Prenatal cadmium exposure in relation to placental and birth size: effect modification by fetal sex and genetic variation in the placental barrier transporter ABCG2

BACKGROUND AND AIM: Cadmium accumulates in the placenta and may adversely impact fetal growth, however results have varied across epidemiological studies. Largely ignored in these studies are polymorphisms in genes encoding placental barrier transporters such as ABCG2, which reduces placental accumulation and fetal chemical exposures. We examined maternal cadmium concentrations in relation to placental and infant size at birth, evaluating effect modification by fetal sex and ABCG2 genotype. METHODS: We measured urinary cadmium in each trimester and in term placenta from mothers participating in the UPSIDE-ECHO cohort (NY,USA; n=254). Birthweight, birth length, and placental weight were obtained from medical records and direct measurement; fetoplacental weight ratio(FPR) was calculated and ABCG2 C421A/Q141K(rs2231142) genotype was assessed. We fit multivariable linear regression models examining log-transformed urinary and placental cadmium concentrations in relation to birthweight, birth length, placental weight, and FPR, adjusting for covariates. RESULTS: Cadmium was measurable in 85-91% of urine samples (by trimester; medians 0.18-0.30 µg/L) and 99% of placentas (median 4.4 µg/g). 17% of placentas had a reduced-function ABCG2 polymorphism (AA or AC genotype). A ln-unit increase in placental cadmium was associated with lower placental weight (β=-19.15g, 95%CI: -36.36,-1.93) and higher FPR (β=0.25, 95%CI: -0.02,0.51); associations with birthweight were inverse, but non-significant. Notably, cadmium was associated with reduced placental weight (β=-48.08g, 95%CI: -96.05,-0.12) and higher FPR (β=0.80, 95%CI: 0.15,1.46) in AA/AC participants, with null associations in wild-type CC participants. Associations with reduced placental weight were stronger in females (β=-24.93g, 95%CI: -49.38,-0.48) compared to males (β=-13.94g, 95%CI: -37.94,11.05). Few associations were observed between specific gravity-adjusted urinary cadmium and newborn/placental size. CONCLUSIONS: Cadmium was associated with reduced placental growth and efficiency in female infants as well as participants with the reduced-function ABCG2 transporter variant, confirming prior in vitro studies. Individuals with ABCG2 polymorphisms may be particularly vulnerable to cadmium’s developmental toxicity.