title: Individual variation of the genetic response to bisphenol a in human foreskin fibroblast cells derived from cryptorchidism and hypospadias patients.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Health Risk Research Section, Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Xian-Yang
authors.initials: XY
authors.lastname: Qin
authors.forename: Hideko
authors.initials: H
authors.lastname: Sone
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kojima
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mizuno
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ueoka
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.forename: Mami
authors.initials: M
authors.lastname: Miyado
authors.forename: Aya
authors.initials: A
authors.lastname: Hisada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Zaha
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Fukuda
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshinaga
authors.forename: Junzo
authors.initials: J
authors.lastname: Yonemoto
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D017398:Alternative Splicing; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D002478:Cells, Cultured; D003456:Cryptorchidism / Q000209:etiology / Q000235:genetics*; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D052816:Foreskin / Q000166:cytology*; D023061:Gene Order; D005838:Genotype; D006801:Humans; D007021:Hypospadias / Q000209:etiology / Q000235:genetics*; D008297:Male; D010636:Phenols / Q000008:administration & dosage / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; D012333:RNA, Messenger; C490989:ARNT2 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds