目的:胎盘外排转运蛋白,如BCRP,降低环境污染物对胎盘和胎儿的毒性,但在围产期环境流行病学中很少受到关注。这里,我们评估产前暴露于镉后BCRP的潜在保护作用,一种优先积聚在胎盘中并对胎儿生长产生不利影响的金属。我们假设在ABCG2(编码BCRP的基因)中具有减少的功能多态性的个体,最容易受到产前镉暴露的不利影响,特别是,较小的胎盘和胎儿大小。
方法:我们从UPSIDE-ECHO研究参与者的每三个月和足月胎盘中测量了孕妇尿液样本中的镉(NY,美国;n=269)。我们拟合了调整后的多变量线性回归和广义估计方程模型,以检查经对数转换的尿液和胎盘镉浓度与出生体重的关系,出生长度,胎盘重量,和胎胎盘重量比(FPR)和ABCG2Q141K(C421A)基因型的分层模型。
结果:总体上有17%的参与者表达了功能降低的ABCG2C421A变体(AA或AC)。胎盘镉浓度与胎盘重量呈负相关(β=-19.55;95CI:-37.06,-2.04),并倾向于更高的FPR(β=0.25;95CI:-0.01,0.52),在421A变异婴儿中具有更强的相关性。值得注意的是,421A变异婴儿胎盘镉浓度升高与胎盘重量降低相关(β=-49.42;95CI:98.87,0.03),和更高的FPR(β=0.85,95CI:0.18,1.52),而较高的尿镉浓度与较长的出生长度相关(β=0.98;95CI:0.37,1.59),较低的体重指数(β=-0.09;95CI:0.15,-0.03),和较高的FPR(β=0.42;95CI:0.14,0.71)。
结论:ABCG2多态性功能降低的婴儿可能特别容易受到镉以及作为BCRP底物的其他外源性物质的发育毒性的影响。需要进行其他工作来检查胎盘转运蛋白在环境流行病学队列中的影响。
Placental efflux transporter proteins, such as BCRP, reduce the placental and fetal toxicity of environmental contaminants but have received little attention in perinatal environmental epidemiology. Here, we evaluate the potential protective role of BCRP following prenatal exposure to cadmium, a metal that preferentially accumulates in the placenta and adversely impacts fetal growth. We hypothesized that individuals with a reduced function polymorphism in ABCG2, the gene encoding BCRP, would be most vulnerable to the adverse impacts of prenatal cadmium exposure, notably, smaller placental and fetal size.
We measured cadmium in maternal urine samples at each trimester and in term placentas from UPSIDE-ECHO study participants (NY, USA; n = 269). We fit adjusted multivariable linear regression and generalized estimating equation models to examine log-transformed urinary and placental cadmium concentrations in relation to birthweight, birth length, placental weight, and fetoplacental weight ratio (FPR) and stratified models by ABCG2 Q141K (C421A) genotype.
Overall 17% of participants expressed the reduced-function ABCG2 C421A variant (AA or AC). Placental cadmium concentrations were inversely associated with placental weight (β = -19.55; 95%CI: -37.06, -2.04) and trended towards higher FPR (β = 0.25; 95%CI: -0.01, 0.52) with stronger associations in 421A variant infants. Notably, higher placental cadmium concentrations in 421A variant infants were associated with reduced placental weight (β = -49.42; 95%CI: 98.87, 0.03), and higher FPR (β = 0.85, 95%CI: 0.18, 1.52), while higher urinary cadmium concentration was associated with longer birth length (β = 0.98; 95%CI: 0.37, 1.59), lower ponderal index (β = -0.09; 95%CI: 0.15, -0.03), and higher FPR (β = 0.42; 95%CI: 0.14, 0.71).
Infants with reduced function ABCG2 polymorphisms may be particularly vulnerable to the developmental toxicity of cadmium as well as other xenobiotics that are BCRP substrates. Additional work examining the influence of placental transporters in environmental epidemiology cohorts is warranted.