Dioxins and Male Pubertal Growth and Development

描述（由申请人提供）：青春期是指从青春期前状态到性成熟和成年生殖能力的生理、行为和激素的动态转变。据报道，特别是女孩的青春期出现提前的时间趋势，而男孩的数据有限。虽然还没有明确确定女性青春期开始年龄变化的风险因素，但环境化学物质的影响以及营养过剩和肥胖对生殖轴的影响都被认为是潜在因素。在男孩中，关于青春期的时间和进展的纵向队列研究有限，关于环境化学品影响的研究很少。对改变男性青春期开始和发展的年龄特别令人关注的环境化学品包括氯代芳香烃，这是一类高毒性环境污染物，包括多氯二苯并-对二恶英、多氯二苯并呋喃和多氯联苯，以及重金属，特别是铅。在实验动物和有限的人体研究中，二恶英、呋喃、多氯联苯和铅被证明会改变青春期的发育和生长，并影响成人睾丸功能。在这个竞争性的延续应用中，我们建议前瞻性地延长我们的499名俄罗斯男孩队列从青春期到成年期的随访。这些男孩住在俄罗斯的查帕耶夫斯克，这是一个工业城镇，有记录显示，那里的二恶英、呋喃、多氯联苯和铅含量很高。具体目的是研究青春期前后血清二恶英、呋喃、多氯联苯和铅的浓度与以下因素的关系：1)男性青春期发育进程和性成熟年龄（以睾丸体积和Tanner分期衡量）；2)躯体生长，特别是身高、身高速度、体重增加和BMI；3)调节身体生长和青春期发育的激素（睾酮、抑制素-B、MIS、LH、FSH、IGF-1、IGF-BP3、TSH和游离T4）的血清浓度改变；4)改变成年睾丸功能，特别是精液质量和成熟睾丸功能和生殖轴的激素标志物（睾酮，抑制素- b， LH和FSH）。这项研究具有创新性，因为它是为数不多的关于环境对男性青春期发育、生长和生殖功能影响的大型前瞻性队列研究之一。青春期和生长时间的改变已被证明具有不利的公共卫生和临床意义。例如，青春期时间的改变会对身体和性成熟、青春期的社会、认知和行为发展产生不利影响，并可能导致成人肥胖和代谢紊乱。此外，在男性青春期发育的敏感窗口期，暴露于环境化学物质可能会通过父亲介导的效应对生育能力和下一代产生不利影响。因此，确定潜在可补救的风险因素，如接触二恶英、呋喃、多氯联苯和铅，对于增进我们对环境对儿童健康影响的理解和保护儿童健康及其后代至关重要。

DESCRIPTION (provided by applicant): Puberty is the dynamic physical, behavioral, and hormonal transition from the pre-pubertal state to sexual maturity and adult reproductive capacity. Temporal trends towards an earlier onset of puberty have been reported particularly for girls with limited data available for boys. Although risk factors have not been clearly identified for this reported change in the age of female pubertal onset, the effects of environmental chemicals and that of over nutrition and obesity on the reproductive axis have both been implicated as potential factors. In boys, there are limited longitudinal cohort studies on the timing and progression of puberty and few studies on the impact of environmental chemicals. Environmental chemicals of particular concern for altered age of onset and progression of male puberty include chlorinated aromatic hydrocarbons, a family of highly toxic environmental contaminants that includes polychlorinated dibenzo-p- dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls (PCBs), and heavy metals, specifically lead. In laboratory animals and limited human studies, dioxins, furans, PCBs and lead were shown to alter pubertal development and growth and affect adult testicular function. In this competing continuation application, we propose to prospectively extend follow-up of our cohort of 499 Russian boys through puberty and into adulthood. The boys reside in Chapaevsk, Russia, an industrial town that has documented high exposure to dioxins, furans, PCBs and lead. The specific aims are to investigate the relationship of peri-pubertal serum concentrations of dioxins, furans, PCBs and lead with: 1) progression of male pubertal development and age at attainment of sexual maturation (measured by testicular volume and Tanner stages); 2) somatic growth, specifically height, height velocity, weight gain, and BMI; 3) altered serum concentrations of hormones that regulate somatic growth and pubertal development (testosterone, inhibin- B, MIS, LH, FSH, IGF-1, IGF-BP3, TSH and free T4); 4) altered adult testis function, specifically semen quality and hormonal markers of mature testis function and the reproductive axis (testosterone, inhibin-B, LH and FSH). The proposed study is innovative because it represents one of the few large prospective cohort studies on the impact of the environment on male pubertal development, growth and reproductive function. Alterations in the timing of puberty and in growth have been shown to have adverse public health and clinical implications. For instance, altered pubertal timing adversely impacts physical and sexual maturation, social, cognitive and behavioral development in adolescence, and subsequent risk of adult obesity and metabolic disorders. Furthermore, exposure to environmental chemicals during the sensitive window of male pubertal development may adversely impact fertility and the next generation through paternally mediated effects. Therefore, the identification of potentially remediable risk factors such as exposure to dioxins, furans, PCBs and lead, is critical to both advancing our understanding of the impact of the environment on child health and protecting both child health and subsequent generations.