Hormonal Indicators of Pubertal Onset & Their Relationship to Blood Lead Levels

以前关于青春期提前开始的研究集中在特定的亚群或临床人群，缺乏具有全国代表性的样本中关于青春期开始模式的数据，即在6至8岁的儿童中。此外，有证据表明，暴露于环境毒素，如环境铅和内分泌干扰物，可能会对激素水平和青春期开始产生不利影响。然而，关于环境毒物如何以及是否可能导致青春期开始下降或延迟的数据很少，通常仅限于年龄较大的儿童和青少年。 这些分析的目标样本是6-11岁的儿童，作为第三次全国健康和营养检查调查(NHANES III，1988-94)的一部分进行了检查。这些针对儿童的残留生物标本(血清)的分析有两个目的：(1)通过激素(男孩和女孩的黄体生成素和抑制素B，男孩的睾酮)的测定，估计6-11岁的具有全国代表性的儿童样本的青春期发育开始的时间，以及8-11岁儿童的激素指标和青春期开始之间的模式和一致性(Tanner性成熟评分)；以及(2)确定最近基于Tanner评分(阴毛)和月经初潮年龄的女孩的血铅水平与成熟延迟之间的联系的研究结果是否可以通过激素分析得到证实，并推广到更年轻的年龄，并确定对于年轻男孩来说，血铅水平是否对成熟时间有影响。NHANES III已经对接受检查的儿童进行了全血铅和尿镉(Cd)的分析。值得注意的是，NHANES III中6-11岁的儿童出生在1977-1988年，在1988年的铅污染控制法案几乎消除汽油中的铅之前，所以NHANES的后续迭代不太可能在回答环境铅暴露与青春期时间之间的关系的问题上同样有用。 重要的初步发现：在774名男孩的样本中，我们发现抑制素B水平随着年龄、生殖器和阴毛阶段的增加而显著增加(p&lt；0.0001)，从第一阶段到第二阶段，从第二阶段到第三阶段或更高阶段。在所有年龄段的非西班牙裔白人(NHW)、非西班牙裔黑人(NHB)和墨西哥裔美国人(MA)男孩中，抑制素B的水平总体上明显高于非西班牙裔白人(NHW)、非西班牙裔黑人(NHB)和墨西哥裔美国(MA)男孩(p&lt；0.01)。在Tanner生殖器阶段1男孩中，种族/民族的影响显著(p=0.02)，其中NHB水平最高，但年龄的影响不显著。相反，在Tanner分期为2或更高的患者中，种族/民族没有显著影响，但年龄有显著影响(p=0.01)。这与睾酮形成对比，睾酮浓度随着年龄和阴毛阶段的增加而显著增加，尽管不是在生殖器阶段，而且在任何年龄都没有统计上显著的种族/民族差异。抑制素B和睾酮在Tanner阶段1和2之间也有相当大的重叠，因此没有明显区分青春期状态开始的临界值，因为个体间差异很大。这些结果代表了第一个具有全国代表性的青春期前和青春期美国男孩样本的荷尔蒙测量。我们观察到，在NHANES III NHB男孩中，抑制素B浓度存在显著的种族/民族差异，这与NHANES III NHB男孩从Tanner生殖器阶段1到2的早期转变平行，尽管NHB男孩在这些年龄段普遍更高的水平的临床意义尚不清楚。 对于女孩来说，铅(PB)是一种已知的生殖毒物，被认为在整个敏感的发育阶段，如青春期，都会扰乱激素的产生。近几十年来，铅暴露水平有所下降，但年轻女孩体内的铅浓度即使低于有毒水平(现在定义为10微克/分升)，仍可能产生不利影响。我们调查了667名6-11岁女孩的血铅和抑制素B之间的关系。用调查线性回归估计持续铅(LOG)和抑制素B水平之间的关系，并用Logistic回归分析暴露类别(&lt；1，1-4.9，=&gt；5ug/dL)。非西班牙裔黑人女孩的铅浓度最高(p&lt；0.0001)(3.1ug/dL)，而墨西哥裔美国女孩(2.2ug/dL)和非西班牙裔白人女孩(1.8ug/dL)的铅浓度最高。在线性模型中，铅与抑制素B显著负相关，调整了种族/民族(β=-0.17log(pg/m L)/log(pg/m l)/log(pg/m l)，SE=0.08，p=0.03)。我们还发现铅和尿镉在降低抑制素B方面存在显著的交互作用(p=0.04)。因此，在年轻女孩中，血铅水平越高，抑制素B的降低和青春期开始的时间越晚。这些发现与NHANES III之前的研究一致，该研究显示，年龄较大的女孩达到性成熟阶段和月经初潮年龄较晚，并表明其机制可能是通过下丘脑-垂体-卵巢轴的全身性破坏，或者更局部地通过对卵巢发育的直接负面影响。

Previous research on the early onset of puberty has focused on specific subpopulations or clinical populations, and data on the patterns of pubertal onset, that is, in children as young as ages 6 to 8 years, in a nationally representative sample are lacking. Further, evidence suggests that exposure to environmental toxins, such as environmental lead (Pb) and endocrine disrupters, may adversely affect hormone levels and pubertal onset. However, data on how and whether environmental toxicants may be implicated in the decline or contribute to a delay in pubertal onset are scarce and have generally been confined to older children and adolescents. The target sample for these analyses is children, ages 6-11 years, examined as part of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-94). There are two objectives of these analyses of residual stored biologic specimens (serum) for children: (1) to estimate by assay of hormones (luteinizing hormone LH and inhibin B for boys and girls, testosterone for boys) the timing of the onset of pubertal development in a nationally representative sample of children, ages 6-11 years, and the patterns and concordance between hormonal indicators and pubertal onset based on physical maturation (Tanner sexual maturation scores) for children, ages 8-11 years; and (2) to determine if the recent findings linking blood lead (Pb) levels and delayed maturation based on Tanner scores (pubic hair) and age at menarche in girls can be confirmed by hormonal analysis and extended to younger ages and to determine for young boys if there are effects of blood Pb levels on timing of maturation. Whole blood Pb and, in addition, urinary cadmium (Cd) have already been analyzed