Acute and long-term effects of in utero exposure of rats to di(n-butyl) phthalate on testicular germ cell development and proliferation
Acute and long-term effects of in utero exposure of rats to di(n-butyl) phthalate on testicular germ cell development and proliferation
复制标题
DOI：
10.1210/en.2006-0527
复制
发表时间：
2006-11-01
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：
Ferrara, Diana;Hallmark, Nina;Sharpe, Richard M.
本研究调查了子宫内暴露[胚胎日龄（e）13.5-e21.5]邻苯二甲酸二丁酯（DBP）对大鼠胎儿生殖细胞和出生后生殖细胞（GC）发育的影响，并重点关注与假定的人类原位癌细胞起源相关的变化（发育延迟）。DBP处理导致对生殖细胞的早期（e15.5-e17.5）和晚期（e19.5-e21.5）效应。前者涉及延迟进入增殖的生殖细胞进入静止期，如八聚体结合转录因子3/4和视网膜母细胞瘤蛋白在Ser 807/811和Ki 67磷酸化的延长/过表达加上生殖细胞凋亡增加2至4倍所示。DBP的晚期效应是诱导多核生殖细胞的发生率增加10倍以上。暴露于DBP的雄性GC数量在e21.5和出生后d（d）4、8和15分别减少37、53、79和80%（P < 0.01），出生后d 25和90之间阴囊睾丸恢复正常。DBP诱导的第4-8天GC数量减少与延迟退出静止期相关，如视网膜母细胞瘤蛋白表达和第6天GC增殖指数降低28%（P < 0.001）所示，尽管后者在第25天增加了84%。出生后GC的变化与早期，但不是晚期，DBP对生殖细胞的影响，短期DBP治疗E19.5至E20.5，诱导多核生殖细胞有效地从E13.5至E20.5治疗，但没有减少GC数的第4天。总之，胎儿DBP暴露延迟了胎儿（早在e15.5）和出生后正常GC的发育，并可能对生育力产生影响。
This study investigated effects of in utero exposure [embryonic day (e)13.5-e21.5] to di(n-butyl) phthalate (DBP) on fetal gonocytes and postnatal germ cell (GC) development in rats and focused on changes (delayed development) relevant to the postulated origins of human carcinoma-in situ cells. DBP treatment resulted in both early (e15.5-e17.5) and late (e19.5-e21.5) effects on gonocytes. The former involved delayed entry of proliferating gonocytes into quiescence, as indicated by prolongation/overexpression of octamer-binding transcription factor 3/4 and retinoblastoma protein phosphorylated at Ser 807/811 and Ki67 plus a 2- to 4-fold increase in gonocyte apoptosis. The late effect of DBP was to induce a greater than 10-fold increase in occurrence of multinucleated gonocytes. GC numbers in DBP-exposed males were reduced (P < 0.01) by 37, 53, 79, and 80% at e21.5 and postnatal d (d) 4, 8, and 15, respectively, with recovery to normal in scrotal testes between postnatal d 25 and 90. The DBP-induced decrease in GC numbers at d 4-8 was associated with delayed exit from quiescence, as indicated by retinoblastoma protein expression and a 28% reduction (P < 0.001) in GC proliferation index at d 6, although the latter was increased by 84% at d 25. The postnatal GC changes were associated with the early, but not late, effects of DBP on gonocytes as short-term DBP treatment from e19.5 to e20.5, induced multinucleated gonocytes as effectively as did treatment from e13.5 to e20.5, but did not reduce GC numbers on d 4. In conclusion, fetal DBP exposure delays normal GC development in both fetal (as early as e15.5) and postnatal life with the possibility of consequences for fertility.