Environmental Exposures And Risk For Cancer and Chronic Diseases In Adults

环境暴露以及成人癌症和慢性病的风险

• 批准号: 10252581
• 负责人: Dale P Sandler
• 金额: $ 4.37万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10252581
• 关键词: 12 year old; 20 year old; Accounting; Address; Adolescent; Adult; Age; Aging; Agricultural Health Study; Agriculture; Aldicarb; Antibodies; Antinuclear Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Baltimore; Biological; Biological Markers; Body mass index; Caring; Cell Aging; Cells; Chemicals; Chronic Disease; Collaborations; Communicable Diseases; Cross-Sectional Studies; DNA; Data; Data Analyses; Data Set; Dermatomyositis; Diabetes Mellitus; Diagnosis; Disease; Elderly; Enrollment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Ethnic Origin; Exposure to; Female; Focus Groups; General Population; Health; Health Surveys; Helicobacter Infections; Helicobacter pylori; Hobbies; Hypertension; Immune; Immune System Diseases; Immunofluorescence Immunologic; Incidence; Inclusion Body Myositis; Indirect Fluorescent Antibody Technique; Individual; Inflammation; Length; Long-Term Effects; Longitudinal Studies; Measures; Medical; Methodology; Myositis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Antigens; Nutrition Surveys; Obesity; Occupational; Occupations; Odds Ratio; Participant; Patient Self-Report; Peripheral Blood Mononuclear Cell; Persons; Pesticides; Petroleum; Play; Polymyositis; Population; Prevalence; Process; Questionnaires; Race; Recording of previous events; Registries; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sample Size; Sampling; Self Tolerance; Seroprevalences; Serum; Sex Differences; Skin Aging; Southern Blotting; Sun Exposure; Sunburn; Sunscreening Agents; Systemic Lupus Erythematosus; Time; UV Radiation Exposure; Ultraviolet Rays; Update; Woman; age related; aged; base; cancer risk; carbamate insecticide; chlorohydrocarbon insecticide; farmer; field study; follow-up; male; men; methyl bromide; multiple chronic conditions; pesticide exposure; population survey; residence; seropositive; sex; standard measure; systemic autoimmune disease; systemic autoimmunity; telomere; trend; ultraviolet

There is growing evidence that autoimmunity and certain autoimmune diseases have been increasing, but findings are limited by the lack of systematic data and methodological challenges. Antinuclear antibodies (ANA), a marker of self-reactivity to DNA and other nuclear antigens, are present in several autoimmune diseases and have been observed in healthy persons in the absence of autoimmune disease. In collaborative research on autoimmunity using data from the National Health and Nutrition Survey (NHANES) we studied whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over time (Dinse et al., 2020). Serum ANA were measured by standard indirect immunofluorescence assays on HEp-2 cells in 14,211 participants age 12 years using NHANES data from 1988-1991, 1999-2004, and 2011-2012. The prevalence of ANA was shown to increase from 11.0% in 1988-1991 to 15.9% in 2011-2012. The increase was seen for both sexes but was more pronounced for men than women. Trends were not explained by obesity or other factors correlated with ANA. The increase was seen for older adults but also among adolescents age 12-19 years, stimulating new research in our group focused on understanding this trend. One candidate being investigated is chemicals in sunscreens, whose use has also increased over this time period. Infectious diseases, such