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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.

Individual Variation of the Genetic Response to Bisphenol A in Human Foreskin Fibroblast Cells Derived from Cryptorchidism and Hypospadias Patients