Project 1: Prenatal Lead Exposure, Early Childhood Growth, and Sexual Maturation

项目 1：产前铅暴露、儿童早期生长和性成熟

• 批准号: 8376827
• 负责人: Karen Eileen Peterson
• 金额: $ 15.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376827
• 关键词: Accounting; Adolescent; Adult; Affect; Age; Age at Menarche; Animals; Biological Markers; Birth; Blood; Body mass index; Boston; Breast; Caliber; Cardiovascular Diseases; Cell physiology; Child; Childhood; Chronic; Chronic Disease; Confidence Intervals; Cross-Sectional Studies; DNA Methylation; Data; Dentin; Development; Diet; Dietary Lead; Disease susceptibility; Dose; Endocrine disruption; Entire hair of pubis; Environmental Exposure; Epigenetic Process; Estradiol; Estrus; Ethnic Origin; Exposure to; Family Sizes; Female; Fetus; Functional disorder; Genes; Genetic Polymorphism; Genital system; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Growth; Growth and Development function; H19 gene; Hormonal; Hormones; Human; Hypertension; Hypothalamic structure; IGF2 gene; IGF2R gene; Income; Infant; Insulin-Like Growth Factor I; Knee bone; Kosovo; Lead; Long-Term Effects; Luteinizing Hormone; Malignant Neoplasms; Measures; Mediating; Menarche; Metabolic Diseases; Methylation; Mexican; Mexican Americans; Modeling; Molecular; Mothers; Mus; National Health and Nutrition Examination Survey; National Institute of Environmental Health Sciences; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Observational Study; Outcome; Outcome Measure; Patient Self-Report; Perinatal; Perinatal Exposure; Physicians; Poverty; Pregnancy; Puberty; Race; Rattus; Reporting; Research; Risk; Rodent; Sampling; Schools; Sexual Maturation; Signal Transduction; Site; Sperm Count Procedure; Staging; Steroid biosynthesis; Surveys; Testosterone; Time; Tubular formation; Umbilical Cord Blood; Vagina; Weight; Weight Gain; aged; blood Pb concentration; blood lead; bone lead; boys; chronic Pb exposure; cohort; design; early childhood; fetal lead exposure; girls; hypothalamic pituitary axis; hypothalamic pituitary gonadal axis; imprint; in utero; infancy; lead exposure; male; neurodevelopment; offspring; postnatal; prenatal; prenatal exposure; prepuberty; programs; residence; response; sertoli cell; trend

Lead exposure, childhood weight status and sexual maturation. Prenatal lead exposure has been associated with smaller size at birth and in infancy [22, 124,135-138]. Among children exposed to high lead level in utero, growth delays appear to persist only among those with high postnatal lead exposure [89, 90], pointing to the importance of repeat measures of exposure to understand genesis of growth delays associated with lead levels in children. Cross-sectional analyses of survey data and observational studies document a 1-2 cm decrement in stature for every 10 pg/dL difference in blood levels in nationally representative samples from NHANES and HHANES, but findings are less consistent for the association with weight [139-141]. Variance in childhood weight reflects both stature and the relationship of weight with stature [142]. Only two studies have investigated the relationship between lead and body habitus in children. Mid-pregnancy blood lead was marginally associated with BMI change from birth to 1 yr (|3=0.04, 95% CI¿0.06 to 0.14) and 1-4 yr (P=0.04, 95%C!=0.00 to 0.08) among 100 and 58 mother-infant pairs, respectively, in Kosovo [143], Among Boston school children followed by Dr. Howard Hu, Co-lnvestigator for the proposed P20, a 10-fold increase in (logio) dentin lead level at 7 yr of age was cross-sectionally associated with a 1.023 increment in BMI among 236 children (P=1.023, SE=0.458, P=0.03). Among 58 ofthese subjects followed-up 10 years later, a 10-fold increase in dentin lead at 7 yr of age was associated with a 2.65 unit increase in BMI (P=2.650, SE= 1.156, P=0.03) [144]. Although dentin lead is a measure of chronic lead exposure, this study did not examine prenatal or early childhood lead exposure, limiting inferences about timing of exposure. In the Kosovo study, child blood lead levels were measured but not adjusted for analyses due to high correlation with maternal blood lead. A recent animal study