| Epidemiological studies have reported that exposure to organophosphate (OP) pesticides is associated with onset of asthma; however few studies have examined the molecular basis for this association. This dissertation used both molecular epidemiology and in vitro experimental approaches to investigate the relationship between exposure to OP pesticides and T-helper-1 and T-helper-2 (Th1 and Th2) cytokine profiles, biological markers that are mechanistically relevant to development of allergic disorders. The two specific aims were: (1) to measure the Th1/Th2 subsets in the CHAMACOS (Center for Health Assessment of Mothers and Children of Salinas) birth cohort of Latino migrant farm workers exposed to elevated levels of OP pesticides, allergens, and endotoxin and (2) to conduct in vitro experiments to examine the specific effects of OP chlorpyrifos (CPF), and its metabolites chlorpyrifos-oxon (CPO) and 3,5,6-Trichloro-2-pyridinol (TCP), alone, and in combination with endotoxin lipopolysaccharide (LPS) or house dust mite Dermatophagoides pteronyssinus (Derp1) allergen, on expression of IFN-gamma/IL-4, Th1/Th2 cytokines, respectively. Th1/Th2 cytokines were measured by flow cytometric detection of intracellular cytokines, ELISA, and Luminex(TM). Elevated Th1 status in CHAMACOS children (N = 286) at 24-months of age was associated with exclusive breastfeeding, pet ownership, having a father who works in agriculture, and mother who works in fields (p < 0.05). Further, higher levels of both CPF and LPS in household dust were associated with elevated Th1 status in children (p < 0.05). Finally, in vitro experiments confirmed that whole blood cultures treated with low doses of CPO (1 and 10mug/mL), in combination with LPS, expressed higher levels of IFN-gamma than LPS alone (p < 0.05). This effect was not observed for combined CPF/LPS and TCP/LPS exposures. Nor was potentiation of IL-4 cytokine expression observed in cultures treated with CPF, CPO, and TCP in combination with the allergen Derp1. No expression of cytokines was detected in cultures treated with CPF, CPO, or TCP alone. In conclusion, our results suggest that CPF, specifically CPO, increases LPS induction of IFN-gamma. This interaction between CPO and LPS, which results in an increased Type 1 immune response, should be further investigated, particularly since the combination of OP pesticides and endotoxin is common in rural, agricultural communities. |
