Environmental Exposures And Risk For Cancer and Chronic Diseases In Adults

National Institute Of Environmental Health Sciences

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Abstract

Growing evidence suggests that autoimmunity and certain autoimmune diseases have been increasing in the population, 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 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 a chemical in sunscreens, whose use has also increased over this time period, as well as Vitamin D, which has shown temporal changes in some subgroups in the population. In younger adults and adolescents, we are also exploring the relationship of ANA with hygiene hypothesis indicators, including evidence of childhood infections, asthma, and allergy. 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)(Meier et al., 2020). 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 (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 among older adults in the general population may be indicative of immune dysfunction resulting from cellular aging processes. In a collaboration with Drs. Lisa Rider and Frederick Miller of the NIEHS Environmental Autoimmunity Group, we studied the association between the autoimmune condition dermatomyositis and exposure to ultraviolet radiation (Parks et al, 2020). Dermatomyositis has been associated with geospatial differences in ultraviolet (UV) radiation. We sought to evaluate associations with individual determinants of UV exposure as well as geocoded estimates of UV intensity. 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 types of myositis 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 a diagnosis of dermatomyositis was associated with reported sunburn in the year before diagnosis, with an odds ratio of 1.77 for having two or more versus no 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). 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 ever 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. A 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. Ongoing research is examining more recent pesticide use as well as other types of agricultural exposures such as organic dusts, solvents, and metals.