Dioxins and Male Pubertal Growth and Development

描述(申请人提供)：青春期是从青春期前状态到性成熟和成年生殖能力的身体、行为和荷尔蒙的动态转变。青春期提前的时间趋势已被报告，特别是女孩，男孩的数据有限。尽管女性青春期发病年龄的这种变化的危险因素尚未明确确定，但环境化学品以及过度营养和肥胖对生殖轴的影响都被认为是潜在的因素。在男孩中，关于青春期时间和进程的纵向队列研究有限，关于环境化学物质影响的研究很少。与男性青春期年龄变化有关的环境化学品包括氯代芳烃，这是一类剧毒的环境污染物，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。在实验室动物和有限的人类研究中，二恶英、呋喃、多氯联苯和铅被证明会改变青春期发育和生长，并影响成人睾丸功能。在这个相互竞争的延续申请中，我们建议前瞻性地将我们的499名俄罗斯男孩的随访延长到青春期和成年期。这些男孩居住在俄罗斯查帕夫斯克，这是一个工业城镇，记录了他们对二恶英、呋喃、多氯联苯和铅的高暴露。其具体目的是研究青春期血清中二恶英、呋喃、多氯联苯和铅的浓度与：1)男性青春期发育进程和达到性成熟年龄(通过睾丸体积和Tanner阶段测量)的关系；2)身体生长，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、管理信息系统、黄体生成素、卵泡刺激素、胰岛素样生长因子-1、胰岛素样生长因子-BP3、促甲状腺激素和游离T4)浓度的变化；4)改变成人睾丸功能，特别是精液质量和成熟睾丸功能的激素标志物和生殖轴(睾酮、抑制素-B、黄体生成素和卵泡刺激素)。这项拟议的研究具有创新性，因为它是为数不多的关于环境对男性青春期发育、生长和生殖功能的影响的大型前瞻性队列研究之一。青春期和发育时间的改变已被证明具有不利的公共卫生和临床影响。例如，青春期时间的改变对青春期的身体和性成熟、社交、认知和行为发育以及随后的成人肥胖和代谢紊乱的风险都有不利影响。此外，在男性青春期发育的敏感时期暴露于环境化学物质可能通过父系影响对生育力和下一代产生不利影响。因此，确定接触二恶英、呋喃、多氯联苯和铅等潜在可补救的风险因素，对于增进我们对环境对儿童健康的影响的了解，以及保护儿童健康和后代至关重要。

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.