DDT inhibits the functional activation of murine macrophages and decreases resistance to infection by Mycobacterium microti.
DDT is still widely used in several parts of the world to control malaria, typhoid and dengue vectors, even though its use was banned in many countries based on toxicity data in wild life species. DDT has been shown to have immunotoxic effects in mice and to increase susceptibility to intracellular pathogens such as Mycobacterium leprae. However, little is known about the mechanisms underlying this effect. Activated macrophages play an important defensive role against intracellular pathogens, therefore our objective was to evaluate the effect of in vitro exposure to technical grade DDT (a mixture of three forms: 1,1,1-thricloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) (85%), o,p'-DDT (15%) and o,o'-DDT (trace amounts)), p,p'-DDT, 1,1-dicloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane on the functional activation of J774A.1 macrophages and their capability to limit growth of intracellular pathogens, using Mycobacterium microti as a model. We evaluated cytotoxicity and the effect on cell proliferation of 2.5, 5.0 and 10 microg/ml of DDT compounds. Functional macrophage activity (NO(*) and O(2)(-) production, and mRNA expression of TNF-alpha, IL-1beta and iNO synthase) and the ability of treated cells to limit infection by M. microti in IFN-gamma-activated macrophages were evaluated in cells exposed to 2.5 microg/ml of DDT compounds. Doses of 5 and 10 microg/ml induced direct cytotoxic effects precluding meaningful analysis of the above parameters, whereas 2.5 microg/ml of all DDT compounds inhibited macrophage activity and reduced their ability to limit the intracellular growth of M. microti without inducing cytotoxicity. Technical grade DDT and p,p'-DDE were the more potent compounds. Therefore, exposure to DDT compounds could represent an important risk for infection development by those intracellular pathogens against which NO(*) and/or O(2)(-) production represent the main immune protective mechanism.
Nuñez G
María Andrea
MA
Sección Externa de Toxicología, Centro de Investigación y de Estudios Avanzados, I.P.N. Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, P.O. Box 14-740, Mexico, D.F., C.P. 07000, Mexico.
Estrada
Iris
I
Calderon-Aranda
Emma S
ES
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003634:DDT / Q000633:toxicity*; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity; D007375:Interleukin-1 / Q000096:biosynthesis; D007536:Isomerism; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D009164:Mycobacterium Infections / Q000276:immunology*; D009569:Nitric Oxide / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003633:Dichlorodiphenyl Dichloroethylene; D003634:DDT; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse