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.
Highlights
Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer in various plastic compounds such as polyvinyl chloride (PVC), and products including toys, food packaging film and sheets, medical devices, and blood storage bags and household products (Tickner et al 2001; Szychowski and Wójtowicz 2013)
Because of the interactions between reactive oxygen species (ROS) and aryl hydrocarbon receptor (AhR) signaling in neuronal cells (Szychowski et al 2016), the present study aimed to investigate the effects of DEHP on ROS production; AhR, Cyp1a1 and Cyp1b1 mRNA, and protein expression; and Cyp1a1related EROD activity in mouse cortical neurons and glial cells in vitro
In neurons exposed to DEHP for 24 h, we observed an increase in ROS production at concentrations of 10, 50, and 100 μM (Fig. 1a)
Summary
Di-(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer in various plastic compounds such as polyvinyl chloride (PVC), and products including toys, food packaging film and sheets, medical devices, and blood storage bags and household products (Tickner et al 2001; Szychowski and Wójtowicz 2013). DEHP and its metabolite, mono-(2-ethylhexyl)-phthalate (MEHP), can be detected in human tissues and bodily fluids, such as amniotic fluid, blood, milk, or urine (Silva et al 2004; Sakhi et al 2017). DEHP and MEHP have been reported to pass through biological barriers, such as the placental barrier or blood-brain barrier, and can affect development and proper nervous system function (Shin et al 2014; Lin et al 2015a; Komada et al 2016). There is an increasing body of evidence that shows the deleterious effects of DEHP on the nervous system, little is known about its mechanism of action on mammalian cerebral cells
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