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Prostaglandins, masculinization and its disorders: effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin.

Dean A, Mungall W, McKinnell C, Sharpe RM - PLoS ONE (2013)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

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.

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Effects of maternal exposure to vehicle or indomethacin (0.8 mg/kg/day; e15.5–e18.5) on serum testosterone levels at Pnd25 and Pnd75 (adulthood).Values are means ± SEM for N = 4–13 animals from a minimum of two litters.
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pone-0062556-g004: Effects of maternal exposure to vehicle or indomethacin (0.8 mg/kg/day; e15.5–e18.5) on serum testosterone levels at Pnd25 and Pnd75 (adulthood).Values are means ± SEM for N = 4–13 animals from a minimum of two litters.

Mentions: By puberty (Pnd25), indomethacin exposed males were significantly heavier (∼24%) than vehicle exposed control animals, and this difference (∼23%) was still evident at Pnd75 (Fig. 3A). AGI at Pnd25 and Pnd75 was unaffected by fetal exposure to indomethacin (Fig. 3B) and in utero exposure to indomethacin did not significantly alter plasma levels of testosterone at either age (Fig. 4).


Prostaglandins, masculinization and its disorders: effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin.

Dean A, Mungall W, McKinnell C, Sharpe RM - PLoS ONE (2013)

Effects of maternal exposure to vehicle or indomethacin (0.8 mg/kg/day; e15.5–e18.5) on serum testosterone levels at Pnd25 and Pnd75 (adulthood).Values are means ± SEM for N = 4–13 animals from a minimum of two litters.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643956&req=5

pone-0062556-g004: Effects of maternal exposure to vehicle or indomethacin (0.8 mg/kg/day; e15.5–e18.5) on serum testosterone levels at Pnd25 and Pnd75 (adulthood).Values are means ± SEM for N = 4–13 animals from a minimum of two litters.
Mentions: By puberty (Pnd25), indomethacin exposed males were significantly heavier (∼24%) than vehicle exposed control animals, and this difference (∼23%) was still evident at Pnd75 (Fig. 3A). AGI at Pnd25 and Pnd75 was unaffected by fetal exposure to indomethacin (Fig. 3B) and in utero exposure to indomethacin did not significantly alter plasma levels of testosterone at either age (Fig. 4).

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus