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

lupus

A study conducted at the University of Maryland School of Medicine finds that exposure to low levels of mercury can speed up and worsen the symptoms of an induced lupus-like disease in mice, even when the exposure occurs before the development of the disease. The researchers say if this relationship were shown to be true in humans, it would redefine the association between mercury exposure and the autoimmune disease lupus. Their study, the first to connect low-level mercury exposure to the severity of lupus in mice after they develop the disease, appears in the August 2003 edition of Environmental Health Perspectives, published by the National Institute of Environmental Health Sciences, part of the National Institutes of Health. The lead investigator of the study, Charles S. Via, M.D., professor of medicine, microbiology and immunology at the University of Maryland School of Medicine, says previous studies have found that mercury exposure in animals can exacerbate pre-existing autoimmune disease and even induce autoimmune disease in susceptible animals.

“Our study takes the link further by demonstrating that exposure to mercury prior to the induction of an autoimmune disease in mice significantly worsens the severity of that disease after it develops,” says Dr. Via, who is also a rheumatologist at the University of Maryland Medical Center.

Scientists are uncertain about the impact of mercury exposure on humans. “There is considerable concern over potential neurotoxic effects associated with current levels of human exposure to mercury,” says study co-author, Ellen K. Silbergeld, Ph.D., a professor of Environmental Health Sciences at the Johns Hopkins Bloomberg School of Public Health, who formerly worked at the University of Maryland School of Medicine. “These results suggest that we should examine the immune system as a target of mercury toxicity in humans.”

One step in that direction involves using special mouse strains to study the links between mercury and autoimmune disease. In one strain, the mice are susceptible to mercury-induced autoimmune disease. Another strain of mice develops an autoimmune disease that is similar to lupus.

In this study, healthy mice that were not genetically susceptible to mercury-induced autoimmune disease were given injections of low-dose inorganic mercury over the course of two weeks. The levels of mercury and the length of exposure chosen were much lower than the range commonly used in mouse studies of mercury toxicity. Five days later, the mice were given cells from the lupus-inclined mouse strain to induce lupus-like chronic graft-versus-host disease, a well-established mouse model of acquired autoimmunity.

Dr. Via says the results surprised him. Mercury exposure accelerated the deaths of the lupus-induced mice and sped up the course of a kidney disease associated with lupus. Further, antibodies, or markers characteristic of lupus-like autoimmunity were significantly elevated in the mice that had been pretreated with mercury. “Our findings suggest that low-level mercury exposure does not cause lupus,” says Dr. Via. “Lupus is clearly multifactorial. You have to have a susceptible individual who has the appropriate environmental exposure. But our study clearly shows that mercury can act as a disease modifier for lupus. Exposure to mercury might either lower the threshold of susceptibility, or increase the severity of the disease.”

According to Dr. Via, the researchers have begun additional studies to determine whether subtle abnormalities remain after mercury clears from the body that may produce the modifications in lupus. “We can speculate about a lot of possible mechanisms, but we clearly need further study to determine exactly how mercury accelerates lupus,” says Dr. Via.

Lupus is a chronic disease that causes inflammation of connective tissue. The most common form of lupus affects exposed areas of the skin, while the more serious and potentially fatal form can affect many systems of the body including the kidneys. It is an autoimmune disorder, in which the immune system for unknown reasons attacks connective tissue as though it were foreign.


Environmental Health Perspectives. 2003 August; 111(10): 1273–1277.

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

Charles S Via, Phuong Nguyen, Florin Niculescu, John Papadimitriou, Dennis Hoover, and Ellen K Silbergeld

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.

Discussion

…It is well recognized that iHg exposure can induce an autoimmune renal disease in genetically susceptible murine strains and that iHg exposure can exacerbate disease in animal models of spontaneously developing autoimmunity.  We found that iHg pretreatment significantly worsened lupus-like disease, as evidenced by earlier onset of proteinuria, more severe histologic features of lupus-like glomerulonephritis, and premature mortality…

…It is important to note that these results were induced using doses of iHg and a duration of treatment that are substantially lower than those used by most other studies of iHg immunotoxicity…

…These results, taken together, indicate that mercury has very potent interactive effects with autoimmunity at doses considerably lower than those required to induce autoimmunity in susceptible mouse strains that do not develop disease in the absence of iHg…

…Our results extend these observations by demonstrating that iHg can also accelerate and exacerbate acquired autoimmune disease even when exposure precedes disease. Studies are in progress to determine the maximal time that iHg exposure can precede disease induction and still exert a synergistic effect on disease expression…

…Our results support the hypothesis that low-level environmental exposure to Hg is one potential factor in the development of autoimmune disease. Specifically, low-level iHg exposure likely does not induce disease by itself; however, it may lower the threshold for disease development in susceptible individuals who later encounter the appropriate infectious or toxic triggers of disease. 

PMCID: PMC1241605

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