In utero exposure to benzophenone-2 causes hypospadias through an estrogen receptor dependent mechanism
In utero exposure to benzophenone-2 causes hypospadias through an estrogen receptor dependent mechanism
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DOI：
10.1016/j.juro.2007.03.190
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发表时间：
2007-10-01
影响因子：
6.6
通讯作者：
Baskin, Laurence S.
中科院分区：
文献类型：
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作者：
Hsieh, Michael H.;Grantham, Erin C.;Baskin, Laurence S.
用途：二苯甲酮-2等添加剂通常用于化妆品和食品容器塑料中，以过滤紫外线。在孕妇中，接触可能导致二苯甲酮-2经胎盘转移至胎儿。二苯甲酮-2在体外和大鼠促子宫试验中具有雌激素样作用。雌激素会导致小鼠尿道下裂，雌激素样化合物也被认为会导致尿道下裂。我们确定是否会发展尿道下裂暴露于二苯甲酮-2在子宫内的雄性小鼠，这种结果是否依赖于雌激素受体pathways.Materials and Methods：定时怀孕C57 BL/6小鼠给药二苯甲酮-2（6.25毫克）或控制车辆通过口服管饲法从妊娠第12天至17日，他们在第18天被处死。胎儿进行称重和性别，肛门生殖器的距离进行测量和生殖器结节被收获的石蜡切片或定量逆转录-聚合酶链反应分析的基因据称参与生殖器结节development.Results：8的57个二苯甲酮-2治疗的男性胎儿（14%），其生殖器结节进行了组织学检查尿道下裂（p = 0.0064）。二苯甲酮-2与雌激素受体拮抗剂EM-800共同给药导致26只小鼠生殖器结节正常，即没有尿道下裂。同样，EM-800或对照治疗的男性生殖器结节均未显示尿道下裂。相对于对照组，二苯甲酮-2给药雄性小鼠的体重调整肛门生殖器距离无变化。逆转录-聚合酶链反应显示，生殖结节的二苯甲酮-2治疗的雄性小鼠表达较高水平的雌激素受体β相对于雄性controls.Conclusions（p = 0.04）：这些研究结果表明，二苯甲酮-2可能会导致尿道下裂通过信号通过雌激素受体。需要进一步研究人类二苯甲酮-2暴露及其影响来支持这一假设。
Purpose: Additives such as benzophenone-2 are commonly used in cosmetic products and food container plastics to filter out ultraviolet light. In pregnant women exposure may result in transplacental transfer of benzophenone-2 to fetuses. Benzophenone-2 is estrogenic in vitro and in the rat uterotropic assay. Estradiol causes hypospadias in mice and estrogen-like compounds are also postulated to cause hypospadias. We determined whether hypospadias would develop in male mice exposed to benzophenone-2 in utero and whether this outcome depended on estrogen receptor pathways.Materials and Methods: Timed pregnant C57BL/6 mice were administered benzophenone-2 (6.25 mg) or control vehicle by oral gavage from gestational days 12 through 17 and they were sacrificed on day 18. Fetuses were weighed and sexed, anogenital distance was measured and genital tubercles were harvested for paraffin sections or quantitative reverse transcriptase-polymerase chain reaction analysis of genes purportedly involved in genital tubercle development.Results: Eight of 57 benzophenone-2 treated male fetuses (14%) whose genital tubercles were examined histologically had hypospadias (p = 0.0064). Co-administration of benzophenone-2 with the estrogen receptor antagonist EM-800 resulted in normal genital tubercles, ie no hypospadias, in 26 of 26 mice. Likewise no EM-800 or control treated male genital tubercles showed hypospadias. Benzophenone-2 treated male mice had no changes in body mass adjusted anogenital distance relative to controls. Reverse transcriptase-polymerase chain reaction revealed that genital tubercles of benzophenone-2 treated male mice expressed higher levels of estrogen receptor-beta relative to male controls (p = 0.04).Conclusions: These findings suggest that benzophenone-2 may cause hypospadias via signaling through the estrogen receptor. Further study of human benzophenone-2 exposure and its effects is needed to support this hypothesis.