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doi: 10.1371/journal.pone.0052756. Epub 2012 Dec 28.

Individual variation of the genetic response to bisphenol a in human foreskin fibroblast cells derived from cryptorchidism and hypospadias patients

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Individual variation of the genetic response to bisphenol a in human foreskin fibroblast cells derived from cryptorchidism and hypospadias patients

Xian-Yang Qin et al. PLoS One. 2012.

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. ARNT2 mRNA levels in control children and child HS and CO patients.
ARNT2 expression were measured in hFFCs derived from the control group (n = 5), HS (n = 21) group and CO (n = 8) group by TaqMan® real-time PCR. (A) Boxplot and (B) summary of the quantitative data.
Figure 2
Figure 2. Difference in the genetic response to low-dose BPA in hFFCs derived from control children and child HS and CO patients.
Cells were treated with 10 nM BPA for 24 h, and then the expression of MMP11 (A) and NTSR1 (B) was measured by TaqMan® real-time PCR. Significance was evaluated by the Mann-Whitney U test or Wilcoxon test. The bottom numbers indicate the fold changes and P value induced by BPA compared with DMSO control.
Figure 3
Figure 3. Association between rs5000770 genotype and ARNT2 expression.
(A) Boxplot of the ARNT2 mRNA level in hFFCs from child HS patients with different genotypes (6 AA and 15 AG/GG) relative to GAPDH measured using TaqMan® real-time PCR. Statistical significance was evaluated by the Mann-Whitney U test. (B) Scheme of the quantitative PCR strategy for screening splicing variants. No splicing variant was detected using intron-spanning RT-PCR in hFFCs either from HS or CO patients.
Figure 4
Figure 4. Effect of SNP rs5000770 genotype on the genetic response to low-dose BPA.
Cells were treated with 10 nM BPA for 24 h, and then MMP11 and NTSR1 mRNA levels were measured by TaqMan® real-time PCR. Boxplot of the quantitative data comparing MMP11 (A) and NTSR1 (B) expression in child HS patients with different genotypes (6 AA and 15 AG/GG). Significance was evaluated by the Mann-Whitney U test.

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