Organophosphorus (OP) compounds are widely used as pesticides, plasticizers, lubricants, and flame-retardants. The most serious effect of acute exposure to the insecticidal OP's is neurotoxicity resulting from their anti-cholinesterase activity. However, most human exposures involve quantities too small to produce substantial neurotoxicity. Possible effects of such exposures on organs or systems other than the nervous system have not been thoroughly studied, but there is evidence that some OP compounds can affect particular cells or functions of the mammalian immune system. Because of the potential for increased rates of infectious disease or cancer in persons with immunological deficits, this matter deserves further investigation. The only immunosuppressive OP compound which has been thoroughly investigated is O,O,S-trimethyl phosphorothioate, a contaminant of some commercial pesticide preparations. Mice treated with this compound have diminished cellular and humoral immune responses which are apparently caused by macrophages which suppress lymphocyte proliferation or fail to properly process and present antigen. Several other OP compounds which have not been as carefully characterized with regard to immunotoxicity also affect macrophage functions. However, there is insufficient evidence to conclude that these alterations could be generalized mechanism of OP immunotoxicity. The study proposed here seeks additional evidence regarding this matter by examining the hypothesis that a commonly used OP insecticide (methyl parathion), which suppresses humoral immunity and host resistance to bacterial challenge, functions by inducing suppressive or dysfunctional macrophages. This hypothesis will be tested by determining the cellular target(s) of immunotoxicity and by examining macrophage suppressive and antigen processing/presenting activity following acute or 21-day exposure of mice to methyl parathion or a negative control OP. In addition, the effects of these compounds on cellular and humoral immunity, complement activity, NK cell activity, macrophage microbicidal activity, and host resistance to microbial challenge will be tested as suggested in the NTP's Guidelines for Immunotoxicity Evaluation in Mice. This will allow assessment of the relevance of the effects of the compounds on macrophages by revealing their overall effect on the immune system and by revealing other possible mechanisms of immunotoxicity as well as possible compensatory mechanisms.
NIH ExPorter
NIH ExPorter