Wolf Cynthia J, LeBlanc Gerald A, Gray L Earl
U.S. Environmental Protection Agency, Office of Research and Development, NHEERL, Reproductive Toxicology Division, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2004 Mar;78(1):135-43. doi: 10.1093/toxsci/kfh018. Epub 2004 Jan 21.
In mammals, androgens are essential in directing mammalian sexual differentiation of the male phenotype. Administration of testosterone during this period alters female development in a male-like direction, whereas exposure to an androgen receptor antagonist like vinclozolin (V) demasculinizes and feminizes the male offspring. In the current study, we administered V (gavage at 200 mg/kg/day) and/or testosterone propionate (TP, sc, at 1 mg/rat/day), alone and in combination to Sprague-Dawley (SD) rats on days 14 through 19 of pregnancy, to determine if V would antagonize the effects of TP in the female and, conversely, if TP would antagonize the effects of V in the male offspring. These doses of TP and V were selected because they significantly alter sexual differentiation in the majority of female and male rat offspring, respectively, without producing severe toxicity in the dam or offspring. The study design is a 2 x 2 factorial (7 dams per group) including vehicle control, V, TP, and V + TP groups. As expected, individually, both V and TP reduced maternal weight gain and the V + TP group was affected in a cumulative fashion. Litter size on postnatal day (PND) 2 was reduced only by V + TP, whereas pup body weight was reduced in all three treated groups, the effect of V + TP again being cumulative. In female offspring, TP-induced alterations (i.e., increased anogenital distance [AGD] and fewer nipples, vaginal agenesis, hydrometrocolpos, induced prostate and bulbourethral glands, and levator ani muscle tissues) were all reversed by coadministration of V. In male offspring, V-induced alterations were only modestly antagonized by TP. At the dosage levels used herein, V + TP-treated male offspring had less well-developed nipples as infants and adults and a lower incidence of ectopic testis than did the V group. However, V-induced changes in reproductive organ weights, AGD, atrophic testes, vaginal pouch, and agenesis of the sex accessory tissues were not antagonized by concurrent TP treatment in male offspring. We observed that the combination of V and TP, two chemicals with opposing endocrine action, antagonized one another during sexual differentiation, especially in the female offspring and induced cumulative effects on maternal and neonatal toxicity. We suspect that antagonism of V by TP would be enhanced in the male if lower dose levels of V were used, but then the antagonism of TP by V in the female would likely be attenuated.
在哺乳动物中，雄激素对于引导雄性表型的哺乳动物性别分化至关重要。在此期间给予睾酮会使雌性发育朝着雄性方向改变，而暴露于诸如乙烯菌核利（V）之类的雄激素受体拮抗剂会使雄性后代去雄化并雌性化。在本研究中，我们在妊娠第14至19天对斯普拉格 - 道利（SD）大鼠单独及联合给予V（以200mg/kg/天灌胃）和/或丙酸睾酮（TP，皮下注射，1mg/大鼠/天），以确定V是否会拮抗TP对雌性的影响，反之，TP是否会拮抗V对雄性后代的影响。选择这些TP和V的剂量是因为它们分别能显著改变大多数雌性和雄性大鼠后代的性别分化，而不会对母鼠或后代产生严重毒性。研究设计为2×2析因设计（每组7只母鼠），包括溶剂对照组、V组、TP组和V + TP组。正如预期的那样，单独来看，V和TP都降低了母鼠体重增加，V + TP组受到累积影响。出生后第2天（PND2）的窝仔数仅在V + TP组减少，而所有三个处理组的幼仔体重均降低，V + TP组的影响同样是累积性的。在雌性后代中，V的共同给药逆转了TP诱导的改变（即增加肛门生殖器距离[AGD]、减少乳头数量、阴道闭锁、子宫积血、诱导前列腺和尿道球腺以及肛提肌组织）。在雄性后代中，TP仅适度拮抗了V诱导的改变。在本文使用的剂量水平下，与V组相比，V + TP处理的雄性后代在婴儿期和成年期乳头发育较差，隐睾发生率较低。然而，在雄性后代中，TP的同时处理并未拮抗V诱导的生殖器官重量、AGD、萎缩睾丸、阴道囊以及性附属组织发育不全的变化。我们观察到，V和TP这两种具有相反内分泌作用的化学物质在性别分化过程中相互拮抗，尤其是在雌性后代中，并对母体和新生儿毒性产生累积影响。我们怀疑，如果使用较低剂量水平的V，TP对V的拮抗作用在雄性中会增强，但V对TP在雌性中的拮抗作用可能会减弱。
