title: Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption.
abstract: BACKGROUND
  In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species-specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates.
  
  
  OBJECTIVE
  In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response.
  
  
  METHODS
  Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points.
  
  
  RESULTS
  Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression.
  
  
  CONCLUSIONS
  Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Heger
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Moses A
authors.initials: MA
authors.lastname: Sandrof
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: McDonnell
authors.forename: Janan B
authors.initials: JB
authors.lastname: Hensley
authors.forename: Erin N
authors.initials: EN
authors.lastname: McDowell
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Martin
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gaido
authors.forename: Kamin J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D052244:Endocrine Disruptors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010795:Phthalic Acids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D052244:Endocrine Disruptors; D010795:Phthalic Acids