Adamsson A, Simanainen U, Viluksela M, Paranko J, Toppari J
Department of Physiology, University of Turku, Turku, Finland.
Int J Androl. 2009 Oct;32(5):575-85. doi: 10.1111/j.1365-2605.2008.00900.x. Epub 2008 Jul 9.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and widely investigated dioxin congener. In utero and lactational exposure to TCDD results in developmental and reproductive defects that are the most sensitive endpoints for TCDD toxicity. TCDD has a potential to interfere with steroid metabolism, but the mechanisms by which this occurs are not well understood. In this study, we investigated the effects of TCDD on prenatal rat steroidogenesis. Pregnant Sprague-Dawley female rats were treated once with TCDD (0, 0.3 or 1 microg/kg) by gavage on embryonic day (ED) 11 and the expression levels of androgen (AR) and estrogen receptors (ER), steroidogenic enzymes (P450scc and 3beta-HSD) and four regulatory factors (StAR, SF-1, GATA-4 and Insl-3) involved in foetal Leydig cell and adrenal function were analysed on ED 19.5. Hormonal status of male foetuses was determined by measuring testicular testosterone (T) levels, plasma luteinizing hormone (LH) and corticosterone concentrations. In utero exposure to TCDD reduced intratesticular T of foetal males (significant at 0.3 microg/kg TCDD) and tended to reduce the protein expression of ERalpha and AR of foetal male rat testis. Foetal male rat plasma LH levels were significantly reduced at the dose of 1 microg/kg TCDD, while corticosterone levels tended to be increased possibly because of the TCDD-induced stress. Only minor alterations in steroidogenesis were observed in rat adrenal. mRNA expression of developmental regulatory factors was not influenced by foetal TCDD exposure, except for significantly reduced adrenal SF-1. The results demonstrate that maternal exposure to TCDD suppressed testicular steroidogenesis of 19.5-day-old foetal male Sprague-Dawley rat. The highest dose of TCDD (1 microg/kg) had also an effect on pituitary LH secretion. Our data implicate that TCDD has direct testicular and pituitary effects on foetal male rat but with different dose-responses. These changes can lead to impaired steroidogenesis and it may result in the maldevelopment of the testis and weaken masculinization.
2,3,7,8-四氯二苯并-对-二恶英（TCDD）是毒性最强且研究最为广泛的二恶英同系物。孕期和哺乳期接触TCDD会导致发育和生殖缺陷，这是TCDD毒性最敏感的终点指标。TCDD有可能干扰类固醇代谢，但其发生机制尚不清楚。在本研究中，我们调查了TCDD对产前大鼠类固醇生成的影响。在胚胎期（ED）11，对怀孕的斯普拉格-道利雌性大鼠经口灌胃给予一次TCDD（0、0.3或1微克/千克），并在ED 19.5分析雄激素（AR）和雌激素受体（ER）、类固醇生成酶（P450scc和3β-HSD）以及参与胎儿睾丸间质细胞和肾上腺功能的四种调节因子（StAR、SF-1、GATA-4和Insl-3）的表达水平。通过测量睾丸睾酮（T）水平、血浆促黄体生成素（LH）和皮质酮浓度来确定雄性胎儿的激素状态。子宫内接触TCDD会降低雄性胎儿的睾丸内T（在0.3微克/千克TCDD时显著），并倾向于降低雄性胎儿大鼠睾丸中ERα和AR的蛋白表达。在1微克/千克TCDD剂量下，雄性胎儿大鼠血浆LH水平显著降低，而皮质酮水平可能由于TCDD诱导的应激而倾向于升高。在大鼠肾上腺中仅观察到类固醇生成的轻微改变。除肾上腺SF-1显著降低外，发育调节因子的mRNA表达不受胎儿TCDD暴露的影响。结果表明，母体接触TCDD会抑制19.5日龄雄性胎儿斯普拉格-道利大鼠的睾丸类固醇生成。TCDD的最高剂量（1微克/千克）也对垂体LH分泌有影响。我们的数据表明，TCDD对雄性胎儿大鼠的睾丸和垂体有直接作用，但具有不同的剂量反应。这些变化会导致类固醇生成受损，可能导致睾丸发育不良并削弱雄性化。
