2004)

2004). 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) recognized in the high mercury/high ANA group. LGB-321 HCl We found positive associations LGB-321 HCl between elevated mercury exposure and up-regulated serum titers of 3760 autoantibodies as recognized by ProtoArray. Autoantibodies identified as potential novel biomarkers of mercury-induced immunotoxicity include antibodies to the following proteins: GSTA1, tumor necrosis element 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 platinum miners had significantly higher serum titers of anti-GSTA1 autoantibody [unadjusted odds percentage = 89.6; 95% confidence interval: 27.2, 294.6] compared to emerald miners (referent populace). Mercury exposure was associated with increased titers of several autoantibodies in serum including anti-GSTA1. These proteins play a wide variety of functions, including as LGB-321 HCl 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 usually believed to play a role in autoimmune diseases such as rheumatoid arthritis, Sj?grens 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. 1. Introduction Mercury is a naturally occurring element and ubiquitous environmental contaminant released from combustion of coal and fossil fuels; mining operations; and metal, cement, and chlor-alkali production (WHO 2007, 2010). Elemental mercury is the primary form of mercury found in the atmosphere where it is stable for approximately 2 years and travels vast distances around the globe (Muir et al. 2009; Nguyen et al. 2010). Elemental mercury can be oxidized in the atmosphere to inorganic mercury which then is returned to the ground by dry and wet deposition. Inorganic mercury contaminates waterways, can be biotransformed to methylmercury, and bioaccumulate in piscivorous species of fish. Consumption of methylmercury-laden fish represents the most common route of exposure for humans (National Research Council (US) Committee around the Toxicological Effects of Methylmercury 2000). Mercury has been shown to cause damage and dysfunction in a number of physiological systems and has been well-documented as detrimental to the neurodevelopment of infants and children (National Research Council (US) Committee around the Toxicological Effects of Methylmercury 2000; WHO 2010). All mercurial species are harmful, differing in toxicodynamics, toxicokinetics and toxicological effects partly due to differences in solubility and bioavailability (Clarkson 1997; Gardner et al. 2010a; National Research Council (US) Committee around the Toxicological Effects of Methylmercury 2000; WHO 2010). A more recent area of research focus has been around the immunotoxic properties of mercury compounds. Dysregulation in the pro- and anti-inflammatory cytokine balance as a result of mercury exposure has been documented (de Vos et al. 2007; Gardner et al. 2009; Gardner et al. 2010b; Hemdan et al. 2007). In a recent study by Gardner (2009) human LGB-321 HCl peripheral blood mononuclear cells (PBMCs) were exposed to inorganic mercury at physiologically relevant concentrations. Only lipopolysaccharide-stimulated PBMCs responded to mercury and produced a concentration-dependent increase in release of pro-inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor- with a concurrent decrease in anti-inflammatory cytokines IL-1Ra and IL-10. In the same system, methylmercury exposure caused comparable cytokine modulation (Gardner et al. 2010a). Interestingly, opposite effects on cytokine production were observed in response to methylmercury when PBMCs were stimulated with monoclonal antibodies against T-cell receptors (Hemdan et al. 2007) or with T-cell mitogen concanavalin A (de Vos et al. 2007). These findings suggest differential effects of mercury compounds upon immune cell subsets. In a cross-sectional study of populations exposed to methylmercury and inorganic mercury as Pax1 a result of small-scale artisanal platinum mining in the Brazilian Amazon, we previously exhibited that mercury exposure (both inorganic mercury and methylmercury) was positively correlated with elevated serum titers of antinuclear autoantibodies (ANA) (Gardner et al. 2010b; Nyland et al. 2011a; Silva et al. 2004). When the mining populace was dichotomized based on mercury exposure and ANA positivity, we found that the high mercury/high ANA group experienced significantly elevated.