as Helicobacter pylori (H. pylori) which produce systemic inflammation, may play a role in the onset of autoimmunity. Data from the 1999-2000 NHANES were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged 20 years (Meier, et al. 2020). H. pylori seropositivity and ANA positivity were common, with estimated prevalence of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA after accounting for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction. In a cross-sectional analysis of data from the Baltimore Longitudinal Study of Aging, we examined the sex-specific relationship between age and ANA as well as associations between ANA and type-2 diabetes and multimorbidity (2 or more chronic diseases. Overall ANA seroprevalence was 12% (15.1% in women, 8.8% in men). We observed a non-linear relationship between age and ANA that varied by sex, with a clear sex differences in younger participants (ages 48-59) which was no longer apparent among the oldest participants the oldest (age 80+). ANA positive women were more likely to have type 2 diabetes and multimorbidity than women who were ANA negative. No statistically significant associations were observed in men. The mechanisms underlying age-related changes in ANA in the general population are unclear. Also using data from the BLSA, we evaluated whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals (Meier et al., 2019). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). We studied ANA positivity at two cross-sectional timepoints (sample sizes N=368 and N=370) and longitudinally among those with samples from both timepoints (N=246) to assess the association between shorter telomere length and incident ANA positivity. No statistically significant cross-sectional associations were observed at either timepoints. However, among those who were ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were also more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes. In a collaboration with Dr. Frederick Millers autoimmunity group, we studied the association between the autoimmune condition dermatomyositis and exposure to ultraviolet radiation (Parks et al, E-pub 2019). Dermatomyositis has been associated with geospatial differences in ultraviolet (UV) radiation. We sought to evaluate associations with individual determinants of UV exposure. We used questionnaire data from 1350 adults in a U.S. national myositis registry (638 with dermatomyositis, 422 polymyositis, and 290 inclusion body myositis diagnosed at ages 18-65 years) to examine the likelihood of having dermatomyositis versus other myositis disorders in relation to self-reported sunburn history and job- and hobby-related sun exposures in the year prior to diagnosis after accounting for age, skin tone, and sex. We also evaluated the proportion of DM by maximum daily ambient UV exposure, based on UV-B erythemal irradiances for participant residence the year prior to diagnosis. We found that dermatomyositis was associated with sunburn in the year before diagnosis, with an odds ratio of 1.77 for having two or more sunburn episodes. Dermatomyositis was also associated with reporting occupational or hobby-related sun exposures. Ambient UV intensity was associated with DM in females, but not overall. In another study, we explored associations between use of pesticides and ANA positivity since farming and pesticide use (e.g. organochlorine insecticides) have been associated with systemic autoimmune diseases (Parks et al., 2019). We measured serum