Prenatal Cadmium Exposure, Placental Transporter Proteins, and Child Health Outcomes

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

PROJECT SUMMARY Cadmium, a non-essential metal, is persistent in the environment and highly detected in pregnant people. Non-smokers are primarily exposed to cadmium via the intake of contaminated foods (e.g., cereals, breads, vegetables). During pregnancy, cadmium concentrates in the placenta and can interfere with biological functions and processes including hormone production and nutrient transfer. As a result, maternal exposure to cadmium may contribute to preterm birth, reduced birth weight, and impaired child growth. Placental transporters such as the breast cancer resistance protein (BCRP/ABCG2) may offer the fetus some protection by removing cadmium from the placenta and returning it to maternal circulation. In vivo and in vitro models show that BCRP reduces placental cadmium concentrations and cellular toxicity. In humans, a nonsynonymous BCRP polymorphism (C421A/Q141K) that is present in 17% of people is associated with ~50% lower placental BCRP protein levels. This F31 fellowship will first leverage existing data from an estimated 4,763 mother-child pairs across 13 cohorts in the NIH’s Environmental Influences on Child Health Outcomes (ECHO) program to determine whether a common variant in the BCRP gene may leave some fetuses more vulnerable to the adverse impacts of cadmium exposure. Second, we will utilize novel placental proteomics data on transporters from a single ECHO cohort (UPSIDE) to examine relationships between urinary and placental cadmium exposures and placental transport protein concentrations. Our aims are: (1) To examine prenatal cadmium concentrations in relation to gestational age at delivery and growth in the ECHO-wide cohort, considering effect modification by BCRP genotype. We hypothesize that higher prenatal cadmium will be associated with increased risk of preterm birth, earlier gestational age at delivery, smaller size at birth, and reduction-pattern growth trajectories. Further, we hypothesize that these associations will be stronger in pregnancies with the reduced-function BCRP polymorphism compared to the wild-type; (2) To examine placental BCRP protein concentrations in relation to prenatal cadmium concentrations in the UPSIDE cohort. We will explore associations with timing of birth and child growth. We hypothesize that placental BCRP protein concentrations will be inversely associated with prenatal cadmium concentrations. In addition to BCRP, we will consider protein concentrations associated with other less prominent gene variants and transporters involved in cadmium transport including a second BCRP variant and the Multidrug Resistance 1 [MDR1] transporter. This work will provide insight on the role of placental transporters in protecting against prenatal cadmium exposure and potentially identify a subpopulation of children at heightened risk of cadmium toxicity due to the BCRP variant. In addition, this research can be extended to improve our understanding of the developmental impacts of additional high priority contaminants that bind to BCRP including bisphenol A, perfluorooctanoic acid (PFOA), and zearalenone.