Low-Dose Exposure to Inorganic Mercury Accelerates Disease and Mortality in Acquired Murine Lupus
Via, Charles S., Nguyen, Phuong, Niculescu, Florin, Papadimitriou, John, Hoover, Dennis, Silbergeld, Ellen K., Environmental Health Perspectives
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 [F.sub.1] 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. Key words: autoimmunity, glomerulonephritis, graft-versus-host disease, lupus, mercury, T cells.
Exposures to mercury compounds are widespread in the U.S. population and throughout the world (Mahaffey and Mergler 1998; National Research Council 2000). Although public health concerns about mercury exposures have generally focused on neurodevelopmental toxicity, mercury, particularly inorganic mercury (iHg), has been extensively studied in animal models for its immunotoxic properties, which include both autoimmunity and immunosuppression. The autoimmune effects of iHg in susceptible rodent strains include induction of specific autoantibodies, polyclonal activation of T and B cells, increased serum immunoglobulin G1 (IgG1) and IgE, cytokine dysregulation, and an immune complex glomerulonephritis (Bigazzi 1994; Griem and Gleichmann 1995; Mathieson 1992; Moszczynski 1997; Pollard and Hultman 1997).
However, despite considerable study, no associations have been found between mercury exposure and autoimmune disease in humans, even in highly exposed workers (Moszczynski 1997; Sweet and Zelikoff 2001; Vimercati et al. 2001). Experimental research in animal models of Hg-induced autoimmunity (HgIA) may suggest the reason for this. In mice, genotype influences not only disease susceptibility but also the specific autoantibodies produced. One of the genes involved in disease susceptibility is within the major histocompatibility complex (MHC) region. As a result, H-[2.sup.s] mice (SJL, B10.S, A.SW) are highly susceptible to HgIA induction to include production of anti-nucleolar and anti-fibrillarin antibodies, whereas mice from other MHC genotypes, for example, CBA (H-[2.sup.k]), C57Bl/10 (H-[2.sup.b]), and DBA/2 (H-[2.sup.d]), are resistant to disease induction (Hultman et al. 1992, 1993, 1996; Hultman and Enestrom 1987, 1992; Pietsch et al. 1992; Warfvinge et al. 1995). Thus, the overt expression of HgIA requires interactions with predisposing factors such as genetic susceptibility; however, recent studies indicate that Hg can also exacerbate ongoing autoimmune disease. Studies in spontaneously autoimmune-prone strains of mice have reported greater autoimmune responses to iHg in (NZB x NZW) [F.sub.1] mice compared with nonautoimmune SJL or BALB/c mice (al-Balaghi et al. 1996) and also reported that iHg treatment greatly increased renal immune complex deposits in young NZB x NZW [F.sub.1] mice (Abedi-Valugerdi et al. 1997). Moreover, in the lupus-prone BXSB mouse, Pollard et al. (2001) found that iHg accelerated systemic autoimmunity, including cellular and humoral features of disease. …