Abstract
Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters. DBP is widely used as a plasticizer in a variety of household industries and consumer products. Because phthalates are not chemically bound to products, they can easily leak out to enter the environment. DBP can pass through the placental and blood–brain barriers due to its chemical structure, but little is known about its mechanism of action in neuronal cells. This study demonstrated the toxic and apoptotic effects of DBP in mouse neocortical neurons in primary cultures. DBP stimulated caspase-3 and LDH activities as well as ROS formation in a concentration (10 nM–100 µM) and time-dependent (3–48 h) manner. DBP induced ROS formation at nanomolar concentrations, while it activated caspase-3 and LDH activities at micromolar concentrations. The biochemical effects of DBP were accompanied by decreased cell viability and induction of apoptotic bodies. Exposure to DBP reduced Erα and Pparγ mRNA expression levels, which were inversely correlated with protein expression of the receptors. Treatment with DBP enhanced Ahr mRNA expression, which was reflected by the increased AhR protein level observed at 3 h after exposure. ERα, ERβ, and PPARγ antagonists stimulated DBP-induced caspase-3 and LDH activities. AhR silencing demonstrated that DBP-induced apoptosis and neurotoxicity are mediated by AhR, which is consistent with the results from DBP-induced enhancement of AhR mRNA and protein expression. Our study showed that AhR is involved in DBP-induced apoptosis and neurotoxicity, while the ERs and PPARγ signaling pathways are impaired by the phthalate.
Highlights
Dibutyl phthalate is one of the most commonly used phthalate esters and is an endocrinedisrupting chemical (EDC)
To explore the molecular mechanisms of DBP action on neocortical neurons, we studied the involvement of estrogen receptor alpha (ERa), estrogen beta receptor (ERb), peroxisome proliferator-activated receptor gamma (PPARc), and aryl hydrocarbon receptor (AhR) in DBP-induced effects
Taking into account the DBP-induced alterations in mRNA and protein levels of nuclear receptors, we suggest that AhR is involved in DBP-induced apoptosis and neurotoxicity, whereas the ERs and PPARc signaling pathways are impaired by the phthalate
Summary
Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters and is an endocrinedisrupting chemical (EDC). A study conducted on male Wistar rats showed that DBP was detected in rat brains after a single oral dose (Williams and Blanchfield 1975). DBP accumulation was much higher after chronic (3 or 6 months) exposure than after a single inhalation (Kawano 1980), indicating effective accumulation of the phthalate in brain tissue. DBP has been shown to pass through the placental and blood–brain barriers in rats (Williams and Blanchfield 1975; Kawano 1980; Saillenfait et al 1998; Huang et al 2014). Little is known about mechanisms of action of DBP in the nervous system, especially in the early developmental stages
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