Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human.
Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human.
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大鼠的胎儿睾丸外植体中邻苯二甲酸酯和邻苯二甲酸苯二甲酸苯甲酸苯甲酸苯甲酸苯胺苯酚的影响：与人体的新生大鼠和新生儿摩尔莫斯群的体内作用与人体的体内作用进行比较。
DOI：
10.1289/ehp.9490
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发表时间：
2007-03
影响因子：
10.4
通讯作者：
Sharpe, Richard M
中科院分区：
文献类型：
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作者：
Hallmark, Nina;Walker, Marion;McKinnell, Chris;Mahood, I Kim;Scott, Hayley;Bayne, Rosemary;Coutts, Shiona;Anderson, Richard A;Greig, Irene;Morris, Keith;Sharpe, Richard M
某些邻苯二甲酸酯会损害子宫内胎鼠的睾丸间质细胞分布和类固醇生成，但尚不清楚是否会在人类中发生类似的影响。本研究的目的是探讨邻苯二甲酸二丁酯（DBP）或其代谢产物邻苯二甲酸单丁酯（MBP）对大鼠和人类胎儿睾丸组织中睾酮生成和Leydig细胞聚集（LCA）的影响，并将结果与DBP暴露大鼠的体内结果进行比较。我们还想确定DBP/MBP是否影响新生雄性绒猴体内睾酮的产生。将从大鼠[妊娠日（GD）19.5]和人（妊娠15-19周）获得的胎儿睾丸外植体在有或没有人绒毛膜促性腺激素（hCG）或22 R-羟基胆固醇（22 R-OH）以及有或没有DBP/MBP的情况下培养24-48小时。对妊娠大鼠和新生雄性绒猴给予500 mg/kg/天DBP或MBP。在GD21.5前，大鼠在子宫内暴露于DBP（500 mg/kg/天）48小时，诱导睾丸内睾酮水平和细胞色素P450侧链裂解酶（P450 SCC）表达的主要抑制;该短期处理诱导LCA，但不如长期（GD13.5-20.5）DBP处理显著。在体外，MBP（10−3 M）不影响胎鼠睾丸外植体的基础或22 R-OH刺激的睾酮生成，但轻微减弱hCG刺激的类固醇生成; MBP在体外诱导轻微的LCA。在用10−3 M MBP培养48小时的人胎儿睾丸外植体中，这些参数均未受到影响。由于DBP/MBP的体内效应在大鼠体内无法在体外重现，因此MBP对人胎儿睾丸的体外效应不存在是不确定的。在新生（第2-7天）绒猴中，单次给予500 mg/kg MBP显著（p = 0.019）抑制了5小时后的血液睾酮水平。与双胞胎对照组相比，对新生双胞胎雄性绒猴进行14天的类似治疗导致每个睾丸的间质细胞体积增加（p = 0.011）;这与MBP诱导的类固醇生成抑制以及随后的代偿性间质细胞增生/肥大一致。这些研究结果表明，MBP/DBP抑制类固醇激素合成的胎儿型Leydig细胞在灵长类动物在啮齿类动物，但这不能在体外研究。
Certain phthalates can impair Leydig cell distribution and steroidogenesis in the fetal rat in utero, but it is unknown whether similar effects might occur in the human. Our aim in this study was to investigate the effects of di(n-butyl) phthalate (DBP), or its metabolite monobutyl phthalate (MBP), on testosterone production and Leydig cell aggregation (LCA) in fetal testis explants from the rat and human, and to compare the results with in vivo findings for DBP-exposed rats. We also wanted to determine if DBP/MBP affects testosterone production in vivo in the neonatal male marmoset. Fetal testis explants obtained from the rat [gestation day (GD)19.5] and from the human (15–19 weeks of gestation) were cultured for 24–48 hr with or without human chorionic gonadotropin (hCG) or 22R-hydroxycholesterol (22R-OH), and with or without DBP/MBP. Pregnant rats and neonatal male marmosets were dosed with 500 mg/kg/day DBP or MBP. Exposure of rats in utero to DBP (500 mg/kg/day) for 48 hr before GD21.5 induced major suppression of intratesticular testosterone levels and cytochrome P450 side chain cleavage enzyme (P450scc) expression; this short-term treatment induced LCA, but was less marked than longer term (GD13.5–20.5) DBP treatment. In vitro, MBP (10−3 M) did not affect basal or 22R-OH-stimulated testosterone production by fetal rat testis explants but slightly attenuated hCG-stimulated steroidogenesis; MBP induced minor LCA in vitro. None of these parameters were affected in human fetal testis explants cultured with 10−3 M MBP for up to 48 hr. Because the in vivo effects of DBP/MBP were not reproduced in vitro in the rat, the absence of MBP effects in vitro on fetal human testes is inconclusive. In newborn (Day 2–7) marmosets, administration of a single dose of 500 mg/kg MBP significantly (p = 0.019) suppressed blood testosterone levels 5 hr later. Similar treatment of newborn co-twin male marmosets for 14 days resulted in increased Leydig cell volume per testis (p = 0.011), compared with co-twin controls; this is consistent with MBP-induced inhibition of steroidogenesis followed by compensatory Leydig cell hyperplasia/hypertrophy. These findings suggest that MBP/DBP suppresses steroidogenesis by fetal-type Leydig cells in primates as in rodents, but this cannot be studied in vitro.