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

以前关于青春期提前的研究集中在特定的亚群或临床人群，缺乏关于青春期提前模式的数据，即在6至8岁的儿童中，缺乏具有全国代表性的样本。 此外，有证据表明，接触环境毒素，如环境铅和内分泌干扰物，可能对激素水平和青春期的开始产生不利影响。 然而，关于环境毒物如何以及是否可能与青春期开始的下降有关或有助于青春期开始的延迟的数据很少，并且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- 1994年）的一部分进行检查。 对儿童残留储存生物标本（血清）进行分析的目的有两个：（1）通过激素测定来估计（男孩和女孩的促黄体生成素LH和睾酮B，男孩的睾酮）在全国代表性的6-11岁儿童样本中青春期发育开始的时间，以及基于身体成熟的激素指标和青春期开始之间的模式和一致性（坦纳性成熟评分）用于8-11岁的儿童;以及（2）根据坦纳评分确定血铅（Pb）水平与发育迟缓之间的联系是否符合最新研究结果（阴毛）和初潮年龄的女孩可以确认的激素分析，并扩展到年轻的年龄，并确定是否有影响的血液铅水平的成熟时间为年轻的男孩。 全血铅，此外，尿镉（Cd）已经分析了检查的儿童在NHANES III。 值得注意的是，NHANES III中的6-11岁儿童出生于1977-1988年，在1988年的铅污染控制法案实际上消除了汽油中的铅之前，因此NHANES的后期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问题时有用。 重要的初步调查结果：对于774名男孩的样本，我们发现，随着年龄的增长，生殖器和阴毛阶段（p<0.0001），从第1阶段到第2阶段，从第2阶段到第3阶段或更高阶段，Escherbin B水平显著增加。 当在所有年龄段的非西班牙裔白色（NHW）、非西班牙裔黑人（NHB）和墨西哥裔美国人（MA）男孩中进行比较时，NHB中的总的Escherbin B水平显著更高（p<0.01）。 在坦纳生殖器1期男孩中，种族/民族（p=0.02）具有显著影响，NHB水平最高，但年龄无显著影响。 相反，在坦纳2期或以上的患者中，人种/种族没有显著影响，但年龄有显著影响（p=0.01）。 这与睾酮相反，睾酮浓度随年龄和阴毛阶段显著增加，尽管生殖器阶段没有，并且在任何年龄都没有统计学显著的种族/民族差异。 在坦纳1期和2期之间，睾酮B和睾酮也有相当大的重叠，因此，由于个体间差异较大，没有明确区分青春期状态开始的临界值。 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激素测量结果。 我们观察到NHANES III NHB男孩中，与早期从坦纳生殖器阶段1到2的过渡平行的Bronbin B浓度的显著种族/民族差异，尽管这些年龄段的NHB男孩中普遍较高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，被认为会在敏感的发育窗口（如青春期）破坏激素的产生。 近几十年来，铅暴露水平有所下降，但即使低于有毒水平（目前定义为10微克/分升），少女体内的铅浓度仍可能产生不利影响。 我们在667名6至11岁的女孩中研究了血铅和胆红素B之间的关系。 调查线性回归用于估计连续铅（log）和胆红素B水平之间的关联，以及暴露类别（< 1，1-4.9，=>5 ug/dL）的逻辑回归。 与墨西哥裔美国人（2.2微克/分升）和非西班牙裔白色女孩（1.8微克/分升）相比，非西班牙裔黑人女孩（NHB）的铅浓度最高（p<0.0001）（3.1微克/分升）。在线性模型中，调整人种/种族后，Pb与胆红素B呈显著负相关（β = -0.17 log（pg/mL）/log（Pb）单位变化，SE=0.08，p=0.03）。 我们还发现了一个显着的相互作用（p=0.04）之间的铅和尿镉在降低尿镉B。因此，较高的血铅水平与降低胆红素B和年轻女孩的青春期开始后的成就。这些发现与NHANES III先前的研究一致，显示年龄较大的女孩性成熟阶段和初潮年龄较晚，并表明该机制可能是通过下丘脑-垂体-卵巢轴的系统性破坏或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.