Mercury exposure at low levels induces autoimmunity
Toxicity from high levels of mercury and other xenobiotics is less widespread a problem than autoimmunity induced by lower levels generally considered to be safe. The largest public health burden is not toxicity but loss of immune tolerance. A study recently published in the journal Environmental Health Perspectives illustrates this in the case of mercury exposure among females of reproductive age. The authors state:
"Autoimmunity, which can include autoantibody formation, represents a breakdown of tolerance against self-antigens. Self-reactive lymphocytes may occur in healthy individuals, and in the absence of related pathology, autoimmunity represents pre- or sub-clinical immune dysregulation. Thus, the term autoimmunity should be distinguished from autoimmune disease, as it does not denote clinical or symptomatic disease...autoantibodies may precede autoimmune diagnoses by several years, and nearly all autoimmune diseases are characterized by circulating autoantibodies. Antinuclear antibodies (ANAs) are highly sensitive for a variety of autoimmune conditions, including systemic lupus erythematosus (SLE), scleroderma, and Sjögren’s syndrome."
Investigating the effect of low levels of mercury
Mercury is ubiquitous and a top priority pollutant with seafood consumption and dental amalgam as common sources of exposure with abundant data on concentrations exceeding what is considered safe by regulatory agencies.
"However, immune effects associated with low levels of exposure to each type of mercury in the general population are not well characterized...Utilizing NHANES data, we explored the associations between three types of biomarkers of mercury exposure and the presence, strength, and patterns of antinuclear antibodies in a representative sample of reproductive-age females from the US population.'
"16% of females were ANA-positive; 96% of ANA-positives had a nuclear staining pattern of speckled. Mercury geometric means (standard deviations) were: 0.22 (0.03) ppm hair, 0.92 (0.05) µg/L blood, and 0.62 (0.04) µg/L urinary. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1352, and 804, respectively), adjusting for confounders: hair odds ratio (OR)=4.10; blood OR=2.32 comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥1:1280) ANA: hair OR=11.41; blood OR=5.93."
This reveals an association of organic mercury exposure (at levels not considered toxic) and antinuclear antibodies.
Pertinent for a wide variety of autoimmune disorders
The authors comment on their findings:
"In this population-based study, we found that mercury exposure is associated with increased risk of high-titer ANA positivity among reproductive-age females in the general US population. Specifically, this association appears to be driven by organic (methyl) mercury, the predominant species in hair and total blood. Notably, a dose-response relationship was observed for low methylmercury exposure levels (<0.37 ppm hair mercury; <1 μg/L total blood mercury), in the range generally considered safe for women of childbearing potential by regulatory agencies (Mergler et al. 2007). The predominant nuclear staining pattern of speckled found in our population is a marker of autoimmunity with a wide variety of clinical associations, including SLE, mixed connective tissue disease, Sjögren’s syndrome, and idiopathic inflammatory myopathies. The methylmercury association was robust across models, whereas other suspected risk factors in the multivariable models, including age and smoking, were not found to be associated with ANA risk."
Regarding the gender of their study subjects...
"Our study focused on females, ages 16-49 years. It is well recognized that females have a higher risk of autoimmune diseases, and that risk among females may also correlate with reproductive stage. Moreover, estrogenic hormones may promote autoimmunity (Somers and Richardson 2014). Mercury metabolism may also contrast between sexes, and differences in mercury excretion and distribution have been observed between sexes in mouse models, as well as immunotoxic effects at lower internal doses in females."
The role of oxidative stress
Oxidative stress can promote autoimmunity which the authors comment on in the case of mercury:
"Oxidative stress has been shown to contribute to the induction of autoimmune phenotypes in animal models, such as through epigenetic mechanisms converting normal “helper” T cells to autoreactive lymphocytes sufficient to cause lupus in the absence of added antigen. Mercury induces oxidative stress through sulphydryl reactivity and depletion of cellular antioxidants. In human T cells treated with methylmercury, reductions in intracellular glutathione (GSH) concentration, glutathione S-transferase activity and mitochondrial transmembrane potential have been observed, followed by generation of reactive oxygen species; intracellular GSH depletion has further been linked to susceptibility of T cells to undergo methylmercury-induced apoptosis."
Low levels of mercury considered safe can induce autoimmunity
Practitioners should recall that binding of mercury and native proteins creates a hapten that can induce loss of immune tolerance to the self-antigen in the bound complex. This can result as undifferentiated autoimmunity with an array of diverse symptoms years before evolving into a well-defined autoimmune disease due to extensive tissue damage already having occurred. The authors conclude on a note of vast importance to clinical practice:
"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."