Ex vivo exposure to p,p'-DDE decreases human macrophage polarization to the M1 phenotype.

Abstract

Evidence from cellular and animal model studies has shown that p,p-dichloro-diphenyl-trichloroethane (p,p'-DDT) and p,p-dichloro-diphenyl-dichloroethylene (p,p'-DDE) negatively affect the macrophage's inflammatory response and resistance to pathogen infections. Still, no evidence is available on the p,p'-DDE effects on human macrophages, even though there is a translational value to human public health. This study aimed to determine p,p'-DDE serum concentrations in human volunteers with non-occupational exposure and to investigate the effect of ex vivo exposure to p,p'-DDE on the polarization of human monocyte-derived macrophages (hMDM) toward the M1 phenotype. p,p'-DDE from thirty healthy male volunteers was quantified by gas chromatography with a micro-electron capture detector. The hMDM were differentiated using GM-CSF. hMDM were exposed to 25-2500 ng/ml p,p'-DDE for 48 h, and after 24 h of exposure, they were activated with LPS+IFN-γ to the M1 phenotype for 24 h. p,p ´ -DDT was detected in 4/30 individuals (mean= 0.54 ± 0.35 ng/ml), and 30/30 had p,p ´ -DDE (mean=0.57 ± 0.34 ng/ml). Ex vivo, p,p ´ -DDE did not affect cell viability but decreased the expression of M1-polarization markers (HLA-DR and CD68). Bivariate and multivariate analyses revealed that in the M1 macrophage phenotype, 25-2500 ng/ml p,p'-DDE, in a concentration-dependent manner, decreased NO^•- -production, IL-1β, TNF-α, and IL-12 secretion, while increasing ROS. Our study showed that humans are still exposed to p,p'-DDE. Experimental results suggest that p,p'-DDE negatively interferes with the polarization of hMDMs toward the M1 phenotype at environmentally relevant concentrations, influencing key inflammatory mediators critical to innate immunity against pathogens and inducing oxidative stress. This study is the first to evaluate the effect of the p,p'-DDE on polarization of hMDMs to the M1-phenotype. It may contribute to addressing studies to determine whether the incidence of pathologies associated with inflammatory macrophage dysfunction is higher in human populations exposed to DDT and its metabolites. These data will be valuable for implementing policy and health intervention strategies in individuals still exposed to this pesticide.