title: Prostaglandins, masculinization and its disorders: effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin.
abstract: Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal 'masculinization programming window' (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG)-mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5-e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p<0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: Afshan
authors.initials: A
authors.lastname: Dean
authors.forename: William
authors.initials: W
authors.lastname: Mungall
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D003456:Cryptorchidism / Q000139:chemically induced* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced* / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D013739:Testosterone; D015232:Dinoprostone; D007213:Indomethacin