Effects of Environmental Phthalates and Chemical Mixtures on Male Puberty and Semen Quality

摘要 从青春期前到性成熟的青春期过渡需要动态的身体、行为和 荷尔蒙的变化。尽管研究报告了女孩青春期提前的时间趋势， 关于青春期开始的时间趋势，男孩的数据有限。更重要的是，缺乏 环境化学物质对男性青春期影响的纵向研究。邻苯二甲酸酯是一类 存在科学和监管方面对其对男性潜在影响的关注的化学品 青春期发育和睾丸功能。这一担忧是基于在 表现出一些邻苯二甲酸酯是抗雄激素的，并且是雄性发育和生殖的啮齿动物 毒物，导致青春期延迟，降低血清睾酮浓度，并损害 精液质量。根据实验数据和有记录的人类广泛接触 邻苯二甲酸盐，在这一竞争更新中，我们建议研究邻苯二甲酸盐(个人)的影响 邻苯二甲酸盐及其混合物)对男性青春期发育、生殖激素和精液质量的影响。 我们将利用我们独特的、定义明确的纵向队列研究，对499名俄罗斯男孩进行跟踪调查 入学年龄为8岁至21岁。我们在队列的一小部分上的试点数据显示尿量高 多种抗雄激素邻苯二甲酸酯代谢物的浓度。在竞争性更新中，我们将衡量 年收集的存档尿样中邻苯二甲酸酯代谢物的尿液浓度 多年的跟踪调查。为了评估在三个敏感窗口期间邻苯二甲酸盐暴露的影响，我们将汇集 每个男孩每年的尿样如下：1)青春期前窗口(汇集每年收集的所有样本 就诊时间：睾丸体积<lt；4毫升)，2)青春期早期至青春期中期窗口(收集所有样本 睾丸体积在4毫升至15毫升以下时的年度就诊)，以及3)青春期晚期窗口(池均为 当睾丸体积为15毫升或更大时，每年访问时收集的样本)。我们的研究将是 首次对男孩进行前瞻性队列研究，评估邻苯二甲酸盐暴露对三种敏感症的影响 关注青春期和精液质量的窗口。我们也有独一无二的机会来调查 接触邻苯二甲酸盐和环境化学品/金属的真实混合物(有机氯，包括 二恶英、呋喃、多氯联苯、杀虫剂和铅)在青春期和 精液质量。改变青春期的时间和进度是一个重要的公共卫生问题，因为它们 可能会对成长、社会功能、认知和行为发展以及成人产生不利影响 代谢和生殖健康。此外，糟糕的精液质量会增加不育的风险。在……里面 结论：阐明流行的环境化学物质与不良男性的关系 生殖发育可能揭示潜在的可改变的危险因素(例如，减少邻苯二甲酸盐 在消费产品中使用)。

ABSTRACT The pubertal transition from pre-puberty to sexual maturity entails dynamic physical, behavioral, and hormonal changes. Although studies report temporal trends towards an earlier onset of puberty in girls, there are limited data in boys on temporal trends of pubertal onset. Moreover, there is a dearth of longitudinal studies on the impact of environmental chemicals on male puberty. Phthalates are one class of chemicals for which there is scientific and regulatory concern regarding their potential effects on male pubertal development and testicular function. This concern is based upon numerous experimental studies in rodents showing that some phthalates are anti-androgenic and are male developmental and reproductive toxicants, causing delayed pubertal onset, decreased serum testosterone concentrations and impaired semen quality. Based on the experimental data and the documented widespread human exposure to phthalates, in this competing renewal we propose to investigate the effect of phthalates (individual phthalates and their mixtures) on male pubertal development, reproductive hormones and semen quality. We will leverage our unique well-defined longitudinal cohort study of 499 Russian boys followed from enrollment at age 8 until 21 years. Our pilot data on a small subset of the cohort shows high urinary concentrations of multiple anti-androgenic phthalate metabolites. In the competing renewal, we will measure urinary concentrations of phthalate metabolites in archived urine samples collected annually during twelve years of follow-up. To evaluate the effect of phthalate exposure during three sensitive windows, we will pool annual urine samples for each boy as follows: 1) pre-pubertal window (pool all samples collected at annual visits when testicular volume <4 ml), 2) early through mid-pubertal window (pool all samples collected at annual visits when testicular volume is between 4 and less than 15 ml), and 3) late-pubertal window (pool all samples collected at annual visits when testicular volume is 15 ml or greater). Our study will be one of the first prospective cohort studies in boys that will assess the effect of phthalate exposure at three sensitive windows on puberty and semen quality. We also have the unique opportunity to investigate the effect of exposure to real-life mixtures of phthalates and environmental chemicals/metals (organochlorines, including dioxins, furans, PCBs, pesticides and lead were measured in our current funding period) on puberty and semen quality. Altered timing and progression of puberty are an important public health issue because they may have adverse effects on growth, social functioning, cognitive and behavioral development, and adult metabolic and reproductive health. Furthermore, poor semen quality increases risk of infertility. In conclusion, elucidating the association of prevalent environmental chemicals with adverse male reproductive development may reveal potentially modifiable risk factors (for example, reducing phthalate use in consumer products).