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

Abstract

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.

Exposure to Phthalates and Cardiovascular Diseases with type 2 Diabetes

“…Given that people are exposed to mixtures of phthalate metabolites, there may be a bene t to drawing conclusions for subclasses of phthalates rather than for individual chemicals. DEHP is one of the most commonly used phthalates and has been shown to have interaction effects on androgen receptors, PPAR receptors and the aryl-hydrocarbon receptor (Stroheker et al, 2005;Wojtowicz et al, 2019). In our study, we did not nd that DEHP was signi cantly associated with self-reported CVD, plaque and CIMT, though a marginal association with CCA diameter (β 0.088, 95% -0.003, 0.179, P 0.057) was found.…”

Di‐(2‐ethylhexyl) phthalate exposure induces female reproductive toxicity and alters the intestinal microbiota community structure and fecal metabolite profile in mice

“…[1][2][3] DEHP is continuously released from plastic products and directly infiltrates food, water and air; thus, humans are exposed to DEHP daily via ingestion, inhalation, and dermal absorption. 2,[4][5][6] In recent years, DEHP and its active metabolic product, mono (2-ethylhexyl) phthalate (MEHP), have been successively detected in many tissues, including the liver, blood, cord blood, breast milk, placenta, amniotic fluid, and early gestation villi. [7][8][9] According to previous studies, DEHP is associated with hepatic, renal and neural injures or diseases.…”

Overexpression of the Aryl Hydrocarbon Receptor (Ahr) Mediates an Oxidative Stress Response following Injection of Fine Particulate Matter in the Temporal Cortex

“…Thus, organic compounds found in PMs could be metabolized by CYPs and produce reactive oxygen species, which in turn may trigger inflammation [ 24 ]. In an in vitro study, activation of the AhR/CYP1A1 pathway in cortical neurons and glial cells was described following exposure to the xenobiotic compound Di-(2-ethylhexyl) phthalate [ 28 ]. Although increases in the levels of CYP1A1 and AhR in the temporal cortex were localized to the side of injection, the expression of CYP1B1 and iNOS was elevated on both sides of the temporal cortex in the PM 2.5 group.…”