshops in reproductive biology and toxicology, and hands-on experimental techniques including ICP/MS and immunohistochemistry. The majority of the training activities will occur at Rutgers University through the interdisciplinary Joint Graduate Program in Toxicology. Overall, this proposed research plan will enhance my development into an independent research scientist through studies completed as part of a Ph.D. dissertation.
The placenta holds great promise in revealing differences between individuals in their response to chemicals in our environment including the metal cadmium (Cd). My research investigates how a protein in the placenta protects against the toxicity of cadmium that leads to poor nutrition and growth in babies.
