Wolf Cynthia J, Hotchkiss Andrew, Ostby Joseph S, LeBlanc Gerald A, Gray L Earl
Reproductive Toxicology Division, Endocrinology Branch, MD 72, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, 86 Alexander Drive, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2002 Jan;65(1):71-86. doi: 10.1093/toxsci/65.1.71.
Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.
睾酮在男性性发育中起主要作用。子宫内的雌性胎儿若接触睾酮，可诱发诸如无排卵、肛殖距（AGD）增加、乳头缺失、保留男性样组织以及阴道下段发育不全等男性化特征。此外，胎儿发育期间雄激素水平过高会导致诸如窝仔数减少和生存能力下降等毒性作用。研究性分化期间给予睾酮的影响，为理解环境雄激素对胎儿（一个敏感亚群）的影响奠定了基础。在本研究中，我们调查了产前给予一系列浓度丙酸睾酮（TP）使雌性后代男性化并改变雄性后代的能力，并测量了母体和胎儿的睾酮水平。将妊娠的斯普拉格 - 道利大鼠在妊娠第14 - 19天（妊娠第1天 = 发现阴栓日）通过皮下注射给予玉米油（赋形剂；0.1 ml/只大鼠）或0.1 ml含0.1、0.5、1、2、5或10 mg/0.1 ml的TP溶液。2、5和10 mg TP剂量时分娩延迟，5和10 mg TP剂量时窝仔数减少，0.5 mg TP及更高剂量时两性幼仔体重均显著降低。任何剂量水平下后代的生存能力均未受影响。0.5 mg TP剂量时在雌性中观察到的雄激素效应包括断奶和成年时AGD增加、乳晕和乳头数量减少、阴茎裂、阴道口小以及存在前列腺组织。该剂量的TP使母体睾酮水平升高10倍，但对胎儿睾酮水平无影响。1 mg TP及以上剂量时，出生后第2天（或交配后第24天[妊娠期 = 22(1/2)天]）雌性的AGD增加；乳晕和乳头几乎消失；出现提肛肌、尿道球腺和精囊（2 mg TP及以上剂量）；所有雌性均未形成阴道口，1和2 mg TP剂量组的许多雌性在青春期后子宫出现极大扩张且充满液体。1 mg TP时母体睾酮水平升高30倍，雌性胎儿睾酮水平增加80%。0.5 mg TP及更高剂量时，雄性后代在出生后第2天AGD和体重降低。这些影响在断奶时不明显，且雄性后代未出现畸形。我们得出结论，妊娠期给予0.5和1 mg TP可使雌性后代男性化，而对幼仔生存能力或母鼠妊娠影响不大。本研究为子宫内检测环境雄激素诱导发育异常的潜力提供了一个有用的模型。
