Novel biomarkers of mercury-induced autoimmune dysfunction: A cross-sectional study in Amazonian Brazil

Abstract

Mercury is an ubiquitous environmental contaminant, causing both neurotoxicity and immunotoxicity. Given its ability to amalgamate gold, mercury is frequently used in small-scale artisanal gold mining. We have previously reported that elevated serum titers of antinuclear autoantibodies (ANA) are associated with mercury exposures of miners in gold mining. The goal of this project was to identify novel serum biomarkers of mercury-induced immunotoxicity and autoimmune dysregulation. We conducted an analysis of serum samples from a cross-sectional epidemiological study on miners working in Amazonian Brazil. In proteomic screening analyses, samples were stratified based on mercury concentrations and ANA titer and a subset of serum samples (N=12) were profiled using Immune Response Biomarker Profiling ProtoArray protein microarray for elevated autoantibodies. Of the up-regulated autoantibodies in the mercury-exposed cohort, potential target autoantibodies were selected based on relevance to pro-inflammatory and macrophage activation pathways. ELISAs were developed to test the entire sample cohort (N=371) for serum titers to the highest of these autoantibodies (anti-glutathione S-transferase alpha, GSTA1) identified in the high mercury/high ANA group. We found positive associations between elevated mercury exposure and up-regulated serum titers of 3760 autoantibodies as identified by ProtoArray. Autoantibodies identified as potential novel biomarkers of mercury-induced immunotoxicity include antibodies to the following proteins: GSTA1, tumor necrosis factor ligand superfamily member 13, linker for activation of T cells, signal peptide peptidase like 2B, stimulated by retinoic acid 13, and interferon induced transmembrane protein. ELISA analyses confirmed that mercury-exposed gold miners had significantly higher serum titers of anti-GSTA1 autoantibody [unadjusted odds ratio = 89.6; 95% confidence interval: 27.2, 294.6] compared to emerald miners (referent population). Mercury exposure was associated with increased titers of several autoantibodies in serum including anti-GSTA1. These proteins play a wide variety of roles, including as antioxidants, in the regulation of pro- and anti-inflammatory cytokines, as well as danger and oxidative stress signaling. Dysregulation of these proteins and pathways is believed to play a role in autoimmune diseases such as rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis. Taken together, these results suggest that mercury exposure can induce complex autoimmune dysfunction and the immunotoxic effects of this dysfunction may be measured by serum titers to autoantibodies such as anti-GSTA1.

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

“…Mercury is a widely distributed environmental and industrial pollutant (42) that in both humans and animals, induces a milder form of autoimmunity including autoAbs and membranous nephropathy (43–46). The characteristics of mercury-induced autoimmunity (HgIA) are similar to SLE and include lymphocyte proliferation, increased class II MHC expression, hypergammaglobulinemia, polyclonal Abs to self-antigens, notably anti-nuclear Abs (ANAs), and to some extent immune complex deposits in mice (47), as well as necrotizing vasculitis in rats (48–52).…”

Occupational mercury exposure in association with prevalence of multiple sclerosis and tremor among US dentists

“…19 In rabbit and rat models, exposure to Hg 0 causes autoimmune disease, similar to the immune cell activity observed in patients with MS. 20, 21 Investigators in studies of Amazonian gold miners have reported associations of low-level urinary Hg 0 concentrations (3.7 mg/L) with both elevated cytokines and antinuclear antibodies, which are biomarkers associated with immune response and autoimmune disease, respectively. [22][23][24] Tremor is an involuntary movement characterized by oscillatory motion, occurring during rest or activity. The prevalence of tremor in people with MS ranges from 25% to 60%, [25][26][27] and this tremor is characterized by demyelinating lesions in the brain that produce intention tremor, the most common type of cerebellar tremor.…”

Effects of Endocrine Disrupters on Immune Function and Inflammation

“…However, among these metals, exposure to mercury is most closely associated with elevated risk of multiple autoimmune conditions as an outcome of immunotoxicity [48]. It also promotes inflammatory disease via induction of both the ecyclooxygenase-2 and inducible nitric oxide synthase genes [49].…”