Prenatal Cadmium Exposure Placental Transporter Proteins and Child Health Outcomes

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 breadsvegetables). During pregnancy cadmium concentrates in the placenta and can interfere with biological functionsand processes including hormone production and nutrient transfer. As a result maternal exposure to cadmiummay contribute to preterm birth reduced birth weight and impaired child growth. Placental transporters such asthe breast cancer resistance protein (BCRP/ABCG2) may offer the fetus some protection by removing cadmiumfrom the placenta and returning it to maternal circulation. In vivo and in vitro models show that BCRP reducesplacental 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 4763 mother-child pairs across 13 cohortsin the NIHs Environmental Influences on Child Health Outcomes (ECHO) program to determine whether acommon variant in the BCRP gene may leave some fetuses more vulnerable to the adverse impacts of cadmiumexposure. 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 transportprotein concentrations. Our aims are: (1) To examine prenatal cadmium concentrations in relation togestational age at delivery and growth in the ECHO-wide cohort considering effect modification byBCRP genotype. We hypothesize that higher prenatal cadmium will be associated with increased risk of pretermbirth earlier gestational age at delivery smaller size at birth and reduction-pattern growth trajectories. Furtherwe hypothesize that these associations will be stronger in pregnancies with the reduced-function BCRPpolymorphism compared to the wild-type; (2) To examine placental BCRP protein concentrations in relationto prenatal cadmium concentrations in the UPSIDE cohort. We will explore associations with timing ofbirth and child growth. We hypothesize that placental BCRP protein concentrations will be inversely associatedwith prenatal cadmium concentrations. In addition to BCRP we will consider protein concentrations associatedwith other less prominent gene variants and transporters involved in cadmium transport including a second BCRPvariant and the Multidrug Resistance 1 [MDR1] transporter. This work will provide insight on the role of placentaltransporters in protecting against prenatal cadmium exposure and potentially identify a subpopulation of childrenat heightened risk of cadmium toxicity due to the BCRP variant. In addition this research can be extended toimprove our understanding of the developmental impacts of additional high priority contaminants that bind toBCRP including bisphenol A perfluorooctanoic acid (PFOA) and zearalenone.