title: Comparative effects of di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts.
abstract: BACKGROUND
  Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.
  
  
  OBJECTIVE
  We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects.
  
  
  METHODS
  We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins.
  
  
  RESULTS
  In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell-germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.
  
  
  CONCLUSIONS
  Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.forename: Ana
authors.initials: A
authors.lastname: Calarrão
authors.forename: Laura
authors.initials: L
authors.lastname: Kennedy
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hutchison
authors.forename: Lenka
authors.initials: L
authors.lastname: Hrabalkova
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Jobling
authors.forename: Sheila
authors.initials: S
authors.lastname: Macpherson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D003993:Dibutyl Phthalate / Q000633:toxicity*; D005333:Fetus / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects*; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013737:Testis / Q000187:drug effects* / Q000196:embryology; D014183:Transplantation, Heterologous
chemical_list: D015386:Hazardous Substances; D003993:Dibutyl Phthalate