Ter Veld Marcel G R, Zawadzka E, van den Berg J H J, van der Saag Paul T, Rietjens Ivonne M C M, Murk Albertinka J
Wageningen University, Postbox 8000, 6700 EA, Wageningen, The Netherlands.
Chem Biol Interact. 2008 Jul 30;174(2):126-33. doi: 10.1016/j.cbi.2008.03.019. Epub 2008 Apr 10.
The present paper aims at clarifying to what extent seven food-associated compounds, shown before to be estrogenic in vitro, can induce estrogenic effects in male mice with an estrogen receptor (ER)-mediated luciferase (luc) reporter gene system. The luc induction was determined in different tissues 8h after dosing the ER-luc male mice intraperitoneally (IP) or 14h after oral dosing. Estradiol-propionate (EP) was used as a positive control at 0.3 and 1mg/kg bodyweight (bw), DMSO as solvent control. The food-associated estrogenic compounds tested at non-toxic doses were bisphenol A (BPA) and nonylphenol (NP) (both at 10 and 50mg/kgbw), dichlorodiphenyldichloroethylene (p,p'-DDE; at 5 and 25mg/kgbw), quercetin (at 1.66 and 16.6mg/kgbw), di-isoheptyl phthalate (DIHP), di-(2-ethylhexyl) phthalate (DEHP) and di-(2-ethylhexyl) adipate (DEHA) all at 30 and 100mg/kgbw. In general IP dosing resulted in higher luc inductions than oral dosing. EP induced luc activity in the liver in a statistically significant dose-related way with the highest induction of all compounds tested which was 20,000 times higher than the induction by the DMSO-control. NP, DDE, DEHA and DIHP did not induce luc activity in any of the tissues tested. BPA induced luc in the liver up to 420 times via both exposure routes. BPA, DEHP and quercetin induced luc activity in the liver after oral exposure. BPA (50mg/kgbw IP) also induced luc activity in the testis, kidneys and tibia. The current study reveals that biomarker-responses in ER-luc male mice occur after a single oral exposure to food-associated estrogenic model compounds at exposure levels 10 to 10(4) times higher than the established TDI's for some of these compounds. Given the facts that (i) the present study did not include chronic exposure and that (ii) simultaneous exposure to multiple estrogenic compounds may be a realistic exposure scenario, it remains to be seen whether this margin is sufficiently high.
本文旨在阐明七种先前已证明在体外具有雌激素活性的与食物相关的化合物，在具有雌激素受体（ER）介导的荧光素酶（luc）报告基因系统的雄性小鼠中能在多大程度上诱导雌激素效应。在给ER-luc雄性小鼠腹腔注射（IP）8小时后或口服给药14小时后，测定不同组织中的荧光素酶诱导情况。丙酸雌二醇（EP）以0.3和1mg/kg体重（bw）作为阳性对照，二甲基亚砜（DMSO）作为溶剂对照。以无毒剂量测试的与食物相关的雌激素化合物有双酚A（BPA）和壬基酚（NP）（均为10和50mg/kgbw）、二氯二苯二氯乙烯（p,p'-DDE；5和25mg/kgbw）、槲皮素（1.66和16.6mg/kgbw）、邻苯二甲酸二异庚酯（DIHP）、邻苯二甲酸二（2-乙基己基）酯（DEHP）和己二酸二（2-乙基己基）酯（DEHA），均为30和100mg/kgbw。一般来说，腹腔注射给药比口服给药导致更高的荧光素酶诱导。EP以统计学上显著的剂量相关方式诱导肝脏中的荧光素酶活性，是所有测试化合物中诱导作用最高的，比DMSO对照诱导作用高20,000倍。NP、DDE、DEHA和DIHP在任何测试组织中均未诱导荧光素酶活性。BPA通过两种暴露途径在肝脏中诱导荧光素酶活性高达420倍。口服暴露后，BPA、DEHP和槲皮素在肝脏中诱导荧光素酶活性。BPA（50mg/kgbw IP）还在睾丸、肾脏和胫骨中诱导荧光素酶活性。当前研究表明，在单次口服暴露于与食物相关的雌激素模型化合物后，ER-luc雄性小鼠中的生物标志物反应会发生，这些化合物的暴露水平比其中一些化合物已确定的每日耐受摄入量（TDI）高10至10⁴倍。鉴于（i）本研究未包括慢性暴露以及（ii）同时暴露于多种雌激素化合物可能是一种现实的暴露情况，这一安全边际是否足够高仍有待观察。
