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].

铅暴露于产后的铅铅较小，其中有些人的sirth具有较高的出生后铅暴露 - 对调查数据和观察性研究的分析记录，来自NHANES和HHANES的全国代表性样本的血液水平每10 pg/dl的地位降低1-2 cm [139-141]。身材和与身材的关系[142]。在100和58个母亲对中的0.06至0.14）和1-4岁（p = 0.04，95％c！= 0.08），在科索沃[143] N，然后是霍华德·胡（Howard Hu）博士，霍华德·霍（Howard Hu） ，在236名儿童的BMI中，（logio）7岁的牙本质铅水平增加了（Logio）铅水平（p = 1.023，SE = 0.458，p = 0.03）。 10年后，BMI（p = 2.650，SE = 1.156，p = 0.03）[144]。测量水平，但由于与母体血液铅的高度相关性而没有调整以进行分析。 一项最近的动物研究检查了鼠类妊娠铅暴露（GLEE）的长期影响 人类等效的模型[1]，发现男性后代的抗剂量反应会影响女性后代的体重，并且在1岁时与男性的体重显着相关，雄性小鼠的重量明显更高： +26％低， +21％中等， +13％d，以考虑围产期铅暴露与分析方法的关联，这些分析方法解释了她对体重的影响。实际上，肥胖症的小鼠也被良好地理解了[1]，肥胖[91]对肥胖和代谢性障碍帽子破坏内分泌信号的遗传多态性[91]。 国家调查数据（NHANES III）的横断面研究暗示，在适应种族/族裔之后，在Giris的延迟自我报告的初潮和青春期开始时（Tanner Stage 2，耻骨发育）的发作（Tanner Stage 2，耻骨发育） ，BMI，年龄，Farban居住和贫困率比率[145]。与SITH乳房发育型NTERVAL（CL）0.63-0.91和阴毛发育（OR 0.70（0.54-0.91）在墨西哥裔美国女孩和所有青春期的所有青春期措施（乳房，镜头，耻骨，初级乳发时代的乳房，初级头发，初级乳发）中，与Sith的明显延迟有关（OR 0.70（0.54-0.91） ）在白色giris中，在青春期的延误中，发现的结果并不静态地[87] DL进入制革商分期G2（95％CI = 0.34至0.95，p = 0.03）的几率降低了44％，并且显示出少量减少的睾丸体积（OR = 0.72，95％CI = 0.48至0.48至1.07，p = 0.11，p = 0.11）[ [88]横截面设计没有任何铅暴露的时间安排，并削弱了纵向数据中围产期暴露与生长和生产率的关系的需求。 在啮齿动物的研究中，可能具有轴（HPA）类固醇生物合成的拟合位点，这些机制可能在人类中行动相似。 ED激素如LH和雌二醇。在青春期相关的激素上的铅已证明是通过IGF-1进行的，这是可以抑制lefterbertal雌性大鼠的[148]。铅与睾丸重量减少有关， 还观察到，还观察到，还观察到，还观察到，在粘液型铅或暴露于饮食的灰度中，还观察到了饮食[32，150-152] d饮食铅暴露以延迟Estrus的青春期开放时间和年龄的时间[30，32，32 ，153-155]。