Low-dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus.

Abstract

Inorganic mercury (iHg) is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, iHg can accelerate and exacerbate disease manifestations. Despite these well-known links between iHg and autoimmunity in animal models, no association between iHg alone and autoimmune disease in humans has been documented. However, it is possible that low-level iHg exposure can interact with disease triggers to enhance disease expression or susceptibility. To address whether exposure to iHg can alter the course of subsequent acquired autoimmune disease, we used a murine model of acquired autoimmunity, lupus-like chronic graft-versus-host disease (GVHD), in which autoimmunity is induced using normal, nonautoimmune prone donor and F1 recipient mice resistant to Hg-induced autoimmunity. Our results indicate that a 2-week exposure to low-dose iHg (20 or 200 micro g/kg every other day) to donor and host mice ending 1 week before GVHD induction can significantly worsen parameters of disease severity, resulting in premature mortality. iHg pretreatment clearly worsened chronic lupus-like disease, rather than GVHD worsening iHg immunotoxicity. These results are consistent with the hypothesis that low-level, nontoxic iHg preexposure may interact with other risk factors, genetic or acquired, to promote subsequent autoimmune disease development.

Harmful Interactions of Non-Essential Heavy Metals with Cells of the Innate Immune System

“…Pre-or post-natal exposure to high levels of MeHg causes mental retardation, cerebral palsy, seizures and ultimately death [66], while inorganic Hg is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, Hg can accelerate and exacerbate disease manifestations [67]. Metals such as Hg may also contribute to the pathogenesis of autoimmune diseases by modulating mast cell activity [68].…”

Immunological effects of mercury (IUPAC Technical Report)

“…Thus, a 14-day pretreatment with HgCl 2 [two weeks of 20-200 µg mercury (kg body mass) -1 , subcutaneous, every second day] followed by an experimental induction of a lupus-like-disease, caused an increase in lupus-like symptoms in nonsusceptible mouse strains [72]. The authors concluded that mercury may act as a cofactor, which favors autoimmune disease when combined with other factors, such as genetic disposition or certain infectious disease [71].…”

“…The first autoimmune responses were seen in rodents at a dose of about 50 µg mercury (kg body mass) -1 (day) -1 [72]. In a study with genetically mercury-susceptible mice, the threshold weekly dose for formation of antinuclear IgG was at 170 µg (kg body mass) -1 , or about 20 µg (kg body mass) -1 (day) -1 , for 10 weeks [40].…”

Understanding sex differences in environmental health: a thought leaders' roundtable.

“…Silbergeld has found that mercury has a profound impact on graft versus host disease (GVHD) models of autoimmunity that mimic lupus (Via et al 2003). In these models, GVHD is induced by injecting splenocytes from one strain of mice (C57BL/6 or DBA/2) into hybrid offspring (C57BL/6 × DBA/2).…”