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: 8250363
• 负责人: Karen Eileen Peterson
• 金额: $ 10.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250363
• 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。产前铅暴露与出生和婴儿期较小有关[22，124,135-138]。在暴露于子宫内铅水平高的儿童中，生长延迟似乎仅在产后铅暴露较高的患者中持续存在[89，90]，这表明重复测量的重要性是了解与儿童铅水平相关的增长延迟的起源。调查数据和观察性研究的横断面分析记录，在NHANES和HHANES的国家代表性样本中，每10 pg/dl的血液水平差异1-2 cm的统计数据降低了1-2 cm，但与体重相关的发现不那么一致[139-141]。儿童体重的差异反映了身材，体重与统计的关系[142]。只有两项研究调查了儿童铅与身体习惯之间的关系。中期血液铅与从出生到1岁的BMI变化略有相关（| 3 = 0.04，95％CI ch 0.06至0.14）和1-4岁（P = 0.04，95％c！= 0.00至0.08）在100和58个母亲中，在Kosovo中分别为100和58个妈妈 - 在Kosovo [143]中，bosovo [143] co nefor boster tr。拟议的P20在7岁年龄的牙本质铅水平上增加了10倍，横截面与236名儿童的BMI的1.023增量相关（p = 1.023，SE = 0.458，p = 0.03）。 10年后，在这些受试者中的58名受试者中，牙本质铅在7岁年龄增长了10倍，与BMI的单位增加2.65相关（P = 2.650，SE = 1.156，P = 0.03）[144]。尽管牙本质铅是慢性铅暴露的量度，但该研究未检查产前或幼儿铅暴露，这限制了有关暴露时间的推论。在科索沃的研究中，测量了儿童血铅水平，但由于与遗传性血液铅的高度相关性，未对分析进行调整。 一项最近的动物研究检查了鼠类妊娠铅暴露（GLE）的长期影响 人类当量GLE [1]的模型，发现对雄性后代的肥胖后肥胖的逆剂量反应影响。 GLE并未显着影响女性后代的体重，并且在1年时与雄性小鼠的体重显着相关，但在Eariier时代也没有显着相关。与对照组相比，雄性小鼠的重量明显更高：低26％，中度 +21％， +13％的GLE。这些发现表明需要考虑围产期铅暴露与分析方法的关联，这些方法解释了儿童敏感时期跨敏感时期的身体生长中非单调响应。另外，使用身体习惯的结果测量（例如BMI）可能会揭示是否对高剂量GLE的小鼠的体重的影响实际上也受到阻碍。无法充分了解分子对肥胖的作用的分子机制[1]，但是发育研究表明，可能与下丘脑下丘脑垂体（HPA）和下丘脑多巴胺能功能障碍[91]有关，与肥胖和代谢性分类相关的遗传多态性和饮食9.92 cross [91]与遗传多态性相关或饮食9.92 crose 3.2 国家调查数据（NHANES III）的横断面研究暗示，在自我报告的初潮中延迟年龄的延迟铅暴露在Giris的青春期（Tanner Stage 2，Pusic Hair Develoption）中，在调整了种族/族裔，BMI，BMI，BMI，年龄，家庭规模，Urban Lissive和Poverty收入率和贫困率[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墨西哥裔女孩和所有青春期措施（乳房，耻骨，年龄）在非西班牙裔黑色giris中，血液铅的浓度与青春期的延迟有关输入的坦纳生殖器分期G2（95％CI = 0.34至0.95，p = 0.03），并且显示出少量减少的测试量（OR = 0.72，95％CI = 0.48至0.48至1.07，p = 0.11）[88]，从这些跨度典型的研究中，对pread seplose andscore conterion和under conterion corments corments corments corments corments corments corments and undscore corne contercore and unders corame corne corne coption persic corne则有限。纵向数据中的成熟。 啮齿动物之间的研究表明，铅可能具有双重作用位点：在下丘脑垂体轴（HPA）的水平上，直接在性腺立体生物合成水平上，尽管这些机制可能无法在人类中相似。在动物中，据信铅可作用于下丘脑 - 垂体 - 基达尔（HPG）轴，通过阻止促性腺激素释放的马龙（GNRH）的释放，从而减少了与青春期相关的马酮（如LH和雌二醇）。已经证明，已经在大鼠中暴露于铅的产前暴露会导致几种与青春期相关的马的降低，例如胰岛素样生长因子1（IGF-1）[146]，黄质龙杆菌（LH）和雌二醇（E2）J30，32,147]。铅对青春期相关马匹的影响已证明可以通过对青春期前雌性大鼠进行IGF-1的影响[148]。在性腺类固醇生物合成水平（第二个作用部位），已证明铅会损害Leydigcell和Sertoli细胞功能[149，150]。铅与测试重量的减小有关 在皮下暴露于铅或暴露于铅的小鼠中，分娩结核病和精子计数[32，150-152]。还观察到，在雌性大鼠和小鼠中，还观察到产前和饮食铅暴露会延迟青春期的时间（例如，通过阴道开放和雌激素的年龄来衡量）[30，32，153-155]。在大鼠研究中，铅与青春期期间睾丸激素和雌二醇水平的降低有关[146，150，156]。