The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

Abstract

Dichlorodiphenyldichloroethylene (DDE) is a primary environmental and metabolic degradation product of the pesticide dichlorodiphenyltrichloroethane (DDT). It is one of the most toxic compounds belonging to organochlorines. DDE has never been commercially produced; however, the parent pesticide DDT is still used in some developing countries for disease-vector control of malaria. DDT and DDE remain in the environment because these chemicals are resistant to degradation and bioaccumulate in the food chain. Little is known, however, about DDE toxicity during the early stages of neural development. The results of the present study demonstrate that DDE induced a caspase-3-dependent apoptosis and caused the global DNA hypomethylation in mouse embryonic neuronal cells. This study also provided evidence for DDE-isomer-non-specific alterations of retinoid X receptor α (RXRα)- and retinoid X receptor β (RXRβ)-mediated intracellular signaling, including changes in the levels of the receptor mRNAs and changes in the protein levels of the receptors. DDE-induced stimulation of RXRα and RXRβ was verified using selective antagonist and specific siRNAs. Co-localization of RXRα and RXRβ was demonstrated using confocal microscopy. The apoptotic action of DDE was supported at the cellular level through Hoechst 33342 and calcein AM staining experiments. In conclusion, the results of the present study demonstrated that the stimulation of RXRα- and RXRβ-mediated intracellular signaling plays an important role in the propagation of DDE-induced apoptosis during early stages of neural development.

Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort

“…p,p'-DDE is a breakdown product of the insecticide dichlorodiphenyltrichloroethane (DDT), well-known for its anti-androgenic activities [59]. Populationbased studies have shown that men with adult [60] or prenatal [61] DDE exposure were sub-fertile [62] and were also associated with impairment of cognitive functions, deficits in psychosocial developments in childhood [63][64][65][66][67], and increased risk of neural degenerative diseases at old age [68]. nPFOS belongs to a group of substances that are widely used in a variety of products including surface treatments for stain resistance, surface treatments on metals, as well as firefighting foams.…”

Triclocarban Disrupts the Epigenetic Status of Neuronal Cells and Induces AHR/CAR-Mediated Apoptosis

“…The apoptotic cells were stained with Hoechst 33342 after 24 h, as previously described [ 38 ]. The neocortical cells cultured on glass cover slips were washed with 10 mM phosphate-buffered saline (PBS) and exposed to the stain (0.6 mg/ml), at room temperature for 5 min.…”

“…To determine the methylation statuses of the DNA in the neocortical cells that were exposed to triclocarban, an Imprint Methylated DNA Quantification Kit was utilized. The capture and detection antibodies detected the methylated DNA that was quantified colorimetrically as previously described [ 38 – 40 ]. The purified DNAs were added to a 96-well plate (150 ng/well) where they bound with the capture antibody.…”

“…The quantity of RNA was determined at 260 nm and 260/280 nm (ND/1000 UV/Vis; Thermo Fisher NanoDrop, USA). The two-step qPCR involved the reverse transcription (RT) reaction and qPCR which were run in the CFX96 Real-Time System (Bio-Rad, USA) as previously described [ 38 ]. The RT reaction was performed using the cDNA reverse transcription kit at a final volume of 20 μl with 300 ng of RNA as a cDNA template.…”

Retinoid X Receptor Antagonists

“…60 Compound 12 is also used as a tool to investigate the influence of environmental hormones on RXR. For example, the mechanism of neurotoxicity by dichlorodiphenyldichloroethylene (DDE), 61 the effect of tributyltin on osteogenesis, 62 and the toxicity of organotin 63 were found to involve transcriptional activation of RXR.…”