examined the long term effects of gestational lead exposure (GLE) in a murine model of human equivalent GLE [1], finding inverse dose-response effects on late onset obesity of male but not female offspring. GLE did not significantly affect weight of female offspring and was significantly associated with weight of male mice at 1 yr but not at eariier ages. Compared with controls, male mice weighed significantly more: +26% low, +21% moderate, +13% high GLE. These findings point to the need to consider associations of perinatal lead exposure with analytic approaches that account for nonmonotonic responses in physical growth across spectrum of sensitive periods in childhood. In addition, use of outcome measure of body habitus (e.g. BMI) may reveal whether effects on weight of mice with high-dose GLE were in fact also stunted. Molecular mechanisms for lead effect on obesity are not well understood [1], but developmental studies suggest effects could be related to altered hypothalamic pituitary axis (HPA) and hypothalamic dopaminergic dysfunction [91], to genetic polymorphisms related to obesity and metabolic disorders, or diet or environmental exposures that disrupt endocrine signaling [92, 93]. Cross-sectional studies of national survey data (NHANES III) implicate low-level lead exposure in delayed age at self-reported menarche and physician-observed onset of puberty (Tanner stage 2, pubic hair development) in giris, after adjustment for race/ethnicity, BMI, age, family size, urban residence and poverty income ratio [145]. In analyses among giris 8-18 yr of age in NHANES III stratified by race/ethnicity, higher (3pg/dL) compared with lower (Ipg/dL) blood lead concentrations, were associated with significant delays in Tanner stages for both breast development (Adjusted OR 0.76; 95% Confidence Interval (Cl) 0.63-0.91 and pubic hair development (OR 0.70 (0.54-0.91) in Mexican-American girls and in all pubertal measures (breast, pubic hair, age at menarche), among non-Hispanic black giris. In white giris, blood lead concentration was associated with delays in pubertal development but these findings were not statistically significant [87]. In a study of 489 Russian boys aged 8-9 yr, those with blood lead levels >5pg/dL had a 44% reduced odds of having entered Tanner genital staging G2 (95%CI= 0.34 to 0.95, P=0.03) and demonstrated marginally reduced testicular volume (OR=0.72, 95%CI=0.48 to 1.07, P=0.11) [88]. Cross-sectional designs nevertheless limit inferences from these studies about the timing of lead exposure and underscore the need to examine relationships of perinatal exposure to growth and maturation in longitudinal data. Studies among rodents suggest lead may have a dual site of action: at the level of hypothalamic pituitary axis (HPA), and directly at the level of gonadal steroid biosynthesis, although these mechanisms may not operate similariy among humans. Among animals, lead is believed to act on the Hypothalamic-Pituitary-Gonadal (HPG) axis by blocking the release of gonadotropin releasing hormone (GnRH) thus decreasing puberty-related hormones such as LH and estradiol. Prenatal exposure to lead among rats has been demonstrated to cause a decrease in several puberty-related hormones such as insulin-like growth factor-1 (IGF-1) [146], luteinizing hormone (LH), and estradiol (E2)J30, 32,147]. The effect of lead on puberty-related hormones has been demonstrated to be reversible by the administration of IGF-1 to prepubertal female rats [148]. At the gonadal steroid biosynthesis level (second site of action), lead has been shown to impair leydigcell and Sertoli cell functions [149, 150]. Lead has been associated with a decrease in testicular weight, seminiferous tubular diameter, and sperm count among mice subcutaneously exposed to lead or exposed to lead though their diet [32, 150-152]. Prenatal and dietary lead exposure has also been observed to delay the timing of puberty (as measured by age of vaginal opening and age of estrus for example) among female rats and mice [30, 32, 153-155]. In rat studies, lead has been related to a reduction in testosterone and estradiol levels during puberty [146, 150, 156].

