Abstract and Introduction
Background: Immune dysregulation associated with mercury has been suggested, although data in the general population are lacking. Chronic exposure to low levels of methylmercury (organic) and inorganic mercury is common, such as through fish consumption and dental amalgams.
Objective: We examined associations between mercury biomarkers and antinuclear antibody (ANA) positivity and titer strength.
Methods: Among females 16–49 years of age (n = 1,352) from the National Health and Nutrition Examination Survey (NHANES) 1999–2004, we examined cross-sectional associations between mercury and ANAs (indirect immunofluorescence; cutoff ≥ 1:80). Three biomarkers of mercury exposure were used: hair (available 1999–2000) and total blood (1999–2004) predominantly represented methylmercury, and urine (1999–2002) represented inorganic mercury. Survey statistics were used. Multivariable modeling adjusted for several covariates, including age and omega-3 fatty acids.
Results: Sixteen percent of females were ANA positive; 96% of ANA positives had a nuclear speckled staining pattern. Geometric mean (geometric SD) mercury concentrations were 0.22 (0.03) ppm in hair, 0.92 (0.05) μg/L blood, and 0.62 (0.04) μg/L urine. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1,352, and 804, respectively), after adjusting for confounders: for hair, odds ratio (OR) = 4.10 (95% CI: 1.66, 10.13); for blood, OR = 2.32 (95% CI: 1.07, 5.03) comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥ 1:1,280) ANA: hair, OR = 11.41 (95% CI: 1.60, 81.23); blood, OR = 5.93 (95% CI: 1.57, 22.47).
Conclusions: Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years; thus, methylmercury exposure may be relevant to future autoimmune disease risk.
Autoimmune disorders, although individually rare, are collectively estimated to afflict 7.6–9.4% of Americans (Cooper et al. 2009) and are among the 10 leading causes of death among women (Thomas et al. 2010; Walsh and Rau 2000). Almost all autoimmune diseases have a strong preponderance among females, with female to male ratios of up to 9:1 and onset often occurring during mid-adulthood (Cooper and Stroehla 2003; Somers et al. 2007, 2014).
Autoimmunity, which can include autoantibody formation, represents a breakdown of tolerance against self-antigens (Lleo et al. 2010). Self-reactive lymphocytes may occur in healthy individuals, and in the absence of related pathology, autoimmunity represents pre- or subclinical immune dysregulation. Thus, the term "autoimmunity" should be distinguished from autoimmune disease, because it does not denote clinical or symptomatic disease. Data are sparse regarding the prognostic significance of preclinical autoimmunity or the "conversion" rate to particular disorders, although autoantibodies may precede autoimmune diagnoses by several years (Arbuckle et al. 2003) and nearly all autoimmune diseases are characterized by circulating autoantibodies (Scofield 2004). Antinuclear antibodies (ANAs) are highly sensitive for a variety of autoimmune conditions, including systemic lupus erythematosus (SLE), scleroderma, and Sjögren's syndrome. Estimates of ANA prevalence in individuals without autoimmune disease vary widely (1–24%) (Fritzler et al. 1985; Rosenberg et al. 1999) due to differing methodologies and population characteristics. ANA prevalence of approximately 13% has been reported in key studies using a 1:80 titer cutoff (Satoh et al. 2012; Tan et al. 1997) based on an immunofluorescence assay, the method recommended by the American College of Rheumatology as the gold standard for ANA testing (Meroni and Schur 2010).
Mercury is a ubiquitous and persistent toxicant with pleiotropic effects, and it is currently ranked as a top three priority pollutant by the U.S. Agency for Toxic Substances and Disease Registry (2011). Consumption of seafood, particularly of large species, is a common source of organic mercury (methylmercury) exposure (Mergler et al. 2007). It has been estimated that in the United States each year, approximately 8% of mothers and 0.6 million newborns have mercury concentrations exceeding levels considered by regulatory agencies to be safe (Trasande et al. 2005). Immunotoxic effects, including autoantibody production, have been clearly demonstrated in murine models in response to both organic and inorganic mercury (Pollard et al. 2010). In humans, occupational mercury exposure (predominantly inorganic and elemental species) among miners has been associated with increased risk of autoimmunity (Gardner et al. 2010; Silva et al. 2004), and an increased risk of SLE has been reported among dental professionals (Cooper et al. 2004). However, immune effects associated with low levels of exposure to each type of mercury in the general population are not well characterized (Mergler et al. 2007).
Because the biologic effects, sources, and patterns of exposure to organic and inorganic mercury are expected to differ, it is important to examine both species. Biomarkers of mercury exposure in humans include hair mercury, representing predominantly organic (methyl) mercury; total blood mercury, a combination of organic and inorganic mercury; and urinary mercury, a marker predominantly of inorganic/elemental mercury. In the U.S. National Health and Nutrition Examination Survey (NHANES), hair mercury was measured in adult females (16–49 years of age) but not in males.
Using NHANES data, we explored the associations between three types of biomarkers of mercury exposure and the presence, strength, and patterns of ANAs in a representative sample of reproductive-age females from the U.S. population.
Environ Health Perspect. 2015;123(8):792-798. © 2015 National Institute of Environmental Health Sciences