Title: Effect of administration of malathion for 14 days on macrophage function and mast cell degranulation Rodgers K, Xiong S Ref: Fundamental & Applied Toxicology, 37:95, 1997 : PubMed
Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T-cell-dependent antigen, mitogenic responses, macrophage function, and mast cell degranulation. While administration of malathion for 14 days did not affect the generation of an immune response to antigen, it was possible that macrophage and mast cell functions were affected. In this report, the effect of malathion administration for 14 days upon these parameters were assessed. This treatment regimen increased the respiratory burst capacity to a maximal level at a dose of 1 mg/kg/day or greater. The effect of oral administration of malathion for 14 days on the degranulation of mast cells in various organs (heart, skin, and small intestine) and peritoneal lavage fluid was also assessed. At doses of 1 mg/kg/day and above, the number of mast cells that was undegranulated decreased and the number that was severely degranulated increased. There was no change in mast cell integrity in biopsies from heart and skin, and in peritoneal fluid after 14-day administration of 0.1 mg/kg/day. However, the number of mast cells associated with the small intestine that had undergone degranulation was increased at this dose of malathion. These data indicate that repeated administration of malathion increased macrophage function at doses as low as 1 mg/kg/day and led to mast cell degranulation at doses as low as 0.1 mg/kg/day.
Title: Contributions of inflammatory mast cell mediators to alterations in macrophage function after malathion administration Rodgers K, Xiong S Ref: Int J Immunopharmacol, 19:149, 1997 : PubMed
Recent studies using mast cell-defined mice showed that the presence of mast cells was necessary for the increase in macrophage function observed after oral administration of malathion and reconstitution with bone marrow-derived mast cells restored the ability of malathion to increase macrophage function. In addition, the release of mast cell mediators (blocked by cromolyn) and histamine (action blocked by pyrilamine) was shown to be involved in the action of malathion on macrophage function. In the present study, the contribution of inflammatory mediators (i.e. arachidonic acid metabolites and tumor necrosis factor [TNF]) which may be generated by mast cells after oral administration of malathion, was examined. Controls in this study included the effects of the agent to be examined on: (1) resident peritoneal macrophages; and (2) macrophages elicited with pristane, and agent shown previously to stimulate macrophage function in the absence of mast cells. Intraperitoneal administration of indomethacin, and inhibitor of cycloxygenase, or neutralizing antibody to TNF 30 h before and 4 h after oral malathion blocked the ability of malathion to increase macrophage function, as measured by the generation of respiratory burst activity and the production of cathepsin D. On the other hand, administration of these agents to mice injected intraperitoneally with pristane did not affect the observed increase in cathepsin D production. Respiratory burst function after elicitation with pristane was slightly decreased (indomethacin) or not affected (antibody to TNF). The effect of intraperitoneal administration of nordihydroguaiaretic acid (NDGA), and inhibitor of both cycloxygenase and lipoxygenase, was also examined. Intraperitoneal administration of NDGA partially blocked the effects of oral administration of malathion on peritoneal macrophage function, but did not affect the function of resident pristane-elicited peritoneal macrophages. These data suggest that inflammatory mediators (potentially released from mast cells upon stimulation) contribute to the elevation in macrophage function observed after oral malathion administration.
Title: Effect of administration of malathion for 90 days on macrophage function and mast cell degranulation Rodgers K, Xiong S Ref: Toxicol Lett, 93:73, 1997 : PubMed
Previous studies have shown that acute, oral administration of malathion modulated the humoral immune response to T cell-dependent antigen, mitogenic responses, macrophage function and mast cell degranulation. In this report, the effects of malathion administration for 90 days on macrophage function, as measured by respiratory burst capacity, phagocytic capability and the production of cathepsin D, and mast cell integrity were assessed. A dose-dependent increase in respiratory burst activity was observed at all doses tested. The production of cathepsin D was elevated at doses of 1 mg/kg/day malathion or greater. The phagocytic capability of peritoneal macrophages was elevated at the dose of 0.1 mg/kg/day, but was suppressed at higher doses. The effect of oral administration of malathion for 90 days on the degranulation of mast cells, in both organs (skin and uterus) and peritoneal lavage fluid, was also assessed. Degranulation (both severe and slight) of mast cells from the skin and peritoneum was observed at a dose of 1.0 mg/kg/day or greater. In addition, the percentage of mast cells that were undegranulated was decreased. In the skin, but not the peritoneum, these effects were dose-dependent. In the uterus, the percentage of mast cells that were undegranulated was decreased and severely degranulated was increased at a dose of 0.1 mg/kg/day or greater. These data indicate that repeated administration of malathion increased macrophage function and led to mast cell degranulation at doses as low as 0.1 mg/kg/day for 90 days.
Title: Effects of malathion metabolites on degranulation of and mediator release by human and rat basophilic cells Xiong S, Rodgers K Ref: J Toxicol Environ Health, 51:159, 1997 : PubMed
In the present study, the effects of malathion and malathion derivatives on histamine and beta-hexosaminidase release by RBL-1 cells, rat peritoneal mast cells (RPMC), and human peripheral blood basophils (HPBB) and cutaneous mast calls were examined. One hour of incubation of RBL-1 cells with all organophosphate compounds tested, except for malathion and malathion monoacid, led to an increase in histamine release. beta-Hexosaminidase, an enzyme released by basophilic cells and a biochemical marker of degranulation, was not released from RBL-1 cells after 1 h of exposure to organophosphate compounds. Within 4 h, all compounds tested increased the release of histamine and beta-hexosaminidase. Longer exposures led to a decrease in the concentration of the compound that was required to cause mediator release. Exposure of RPMC to organophosphate compounds, with the exception of malathion monoacid and malathion (30 min) or malathion monoacid (1 h), led to the release of histamine, but not beta-hexosaminidase. Incubation of HPBB with malaoxon (51.4 +/- 2.8% total histamine released), malathion diacid (25.7 +/- 2.9%), beta-malathion monoacid (31.4 +/- 2.8%), and isomalathion (57.1 +/- 17.1%) for 1 h led to the release of histamine. Only malaoxon and isomalathion caused beta-hexosaminidase release from HPBB after a 1-h incubation. Incubation of cutaneous mast cells with malaoxon and beta-monoacid for 4 h led to increased release of histamine and beta-hexosaminidase at levels comparable to compound 48/80. These data suggest that malathion metabolites can cause rapid release of histamine from basophilic cells from a variety of origins and species. With prolonged incubation, malathion itself caused the release of mast-cell mediators, suggesting that the cells may be capable of metabolizing malathion. These data also indicate a disparity between the release kinetics of two different mast-cell mediators contained in granules by organophosphates, and that there are different mechanisms of mediator release.
Title: The immunotoxicity of pesticides in rodents Rodgers K Ref: Hum Exp Toxicol, 14:111, 1995 : PubMed
Many pesticides that are widely used and have great potential for occupational and public exposure have received only a cursory examination with regards to their immunotoxic potential. Many of the studies that are available were done during the early period of immunotoxicology and many reports do not state whether or not any other toxic signs were observed and the dose-response relationships were not generally examined. Most studies were done in multiple species, through various routes of administration and using a variety of assays of immune function and do not allow a comparison. For the compounds extensively studied, the site of action has been determined at the cellular and perhaps the biochemical level, but the molecular site of action has not been determined. The approach to evaluate the mechanism of action will vary from compound to compound.
