Stoker Tammy E, Laws Susan C, Crofton Kevin M, Hedge Joan M, Ferrell Janet M, Cooper Ralph L
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2004 Mar;78(1):144-55. doi: 10.1093/toxsci/kfh029.
DE-71, a commercial mixture, was used to test the sensitivity of the female and male pubertal protocol to detect thyroid active chemicals. These protocols are being evaluated for the U.S. EPA's Endocrine Disruptor Screening Program as part of a Tier I Screening Battery. To examine the ability of these protocols to screen for chemicals that induce the clearance of thyroid hormone, we examined male and female Wistar rats following DE-71 exposure. Rats were gavaged daily with 0, 3, 30, or 60 mg/kg DE in corn oil from postnatal day (PND) 23-53 in the male or PND 22-41 in the female. The temporal effects of DE-71 on liver enzymes and thyroid hormones were measured in another group of males and females following only 5 days of dosing (PND 21 to 26 in females and PND 23 to 28 in males). Serum T4 was significantly decreased at 30 and 60 mg/kg following the 5-day exposures and in the 21-day exposed females. Doses of 3, 30, and 60 mg/kg decreased T4 in 31-day exposed males. Serum T3 was decreased and TSH elevated by 30 and 60 mg/kg in the 31-day exposed males only. Decreased colloid area and increased follicular cell heights (indicative of the hypothyroid state) were observed in thyroids of the 60 mg/kg groups of 20- and 31-day exposed female and males. Increased liver-to-body weight ratios coincided with a significant induction of uridinediphosphate-glucuronosyltransferase (UDGPT; two to four-fold), and ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD) at the two highest doses in all exposures. Of the androgen dependent tissues in the 31-day exposed males, seminal vesicle (SV) and ventral prostate (VP) weights were reduced at 60 mg/kg, while testes and epididymal weights were not affected. Preputial separation (PPS) was also significantly delayed by doses of 30 and 60 mg/kg. In the female, the 60 mg/kg dose also caused a significant delay in the age of vaginal opening. Based upon the thyroid hormone response data, this study provides evidence that the 31-day alternative Tier 1 male protocol is a more sensitive test protocol than the 5-day or female pubertal protocol for thyrotoxic agents that act via up-regulation of hepatic metabolism. This apparent greater sensitivity may be due a greater body burden attained following the longer dosing regimen as compared with that of the female protocol, or to gender specific differences in thyroid hormone metabolism. Also, the delay in PPS and reduction in SV and VP weights may indicate a modification or inhibition of endogenous androgenic stimulation directly by DE-71 or a secondary effect that occurs in response to a DE-induced change in thyroid hormones.
商用混合物DE - 71用于测试雌性和雄性青春期实验方案检测甲状腺活性化学物质的敏感性。这些实验方案正在作为美国环保署内分泌干扰物筛查计划一级筛查组合的一部分进行评估。为了检验这些实验方案筛查诱导甲状腺激素清除的化学物质的能力，我们在DE - 71暴露后对雄性和雌性Wistar大鼠进行了检测。从出生后第23天至53天（雄性）或第22天至41天（雌性），大鼠每天经口灌胃给予0、3、30或60 mg/kg溶解于玉米油中的DE。在另一组仅给药5天的雄性和雌性大鼠中（雌性为出生后第21天至26天，雄性为出生后第23天至28天），测定DE - 71对肝酶和甲状腺激素的时间效应。5天暴露后，30和60 mg/kg剂量组以及暴露21天的雌性大鼠血清T4显著降低。3、30和60 mg/kg剂量使暴露31天的雄性大鼠T4降低。仅在暴露31天的雄性大鼠中，30和60 mg/kg剂量使血清T3降低，TSH升高。在暴露60 mg/kg剂量的20天和31天的雌性和雄性大鼠甲状腺中，观察到胶体面积减小和滤泡细胞高度增加（提示甲状腺功能减退状态）。在所有暴露组中，肝脏与体重比增加与尿苷二磷酸葡萄糖醛酸转移酶（UDGPT；增加2至4倍）以及乙氧基和戊氧基间苯二酚 - O - 脱乙基酶（EROD和PROD）在两个最高剂量下的显著诱导同时出现。在暴露31天的雄性大鼠的雄激素依赖组织中，60 mg/kg剂量使精囊（SV）和腹侧前列腺（VP）重量降低，而睾丸和附睾重量未受影响。30和60 mg/kg剂量也显著延迟了包皮分离（PPS）。在雌性大鼠中，60 mg/kg剂量也导致阴道开口年龄显著延迟。基于甲状腺激素反应数据，本研究提供了证据表明，对于通过上调肝脏代谢起作用的甲状腺毒性剂，31天替代一级雄性实验方案比5天或雌性青春期实验方案更敏感。这种明显更高的敏感性可能是由于与雌性实验方案相比，更长给药方案后达到的更高体内负荷，或者是由于甲状腺激素代谢的性别特异性差异。此外，PPS延迟以及SV和VP重量降低可能表明DE - 71直接对内源性雄激素刺激的改变或抑制，或者是对DE诱导的甲状腺激素变化产生的继发效应。