for examined children in NHANES III. It is important to note that the 6-11 year old children in NHANES III were born in the years 1977-1988, before the Lead Contamination Control Act of 1988 virtually eliminated Pb in gasoline, so it is unlikely that later iterations of NHANES will be as useful in answering the question about the relationship between environmental Pb exposure and timing of puberty. Significant preliminary findings: For the sample of 774 boys, we found that inhibin B levels increased significantly with increasing age, genital and pubic hair stage (p<0.0001), with progressive increases from stages 1 to 2, and from 2 to 3 or greater. When compared across all ages for non-Hispanic White (NHW), non-Hispanic Black (NHB), and Mexican-American (MA) boys, levels of inhibin B were significantly higher overall in NHB (p<0.01). Among Tanner genital stage 1 boys, there was a significant effect of race/ethnicity (p=0.02) with NHB having the highest levels, but no significant effect of age. Conversely, among those with Tanner stage 2 or greater, there was no significant effect of race/ethnicity, but there was a significant effect of age (p=0.01). This is in contrast with testosterone, where concentrations increased significantly with both age and pubic hair stage, although not for genital stage, and there were no statistically significant racial/ethnic differences at any age. There was also considerable overlap in both inhibin B and testosterone between Tanner stages 1 and 2, and thus no cut-off level that clearly discriminates the onset of pubertal status because of the high inter-individual variation. These results represent hormone measurements in the first nationally-representative sample of pre-pubertal and pubertal U.S. boys. We observed significant racial/ethnic differences in inhibin B concentrations that parallel the earlier transition from Tanner genital stage 1 to 2 in NHANES III NHB boys, although the clinical significance of the generally higher levels in NHB boys at these ages is unclear. For girls, lead (PB) is a known reproductive toxicant thought to disrupt hormone production throughout sensitive developmental windows, such as puberrty. Lead exposure levels have decreased in recent decades, but concentrations even below toxic levels (defined now as 10 ug/dL) in young girls may still have adverse effects. We examined the association between blood Pb and inhibin B, in 667 6- to 11-year-old girls. Survey linear regression was used to estimate the association between continuous lead (log) and inhibin B levels and logistic regression for exposure categories (< 1, 1-4.9, =>5 ug/dL). Non-Hispanic black (NHB) girls had the highest (p<0.0001) lead concentrations (3.1 ug/dL), compared with Mexican-American (2.2 ug/dL) and non-Hispanic white girls (1.8 ug/dL). In linear models, Pb was significantly inversely associated with inhibin B, adjusting for race/ethnicity (beta = -0.17 log(pg/mL) per unit change in log(Pb), SE=0.08, p=0.03). We also found a significant interaction (p=0.04) between Pb and urinary cadmium in decreasing inhibin B. Thus, higher blood Pb levels were associated with decreased inhibin B and later achievement of the onset of puberty in young girls. These findings are consistent with prior research with NHANES III showing a later attainment of sexual maturation stages and age at menarche in older girls and suggest that the mechanism may be through systemic disruptions in the hypothalamic-pituitary-ovarian axis or more locally through a direct negative effect on ovarian development.