ORIGINAL ABSTRACT

Pesticides are used to combat agricultural pests but also trigger side effects on non-target organisms. Particularly, immune system dysregulation is a major concern due to the organism's increased vulnerability to diseases, including cancer development. Macrophages play essential roles in innate and adaptive immunity and can undergo classical (M1) or alternative (M2) activation. The M1 pro-inflammatory phenotype has an antitumor role, while M2 favors tumor promotion. Although previous studies have linked pesticide exposure to immune compromise, macrophage polarization is still poorly studied. Here, we investigated the effects of 72 h-long exposure to the mixture of four pesticides widely used in Brazil (glyphosate, 2,4-D, mancozeb, and atrazine), and their main metabolites (aminomethylphosphonic acid, 2,4-diclorophenol, ethylenethiourea, and desethylatrazine) on human leukemia monocytic THP-1 cell line at concentrations based on the Acceptable Daily Intake (ADI) value established in the country. The data revealed immunotoxicity related to impaired cell metabolism in all exposed groups, decreased cell attachment (Pes: 10-1; Met: 10-1; Mix: all concentrations), and disturbance in nitric oxide (NO) levels (Met: 10-1, 101; Mix: all concentrations). The polarization of macrophages towards a more pro-tumor M2-like phenotype was also supported by decreased secretion of the pro-inflammatory cytokine TNF-α (Pes 100, 101) and increased IL-8 (Pes 101). These outcomes alert about the risk of pesticide exposure in the Brazilian population.