铅暴露、儿童体重状况和性成熟。产前铅暴露与出生时和婴儿期体型较小有关[22, 124,135-138] 在子宫内暴露于高铅水平的儿童中，生长迟缓似乎仅在这些儿童中持续存在。出生后铅暴露量较高 [89, 90]，指出重复测量暴露对于了解与儿童铅水平相关的生长迟缓的起源的重要性，对调查数据和观察性研究的横断面分析记录了这一点。在 NHANES 和 HHANES 的全国代表性样本中，血液水平每 10 pg/dL 差异，身高就会减少 1-2 cm，但与体重的相关性研究结果不太一致 [139-141] 儿童体重的差异反映了身高和体重。体重与身高的关系[142]，只有两项研究调查了儿童怀孕中期血铅与体重指数从出生到1的变化之间的关系。年 (|3=0.04, 95% CI¿ 0.06 至 0.14) 和 1-4 岁 (P=0.04, 95%C!=0.00 至 0.08)，分别在科索沃 100 对和 58 对母婴中[143]，霍华德·胡 (Howard Hu) 博士跟踪的波士顿学童中，拟议 P20 的联合研究者，(logio) 牙本质铅水平增加 10 倍，达到 7 236 名儿童中 1.023 岁的年龄与 BMI 增加有关（P=1.023，SE=0.458，P=0.03），其中 10 年后随访的 58 名受试者中，牙本质增加了 10 倍。 7 岁时摄入铅与 BMI 增加 2.65 个单位相关（P=2.650，SE= 1.156，P=0.03）[144]，虽然牙本质铅是慢性铅暴露的衡量标准，但本研究没有检查产前或儿童早期的铅暴露，限制了对暴露时间的推断。由于与母体血铅高度相关，已测量但未针对分析进行调整。 最近的一项动物研究检查了妊娠期铅暴露 (GLE) 对小鼠的长期影响 人类等效 GLE 模型 [1]，发现 GLE 对雄性后代迟发性肥胖的反向剂量反应效应，但对雌性后代没有显着影响，并且与雄性小鼠 1 岁时的体重显着相关，但与 1 岁时的体重无关。与对照组相比，雄性小鼠的体重显着增加：GLE 低 26%，中度 21%，高 13%。这些发现表明需要考虑围产期铅暴露与分析方法之间的关联。此外，使用身体习惯（例如体重指数）的结果测量可能会揭示高剂量 GLE 对体重的影响实际上是否也受到了铅的分子机制的阻碍。对肥胖的影响尚不清楚 [1]，但发育研究表明，影响可能与下丘脑垂体轴 (HPA) 改变和下丘脑多巴胺能功能障碍 [91] 以及遗传多态性有关与肥胖和代谢紊乱、或破坏内分泌信号的饮食或环境暴露有关[92, 93]。 国家调查数据 (NHANES III) 的横断面研究表明，在调整种族/后，低水平的铅暴露会导致自我报告的初潮年龄延迟和医生观察的 giris 青春期开始（Tanner 2 期，阴毛发育）种族、BMI、年龄、家庭规模、城市居住和贫困收入比率 [145] 在 NHANES III 中对 8-18 岁的青少年进行了分层分析。种族/族裔，较高的 (3pg/dL) 与较低的 (Ipg/dL) 血铅浓度相比，与双侧乳房发育的 Tanner 阶段显着延迟相关（调整后 OR 0.76；95% 置信区间 (Cl) 0.63-0.91 和墨西哥裔美国女孩和所有青春期指标（乳房、阴毛）的阴毛发育（OR 0.70 (0.54-0.91)）在非西班牙裔黑人中，血铅浓度与青春期发育延迟有关，但在一项针对 489 名 8-9 岁俄罗斯男孩的研究中，这些发现并不具有统计学意义。年，血铅水平 >5pg/dL 的患者进入 Tanner 生殖器分期 G2 的几率降低了 44%（95%CI= 0.34 至 0.95， P=0.03），并且睾丸体积略有减少（OR=0.72，95%CI=0.48 至 1.07，P=0.11）[88]，但横截面设计限制了这些研究对铅暴露时间的推论，并强调了需要检查纵向数据中围产期暴露与生长和成熟的关系。 对啮齿类动物的研究表明，铅可能具有双重作用位点：在下丘脑垂体轴（HPA）水平，以及直接在性腺类固醇生物合成水平，尽管这些机制在人类中可能不相似，但据信铅的作用在人类中可能不同。通过阻断促性腺激素释放激素（GnRH）的释放来作用于下丘脑-垂体-性腺（HPG）轴，从而减少青春期相关激素，例如LH 和雌二醇已被证明会导致大鼠产前暴露于多种青春期相关激素的减少，例如胰岛素样生长因子-1 (IGF-1) [146]、黄体生成素 (LH) 和雌二醇。 E2)J30, 32,147] 已证明，通过给青春期前雌性大鼠施用 IGF-1，铅对青春期相关激素的影响是可逆的。 [148] 在性腺类固醇生物合成水平（第二个作用位点），铅会损害间质细胞和支持细胞功能 [149, 150]。 皮下暴露于铅或通过饮食暴露于铅的小鼠的生精管直径和精子数量也被观察到会延迟青春期时间（通过阴道年龄测量）。在雌性大鼠和小鼠中，例如发情期的开始和年龄）[30,32,153-155]，在大鼠研究中，铅与睾酮和雌二醇水平的降低有关。青春期期间[146,150,156]。