antinuclear autoantibodies (ANA) by immunofluorescence on Hep-2 cells in 668 male farmers in the study of Biomarkers of Exposure and Effect in Agriculture (BEEA; 2010-2013), an Agricultural Health Study (AHS) subcohort. We examined ANA in relation to lifetime use of 46 pesticides first reported at AHS enrollment (1993-1997) and updated at intervals through BEEA enrollment. Having ANA antibodies (3 or 4+ intensity at a 1:80 dilution, 21% of study participants) was associated with a reported history of seeking medical care due to exposure to pesticides and with use of specific pesticides including the fumigant methyl bromide, petroleum oil/distillates and, using a higher threshold (3 or 4+ at a 1:160 dilution, 9%) to define ANA positivity, with the carbamate insecticide aldicarb. Furthermore, greater combined use of four cyclodiene organochlorine insecticides was also associated with ANA. Findings suggest that specific pesticide exposures may have long-term effects on ANA prevalence and support the hypothesis that certain organochlorine insecticides may increase the risk of developing systemic autoimmunity.

越来越多的证据表明自身免疫和某些自身免疫疾病一直在增加，但由于缺乏系统数据和方法学挑战，研究结果受到限制。抗核抗体 (ANA) 是 DNA 和其他核抗原自身反应的标志物，存在于多种自身免疫性疾病中，并且在没有自身免疫性疾病的健康人中也观察到了这种抗体。在利用国家健康和营养调查 (NHANES) 数据进行的自身免疫合作研究中，我们研究了抗核抗体 (ANA)（最常见的自身免疫生物标志物）的流行率是否随时间变化（Dinse 等人，2020）。 使用 1988-1991 年、1999-2004 年和 2011-2012 年的 NHANES 数据，通过标准间接免疫荧光测定法对 14,211 名 12 岁参与者的 HEp-2 细胞进行血清 ANA 测量。 ANA 的患病率从 1988-1991 年的 11.0% 增加到 2011-2012 年的 15.9%。男女都有这种增加，但男性比女性更明显。肥胖或其他与 ANA 相关的因素无法解释这一趋势。这种增长不仅出现在老年人中，而且出现在 12-19 岁的青少年中，这激发了我们小组开展新的研究，重点是了解这一趋势。正在研究的候选物之一是防晒霜中的化学物质，其使用量在此期间也有所增加。 传染病，例如产生全身炎症的幽门螺杆菌（H. pylori），可能在自身免疫的发生中发挥作用。 1999-2000 年 NHANES 的数据用于评估美国 20 岁成年人幽门螺杆菌血清阳性率与 ANA 阳性之间的横断面关联（Meier 等人，2020）。幽门螺杆菌血清阳性和 ANA 阳性很常见，估计患病率分别为 33.3% 和 9.9%。两者都与年龄增长有关。考虑到年龄、性别、种族/民族、教育程度和体重指数后，幽门螺杆菌血清阳性与 ANA 的较高几率相关。幽门螺杆菌感染可能是导致自我耐受性丧失、导致免疫功能障碍的关键因素之一。 在对巴尔的摩老龄化纵向研究数据的横断面分析中，我们研究了年龄和 ANA 之间的性别特异性关系，以及 ANA 与 2 型糖尿病和多种疾病（2 种或更多慢性疾病）之间的关联。总体 ANA 血清阳性率为 12%（女性为 15.1%，男性为 8.8%），我们观察到年龄和 ANA 之间存在非线性关系，该关系因性别而异，年轻参与者中存在明显的性别差异。在年龄最大的参与者（48-59 岁）中，这一点不再明显，即 ANA 阳性女性比 ANA 阴性女性更有可能患有 2 型糖尿病和多种疾病。男人。 一般人群中 ANA 与年龄相关的变化的机制尚不清楚。我们还使用 BLSA 的数据，评估了较短的外周血单核细胞 (PBMC) 端粒长度（生物年龄较高的标志）是否与中老年无自身免疫性疾病个体的 ANA 阳性患病率和发生率相关（Meier 等人）等，2019）。端粒长度通过 Southern Blot 测量并分为三分位数。使用 HEp-2 细胞（血清阳性 = 3 或 4）通过免疫荧光法测量 1:80 和 1:160 稀释血清中的 ANA。我们研究了两个横截面时间点（样本量 N=368 和 N=370）的 ANA 阳性率，并纵向研究了两个时间点样本（N=246）的 ANA 阳性率，以评估较短端粒长度与事件 ANA 阳性率之间的关联。在两个时间点均未观察到统计学上显着的横截面关联。 然而，在基线时 ANA 阴性的人中，端粒较短的个体在随访（平均 13 年后）时更有可能呈 ANA 阳性。在这两个时期端粒较短的个体也更有可能呈 ANA 阳性。研究结果表明，一般人群中的 ANA 阳性可能表明晚期细胞衰老过程导致免疫功能障碍。 在与 Frederick Millers 博士自身免疫小组的合作中，我们研究了自身免疫性疾病皮肌炎与暴露于紫外线辐射之间的关联（Parks 等人，E-pub 2019）。 皮肌炎与紫外线 (UV) 辐射的地理空间差异有关。我们试图评估与紫外线暴露的个体决定因素的关联。我们使用了美国国家肌炎登记处 1350 名成年人（638 名患有皮肌炎、422 名多发性肌炎和 290 名在 18-65 岁诊断出的包涵体肌炎）的问卷数据，以检查与自我相关的皮肌炎与其他肌炎疾病的可能性。在考虑年龄、皮肤后，报告诊断前一年的晒伤史以及与工作和爱好相关的阳光照射语气和性别。我们还根据诊断前一年参与者居住的 UV-B 红斑辐照度，通过最大每日环境紫外线暴露评估了 DM 的比例。我们发现皮肌炎与诊断前一年的晒伤有关，发生两次或两次以上晒伤的比值比为 1.77。 皮肌炎也与职业或爱好相关的阳光照射有关。 环境紫外线强度与女性糖尿病相关，但总体而言并非如此。 在另一项研究中，我们探讨了农药的使用与 ANA 阳性之间的关联，因为农业和农药的使用（例如有机氯杀虫剂）与系统性自身免疫性疾病有关（Parks 等人，2019）。我们在农业暴露和影响生物标志物研究（BEEA；2010-2013）（农业健康研究 (AHS) 子队列）中，通过免疫荧光法测量了 668 名男性农民的 Hep-2 细胞血清抗核自身抗体 (ANA)。我们检查了 ANA 与 46 种农药终生使用的关系，这些农药首次在 AHS 登记时报告（1993-1997 年），并通过 BEEA 登记定期更新。拥有 ANA 抗体（1:80 稀释度为 3 或 4+ 强度，21% 的研究参与者）与因接触农药和使用特定农药（包括熏蒸剂溴甲烷、石油）而就医的报告历史相关油/蒸馏物，并使用更高的阈值（3 或 4+，1:160 稀释度，9%）来定义 ANA 阳性，使用氨基甲酸酯杀虫剂涕灭威。此外，四种环二烯有机氯杀虫剂的更多联合使用也与 ANA 相关。研究结果表明，特定农药暴露可能对 ANA 患病率产生长期影响，并支持某些有机氯杀虫剂可能增加发生系统性自身免疫的风险的假设。