Developmental Neurotoxicity of Phthalate Esters

描述（由申请人提供）：该R21提案基于以下假设：产前暴露于邻苯二甲酸酯将改变正常的大脑发育和相关的行为结果。邻苯二甲酸酯是化妆品、家居用品、医疗器械、玩具和许多其他产品中普遍存在的环境污染物。人类接触是普遍的。最近的人类数据显示，妊娠期间母体尿液中邻苯二甲酸酯代谢物水平与男性儿童肛门生殖器距离缩短之间存在显著关系，这引起了人们对邻苯二甲酸酯可能对神经行为发育构成重大威胁的担忧。在大鼠中，妊娠期间暴露于某些邻苯二甲酸酯会诱导雄性后代生殖道畸形以及女性化的标志，如肛门生殖器距离缩短。这种综合征意味着雄激素介导的发育障碍，可归因于胎儿睾丸产生睾酮的减少。由于睾丸激素控制着大脑的性别分化，因此胎儿输出量的减少预计会导致大脑解剖结构的去男性化及其在行为中的表达。为了检验这一假设，妊娠大鼠将在妊娠第12-20天期间给予选定的邻苯二甲酸酯（邻苯二甲酸二乙基己酯或DEHP和邻苯二甲酸二丁酯或DBP）或两者的组合，这包括雄性胎儿的睾酮激增。雄性和雌性后代都将进行行为和形态学评估，重点是被认为是性二态的行为和结构。行为测量包括游戏行为、探索行为、糖精偏好、性伴侣偏好和时间表控制的操作行为。形态学评估是基于视前区性二形核（SDN-POA）的体积。这项研究解决了人类数据中出现的一个紧迫问题。这将使我们能够使用大鼠作为胎儿发育过程中人体邻苯二甲酸酯暴露的实验室模型，仔细控制暴露剂量和时间，并通过实验室调查来放大和扩展流行病学研究结果。邻苯二甲酸酯是用作个人护理用品中增塑剂的化学品，如洗发水，医用管，塑料玩具，食品包装和许多其他产品。它们在动物模型中损害男性生殖系统发育，最近的研究表明在人类中也有类似的影响。由于邻苯二甲酸酯作为抗雄激素，它们有可能干扰人类大脑和行为发育。这项拟议中的研究将在老鼠身上研究这个问题，并将其意义转化为人类的相关性。

DESCRIPTION (provided by applicant): This R21 proposal is based on the hypothesis that prenatal exposure to phthalate esters will alter normal brain development and associated behavioral outcomes. Phthalates are ubiquitous environmental contaminants found in cosmetics, household furnishings, medical devices, toys, and numerous other products. Human exposures are universal. Recent human data, showing a significant relationship between levels of phthalate metabolites in maternal urine during pregnancy and shortened anogenital distance in male children, provoke concerns that phthalates may pose significant threats to neurobehavioral development. In rats, exposure during gestation to certain phthalates induces malformations in the reproductive tract of male offspring as well as markers of feminization such as shortened anogenital distance. This syndrome signifies a disturbance in androgen-mediated development attributable to a decrease in fetal testicular production of testosterone. Because testosterone governs sexual differentiation of the brain, reductions in fetal output would be expected to engender demasculinization of brain anatomy and its expression in behavior. To test this hypothesis, pregnant rats will be administered selected phthalate esters (diethylhexyl phthalate, or DEHP, and dibutyl phthalate, or DBP), or a combination of the two, during gestational days 12-20, which encompass the testosterone surge in fetal males. Both male and female offspring will be evaluated behaviorally and morphologically, with an emphasis on behaviors and structures recognized as sexually dimorphic. Behavioral measures include play behavior, exploratory behavior, saccharin preference, sex partner preference, and schedule-controlled operant behavior. Morphological assessments are based on the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA). This research addresses an urgent question arising from the human data. It will enable us to use the rat as a laboratory model for human phthalate exposures during fetal development, to carefully control exposure dose and timing, and to to amplify and extend the epidemiological findings by subjecting certain of their implications to laboratory investigation. Phthalate esters are chemicals used as plasticizers in personal care items such as shampoos, medical tubing, plastic toys, food packaging, and many other products. They impair male reproductive system development in animal models, and recent studies show similar effects in humans. Because phthalates act as anti-androgens, they have the potential to interfere with human brain and behavioral development. The proposed research will examine this question in rats, and translate its implications into human relevance.