Health Risk Research Section, Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
PLoS One. 2012;7(12):e52756. doi: 10.1371/journal.pone.0052756. Epub 2012 Dec 28.
BACKGROUND/PURPOSE: We hypothesized that polymorphic differences among individuals might cause variations in the effect that environmental endocrine disruptors (EEDs) have on male genital malformations (MGMs). In this study, individual variation in the genetic response to low-dose bisphenol A (BPA) was investigated in human foreskin fibroblast cells (hFFCs) derived from child cryptorchidism (CO) and hypospadias (HS) patients.
METHODOLOGY/PRINCIPAL FINDINGS: hFFCs were collected from control children without MGMs (n=5) and child CO and HS patients (n=8 and 21, respectively). BPA exposure (10 nM) was found to inhibit matrix metalloproteinase-11 (MMP11) expression in the HS group (0.74-fold, P=0.0034) but not in the control group (0.93-fold, P=0.84) and CO group (0.94-fold, P=0.70). Significantly lower levels of MMP11 expression were observed in the HS group compared with the control group (0.80-fold, P=0.0088) and CO group (0.79-fold, P=0.039) in response to 10 nM BPA. The effect of single-nucleotide polymorphism rs5000770 (G>A), located within the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) locus, on individual sensitivity to low-dose BPA was investigated in the HS group. A significant difference in neurotensin receptor 1 (NTSR1) expression in response to 10 nM BPA was observed between AA and AG/GG groups (n=6 and 15, respectively. P=0.031). However, no significant difference in ARNT2 expression was observed (P=0.18).
CONCLUSIONS/SIGNIFICANCE: This study advances our understanding of the specificity of low-dose BPA effects on human reproductive health. Our results suggest that genetic variability among individuals affects susceptibility to the effects of EEDs exposure as a potential cause of HS.
背景/目的：我们假设个体之间的多态性差异可能导致环境内分泌干扰物（EEDs）对男性生殖器畸形（MGMs）的影响发生变化。在这项研究中，我们研究了源自儿童隐睾症（CO）和尿道下裂（HS）患者的人包皮成纤维细胞（hFFC）中对低剂量双酚 A（BPA）的遗传反应的个体差异。
方法/主要发现：从无 MGMs 的对照儿童（n=5）和儿童 CO 和 HS 患者（n=8 和 21）中收集 hFFC。发现 BPA 暴露（10 nM）抑制了 HS 组中基质金属蛋白酶-11（MMP11）的表达（0.74 倍，P=0.0034），但未抑制对照组（0.93 倍，P=0.84）和 CO 组（0.94 倍，P=0.70）。与对照组（0.80 倍，P=0.0088）和 CO 组（0.79 倍，P=0.039）相比，HS 组在对 10 nM BPA 的反应中观察到 MMP11 表达水平明显降低。在 HS 组中，研究了位于芳香烃受体核转位蛋白 2（ARNT2）基因座内的单核苷酸多态性 rs5000770（G>A）对个体对低剂量 BPA 敏感性的影响。在对 10 nM BPA 的反应中，观察到神经降压素受体 1（NTSR1）表达在 AA 和 AG/GG 组之间存在显著差异（n=6 和 15，分别，P=0.031）。但是，ARNT2 表达无显著差异（P=0.18）。
结论/意义：本研究增进了我们对低剂量 BPA 对人类生殖健康影响的特异性的理解。我们的结果表明，个体之间的遗传变异性会影响对 EEDs 暴露影响的易感性，这可能是 HS 的一个潜在原因。
