Low-Dose Inorganic Mercury Increases Severity and Frequency of Chronic Coxsackievirus-Induced Autoimmune Myocarditis in Mice

Abstract

Mercury is a widespread environmental contaminant with neurotoxic impacts that have been observed over a range of exposures. In addition, there is increasing evidence that inorganic mercury (iHg) and organic mercury (including methyl mercury) have a range of immunotoxic effects, including immune suppression and induction of autoimmunity. In this study, we investigated the effect of iHg on a model of autoimmune heart disease in mice induced by infection with coxsackievirus B3 (CVB3). We examined the role of timing of iHg exposure on disease; in some experiments, mice were pretreated with iHg (200 μg/kg, every other day for 15 days) before disease induction with virus inoculation, and in others, they were treated with iHg after the acute (viral) phase of disease but before the development of dilated cardiomyopathy (DCM). iHg alone had no effect on heart pathology. Pretreatment with iHg before CVB3 infection significantly increased the severity of chronic myocarditis and DCM compared with control animals receiving vehicle alone. In contrast, treatment with iHg after acute myocarditis did not affect the severity of chronic disease. The increased chronic myocarditis, fibrosis, and DCM induced by iHg pretreatment were not due to increased viral replication in the heart, which was unaltered by iHg treatment. iHg pretreatment induced a macrophage infiltrate and mixed cytokine response in the heart during acute myocarditis, including significantly increased interleukin (IL)-12, IL-17, interferon-γ, and tumor necrosis factor-α levels. IL-17 levels were also significantly increased in the spleen during chronic disease. Thus, we show for the first time that low-dose Hg exposure increases chronic myocarditis and DCM in a murine model.

Effects of Endocrine Disrupters on Immune Function and Inflammation

“…In contrast, type I interferon production does not appear to be involved [50]. The role of altered innate immune cell responses was also noted by Nyland et al [51], who found that prior mercury exposure caused a problematic, macrophage-driven response to viral infection in mice, leading to cardiac inflammation and an increased likelihood of autoimmunity. Mercury exposure affects the function of many organs; among these are the brain and neurological system, which are vulnerable to oxidative-induced damage [52].…”

Low-dose mercury heightens early innate response to coxsackievirus infection in female mice

“…Previously, we found that in order for mercury to increase chronic myocarditis and dilated cardiomyopathy, mercury exposure had to occur prior to CVB3 infection [17]. Thus, we hypothesize that mercury modulates the early innate immune response to CVB3 infection and thereby sets in place a cascade of events ending in increased severity of myocarditis and prevalence of dilated cardiomyopathy.…”

“…In lupus-prone female BXSB mice, low dose mercury can accelerate kidney disease [15] and pretreatment with low dose mercury accelerates disease in the chronic Graft-versus-Host model of lupus in female, but not in male mice [16]. We recently reported that pretreatment with low dose mercury increases the severity of chronic autoimmune myocarditis and the prevalence of dilated cardiomyopathy in the coxsackievirus B3 (CVB3) and experimental autoimmune myocarditis models [17, 18]. However, the precise mechanisms for enhanced disease remain unclear.…”

“…We confirmed that mercury exposure exacerbates chronic autoimmune myocarditis in female BALB/c mice as in our previous report in males. In addition, we have shown that mercury exposure without CVB3 infection does not induce myocarditis in female BALB/c mice [17]. …”

60-Day Chronic Exposure to Low Concentrations of HgCl2 Impairs Sperm Quality: Hormonal Imbalance and Oxidative Stress as Potential Routes for Reproductive Dysfunction in Rats

“…The main contribution to human exposure is the ingestion of fish and seafood (methylmercury); however, it can also occur from dental amalgam fillings (metallic mercury), vaccines (ethylmercury) and contaminated water and air (mercury chloride) [1], [2].…”