Prenatal Plus Postnatal Exposure to Di(n-Butyl) Phthalate and/or Flutamide Markedly Reduces Final Sertoli Cell Number in the Rat
Prenatal Plus Postnatal Exposure to Di(n-Butyl) Phthalate and/or Flutamide Markedly Reduces Final Sertoli Cell Number in the Rat
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DOI：
10.1210/en.2010-0108
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Sharpe, Richard M.
中科院分区：
文献类型：
--
作者：
Auharek, Sarah A.;de Franca, Luiz R.;Sharpe, Richard M.
雄激素可能是围产期支持细胞（SC）增殖的重要调节因子，与睾丸发育不全综合征（TDS）假说有关。大鼠胎仔暴露于500 mg/kg。d邻苯二甲酸二丁酯（DBP）降低出生时胎儿睾酮的产生和SC数量，但SC数量在出生后d（Pnd）25恢复正常。目前尚不清楚DBP暴露在产前何时以及如何影响SC增殖，或何时以及如何发生产后补偿。本研究解决了这些问题，并调查了母体在Pnd 1-Pnd 15期间持续暴露于DBP或氟替卡松是否会阻止SC数量补偿，因为这可能会影响TDS中精子计数的降低。DBP暴露在胚胎d（e）15.5-e21.5期间使SC增殖减弱7-18%（在e21.5时P < 0.05）。出生后，在产前暴露于DBP的动物中，SC增殖在Pnd 6和Pnd 10之间显著增加（> 1.5倍），解释了补偿。出生后继续母体给予DBP减弱（减少19%）Pnd 25时SC数量补偿，母体给予氟替卡松（100 mg/kg . d）对产前DBP暴露的动物甚至更有效（减少42%），表明产前DBP暴露后SC增殖的产后代偿性增加是雄激素依赖性的。根据关键蛋白表达的分析，SC成熟（Pnd 25）未受影响，但管腔形成/扩张与处理诱导的SC数量减少平行减弱。我们的研究结果提供了进一步的证据表明，围产期SC增殖是雄激素依赖性的，重要的是，表明母亲在出生前和哺乳期暴露于抗雄激素化学物质会减少最终SC数量，这与TDS中精子计数低的起源有关。（内分泌学151：2868-2875，2010）
Androgens may be important regulators of Sertoli cell (SC) proliferation perinatally, with implications for the testicular dysgenesis syndrome (TDS) hypothesis. Fetal exposure of rats to 500 mg/kg . d di(n-butyl) phthalate (DBP) reduces fetal testosterone production and SC number at birth, but SC number recovers to normal by postnatal d (Pnd)25. It is unclear when and how SC proliferation is affected prenatally by DBP exposure or when and how postnatal compensation occurs. This study addressed these questions and investigated whether continued maternal exposure to DBP or to flutamide from Pnd1-Pnd15 could prevent SC number compensation, because this would have implications for how sperm counts might be lowered in TDS. DBP exposure attenuated SC proliferation by 7-18% throughout embryonic d (e) 15.5-e21.5 (P < 0.05 at e21.5). After birth, SC proliferation increased significantly (> 1.5-fold) between Pnd6 and Pnd10 in prenatally DBP-exposed animals, explaining the compensation. Continued maternal administration of DBP after birth attenuated (19% reduction) SC number compensation at Pnd25 and maternal administration of flutamide (100 mg/kg . d) to prenatally DBP-exposed animals was even more effective (42% reduction), suggesting the postnatal compensatory increase in SC proliferation after prenatal DBP exposure is androgen dependent. SC maturation (Pnd25) was unaffected, based on analysis of expression of key proteins, but lumen formation/expansion was attenuated in parallel with treatment-induced reduction in SC number. Our results provide further evidence that perinatal SC proliferation is androgen dependent and, importantly, show that similar exposure of mothers to antiandrogenic chemicals before birth and during lactation reduces final SC number, with implications for the origin of low sperm counts in TDS. (Endocrinology 151: 2868-2875, 2010)