Developmental Neurotoxicity of Phthalate Esters

描述（由申请人提供）：本R21提案基于产前接触邻苯二甲酸酯会改变正常大脑发育和相关行为结果的假设。邻苯二甲酸盐是无处不在的环境污染物，存在于化妆品、家居家具、医疗设备、玩具和许多其他产品中。人类接触是普遍存在的。最近的人类数据显示，怀孕期间母亲尿液中邻苯二甲酸酯代谢物水平与男孩肛门生殖器距离缩短之间存在显著关系，这引发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，在怀孕期间暴露于某些邻苯二甲酸盐会导致雄性后代的生殖道畸形以及雌性化的标志，如肛门生殖器距离缩短。这种综合征表明雄激素介导的发育障碍可归因于胎儿睾丸睾酮分泌减少。由于睾酮控制着大脑的性别分化，胎儿产出的减少可能会导致大脑解剖结构及其行为表现的男性化。为了验证这一假设，怀孕的大鼠将在妊娠期12-20天内被给予选择的邻苯二甲酸酯（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，这包含了胎儿雄性睾酮的激增。雄性和雌性后代将在行为和形态上进行评估，重点是被认为是两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（SDN-POA）两性二态核的体积。本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期间人类邻苯二甲酸盐暴露的实验室模型，仔细控制暴露剂量和时间，并通过将其某些影响纳入实验室调查来扩大和扩展流行病学发现。邻苯二甲酸酯是一种用作个人护理用品增塑剂的化学物质，如洗发水、医用软管、塑料玩具、食品包装和许多其他产品。在动物模型中，它们会损害男性生殖系统的发育，最近的研究表明，它们对人类也有类似的影响。因为邻苯二甲酸盐具有抗雄激素的作用，它们有可能干扰人类的大脑和行为发育。拟议的研究将在大鼠身上检验这个问题，并将其含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.