Prolongation of Human Neutrophil Survival by Low-Level Mercury via Inhibition of Spontaneous Apoptosis

Abstract

Low levels of organic and inorganic mercury compounds have been reported previously to induce cell death by apoptosis in human peripheral blood mononuclear cells (MNC). but little is known about their potential effects on the viability and death of polymorphonuclear neutrophils (PMN). In contrast to MNC, PMN are known to undergo readily spontaneous apoptosis both in vivo and in vitro. Therefore, it was hypothesized that PMN may differ from MNC in their reactions to low mercury levels. The effects of methylmercuric chloride (MeHgCl) and mercuric chloride (HgCl2) were evaluated in concentration-response and time-course studies on human PMN viability and on their modes of cell death after in vitro incubation at 37 degrees C. Cell death by apoptosis or necrosis was assessed by annexin V-fluorescein isothiocyanate binding to externalized phosphatidylserine in conjunction with propidium iodide, and flow cytometry analysis. Morphologic counting of pyknotic nuclei and the fluorescence properties of the DNA-binding dye Hoechst 33342 in combination with propidium iodide were used to further confirm apoptotic cell death and to characterize the sequence of Hg-induced cell death. Results show that low concentrations of MeHgCl (1-7.5 microM) that were cytotoxic to MNC actually inhibited PMN spontaneous apoptosis. Low-level HgCl, reproduced the anti-apoptotic effects of MeHgCl on PMN, but to a lower extent. Higher concentrations of MeHgCl and HgCl2 were necrogenic to PMN, but MeHgCl was about an order of magnitude more toxic, and discrete differences were observed in the modalities of cell death induced by both species. These data reveal for the first time that (1) low levels of organic and inorganic mercury species protect human PMN from cell death via inhibition of spontaneous apoptosis, and (2) PMN are more resistant than MNC to mercury-induced cytotoxicity. Since delayed apoptosis and increased resistance to toxicant-induced cell death may lead to excessive accumulation of senescent PMN, evidence indicates that findings of this study may have implications for mercury-induced autoimmunity and inflammation.

Children’s white blood cell counts in relation to developmental exposures to methylmercury and persistent organic pollutants

“…In the Faroes, total mercury concentrations in blood and hair primarily indicate exposures to methylmercury [38], thus suggesting that different chemical speciations may affect the mercury-associated toxicity. Mercury-induced cytotoxicity has been demonstrated in cells of the immune system, including B cells, T cells, and monocytes [39, 40], and two in vitro studies demonstrated that Hg exposure causes mitochondrial dysfunction and enhances the apoptosis of neutrophils and mononuclear cells including T cells [41, 42]. However, mercury has also been shown to exert immunomodulatory and anti-apoptotic effects in animals [43] and to be associated with autoimmune diseases in both animals and humans [44].…”

Toxaphene, but Not Beryllium, Induces Human Neutrophil Chemotaxis and Apoptosis via Reactive Oxygen Species (ROS): Involvement of Caspases and ROS in the Degradation of Cytoskeletal Proteins

“…In contrast, we have found that tributyltin (TBT) can induce neutrophil apoptosis (18). Intriguingly, mercury was found to delay or induce neutrophil apoptosis, depending on the concentration used and the duration of treatment (34).…”

Acute Depletion and Recovery of Peritoneal B-1 Lymphocytes in BALB/c Mice after a Single Injection of Mercury Chloride

“…Our finding of apoptosis resistance of neutrophils induced by Hg strengthens recent in vitro evidence of the preventive effect of Hg on neutrophil cell death. (28,29) It is plausible that our described severe loss of B cells induced by Hg may lead to permanent unbalance in the repertoire of antibody-producing cells. This is important because cell interactions among members of a complete repertoire of B lymphocytes are required for the suppression of pathogenic autoimmune reactivities.…”