4-(2-phenyl-5-7-bis(trifluoromethyl)pyrazolo(1-5-a)pyrimidin-3-yl)phenol and alpha-naphthoflavone

Extended residual persistence of the pesticide dichlorodiphenyltrichloroethane (DDT) raises concerns about its long-term neurotoxic effects. Little is known, however, about DDT toxicity during the early stages of neural development. This study demonstrated that DDT-induced apoptosis of mouse embryonic neuronal cells is a caspase-9-, caspase-3-, and GSK-3β-dependent process, which involves p,p'-DDT-specific impairment of classical ERs. It also provided evidence for DDT-isomer-nonspecific alterations of AhR- and GPR30-mediated intracellular signaling, including changes in the levels of the receptor and receptor-regulated mRNAs, and also changes in the protein levels of the receptors. DDT-induced stimulation of AhR-signaling and reduction of GPR30-signaling were verified using selective ligands and specific siRNAs. Co-localization of the receptors was demonstrated with confocal microscopy, and the presence of functional GPR30 was detected by electrophysiology. This study demonstrates that stimulation of AhR-signaling and impairment of GPR30-signaling play important roles in the propagation of DDT-induced apoptosis during the early stages of neural development.

Topics: Animals; Apoptosis; Benzodioxoles; Benzoflavones; beta-Naphthoflavone; Caspase 3; Caspase Inhibitors; Cells, Cultured; Cytochrome P-450 CYP1A1; DDT; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Isomerism; L-Lactate Dehydrogenase; Mice; Neurons; Pyrazoles; Pyrimidines; Quinolines; Receptors, Aryl Hydrocarbon; Receptors, Estrogen; Receptors, G-Protein-Coupled; RNA, Messenger; Signal Transduction; Time Factors