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

Mercury is a 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.

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