Abstract
Background/PurposeWe 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 FindingshFFCs 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/SignificanceThis 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.
Highlights
Cryptorchidism (CO) and hypospadias (HS) are the two most common congenital male genital malformations (MGMs) with a global prevalence of approximately 2–9% and 0.2–1%, respectively [1,2]
We have previously investigated the association between single-nucleotide polymorphisms (SNPs) of genes involved in endocrine disruptors (EEDs) metabolism and the risk of CO and HS in a Japanese population and found that SNP rs5000770 (G.A) within intron 1 of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) was significantly associated at both allele and genotype levels with increased risk of CO and HS [8]
No significant difference was observed between the control group and HS group (P = 0.16), while lower ARNT2 expression was observed in CO group compared with control group only on the borderline of significance (P = 0.054)
Summary
Cryptorchidism (CO) and hypospadias (HS) are the two most common congenital male genital malformations (MGMs) with a global prevalence of approximately 2–9% and 0.2–1%, respectively [1,2]. ARNT2 is a member of the basic helix-loop-helix Per-ARNTSIM (bHLH-PAS) family of transcription factors that is involved in the regulation of many physiological pathways, including responses to environmental contaminants [9,10]. ARNT2 polymorphisms have been linked with the risk of some specific congenital malformations in humans such as cleft palate [14]. Little is known about the relationship of ARNT2 polymorphisms and the risk of MGMs. we aimed to investigate whether the polymorphic differences among individuals might cause variations in the ability of EEDs to cause MGMs. It is likely that further investigations on this issue will shed increased light on the link between EEDs exposure and the development of MGMs
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