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RESEARCH PRODUCT

The Action of Di-(2-Ethylhexyl) Phthalate (DEHP) in Mouse Cerebral Cells Involves an Impairment in Aryl Hydrocarbon Receptor (AhR) Signaling

Konrad A. SzychowskiAgnieszka M. Sitarz-głowniaMalgorzata SzczesnaAnna Wójtowicz

subject

0301 basic medicineNervous systemendocrine systemCYP1B1Gene ExpressionNeocortexToxicologyMice03 medical and health scienceschemistry.chemical_compound0302 clinical medicineDiethylhexyl PhthalateGliaCytochrome P-450 CYP1A1medicineAnimalsCyp1a1RNA MessengerCells Culturedchemistry.chemical_classificationNeuronsReactive oxygen speciesMessenger RNADose-Response Relationship DrugbiologyDEHPChemistryGeneral NeuroscienceAhRPhthalateROSrespiratory systemAryl hydrocarbon receptorIn vitroCell biology030104 developmental biologymedicine.anatomical_structureReceptors Aryl HydrocarbonCytochrome P-450 CYP1B1biology.proteinOriginal ArticleSignal transductionReactive Oxygen SpeciesNeuroglia030217 neurology & neurosurgerySignal Transduction

description

Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer in various plastic compounds, such as polyvinyl chloride (PVC), and products including baby toys, packaging films and sheets, medical tubing, and blood storage bags. Epidemiological data suggest that phthalates increase the risk of the nervous system disorders; however, the impact of DEHP on the brain cells and the mechanisms of its action have not been clarified. The aim of the present study was to investigate the effects of DEHP on production of reactive oxygen species (ROS) and aryl hydrocarbon receptor (AhR), as well as Cyp1a1 and Cyp1b1 mRNA and protein expression in primary mouse cortical neurons and glial cells in the in vitro mono-cultures. Our experiments showed that DEHP stimulated ROS production in both types of mouse neocortical cells. Moreover, the results strongly support involvement of the AhR/Cyp1A1 signaling pathway in the action of DEHP in neurons and glial cells. However, the effects of DEHP acting on the AhR signaling pathways in these two types of neocortical cells were different. In neurons, AhR mRNA expression did not change, but AhR protein expression decreased in response to DEHP. A similar trend was observed for Cyp1a1 and Cyp1b1 mRNA and protein expression. Failure to induce Cyp1a1 in neurons was confirmed by EROD assay. In primary glial cells, a decrease in AhR protein level was accompanied by a decrease in AhR mRNA expression. In glial cells, mRNA and protein expression of Cyp1a1 as well as Cyp1a1-related EROD activity were significantly increased. As for Cyp1b1, both in neurons and glial cells Cyp1b1 mRNA expression did not significantly change, whereas Cyp1b1 protein level were decreased. We postulate that developmental exposure to DEHP which dysregulates AhR/Cyp1a1 may disrupt defense processes in brain neocortical cells that could increase their susceptibility to environmental toxins.

yearjournalcountryeditionlanguage
2018-03-26Neurotoxicity Research
10.1007/s12640-018-9946-7https://doi.org/10.1007/s12640-018-9946-7