Wang Xiu, Wang Yong, Song Qi, Wu Jianhui, Zhao Yan, Yao Shunheng, Sun Zuyue, Zhang Yunhui
Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, 200032.
National Evaluation Centre for the Toxicology of Fertility Regulating Drug, Department of Pharmacology and Toxicology, Shanghai Institute of Planned Parenthood Research, Shanghai, 200032, PR China; Key Laboratory of Reproduction Regulation of NPFPC, Shanghai, 200032, PR China; Reproductive and Developmental Research Institute of Fudan University, Shanghai, 200032, PR China.
Reprod Toxicol. 2017 Apr;69:60-67. doi: 10.1016/j.reprotox.2017.01.008. Epub 2017 Jan 20.
di(2-ethylhexyl) phthalate (DEHP) is one of the most commonly-used plasticizers and can exert estrogen-like effects and anti-androgen-like effects after entering the body. The critical windows for DEHP exposure are in utero and during lactation. There's substantial evidence that hormonally active environmental estrogen perturbations in early life are associated with prostate carcinogenesis susceptibility later in life. In order to explore the effects of in utero and lactational exposure to DEHP on the male offspring's susceptibility to prostate carcinogenesis, we established a rat model of developmental estrogenization: pregnant rats in three treatment groups were treated with DEHP at 0.01, 0.1 and 1mg/kg BW/day from GD7 to PND21, and the male pups in positive group were treated with EB at 25ug/pup on PND 1, 3, 5. In order to induce the prostate carcinogenesis, half of the male offspring were given implants packed with estradiol and testosterone, and the other half were given empty tubes on PND90. The prostate weight, concentration of PSA in serum and histopathological changes were measured in male offspring on PND196. Data was analyzed by one-way analysis of variance (ANOVA) and x using SPSS Statistics software. Results showed that in utero treatment of DEHP decreased the prostate weight, prostate/body weight ratio and increased PSA concentrations of male pups in a dose-dependent manner. Compared with non-T+E treatment groups, T+E treatment increased the prostate weight and ratio of prostate/body weight, as well as the concentration of PSA. The results of prostate carcinogenesis parameters including PIN scores/frequency and Gleason scores/frequency were consistent with PSA, which meant that in utero and lactational exposure of DEHP was a risk factor of prostate carcinogenesis, and the increased estrogen/testosterone (E/T) ratio in adult might exert synergistic effects in the process of prostate carcinogenesis formation.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是最常用的增塑剂之一，进入人体后可产生类雌激素效应和抗雄激素效应。DEHP暴露的关键窗口期是在子宫内和哺乳期。有大量证据表明，生命早期具有激素活性的环境雌激素干扰与生命后期前列腺癌发生易感性有关。为了探讨子宫内和哺乳期暴露于DEHP对雄性后代前列腺癌发生易感性的影响，我们建立了发育性雌激素化大鼠模型：三个治疗组的孕鼠在妊娠第7天至出生后第21天每天按0.01、0.1和1mg/kg体重给予DEHP，阳性组的雄性幼崽在出生后第1、3、5天每只给予25μg己烯雌酚（EB）。为了诱导前列腺癌发生，一半雄性后代在出生后第90天植入装有雌二醇和睾酮的植入物，另一半植入空管。在出生后第196天测量雄性后代的前列腺重量、血清中前列腺特异性抗原（PSA）浓度和组织病理学变化。使用SPSS统计软件通过单因素方差分析（ANOVA）和x对数据进行分析。结果表明，子宫内给予DEHP可使雄性幼崽的前列腺重量、前列腺/体重比降低，并使PSA浓度呈剂量依赖性增加。与未进行睾酮+雌二醇（T+E）治疗的组相比，T+E治疗增加了前列腺重量、前列腺/体重比以及PSA浓度。包括前列腺上皮内瘤变（PIN）评分/频率和Gleason评分/频率在内的前列腺癌发生参数结果与PSA一致，这意味着子宫内和哺乳期暴露于DEHP是前列腺癌发生的一个危险因素，成年后雌激素/睾酮（E/T）比值升高可能在前列腺癌发生形成过程中发挥协同作用。
