In vitro and in silico investigations of endocrine disruption induced by metabolites of plasticizers through glucocorticoid receptor. (September 2021)

• Record Type: Journal Article
• Authors: Leng, Yue; Ren, Li; Niu, Shu; Zhang, Tiehua; Zhang, Jie
• Is Part Of: Food and chemical toxicology. Volume 155(2021)
• Publication Date: 2021-09
• Subjects: Glucocorticoid receptor -- Metabolites of plasticizers -- Endocrine disrupters -- Synergism; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112413
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: The endocrine disruptive capability of plasticizers to activate nuclear receptors has attracted great interest. This study is aimed to assess the potential glucocorticoid effects of metabolites of plasticizers. The effects of metabolites of plasticizers on the transcriptional activity of glucocorticoid receptor (GR) were investigated using reporter gene assays. All of them failed to exhibit agonistic/antagonistic effects on GR. However, a combination of dexamethasone and monobutyl phthalate (MBP) could synergistically activate GR. MBP combined with dexamethasone also enhanced GR nuclear translocation by Western blot, while mifepristone restrained GR cytoplasmic-to-nuclear translocation. MBP co-treated with dexamethasone resulted in synergistic induction of PEPCK and MKP-1 gene expression by real-time PCR and PEPCK protein level by Western blot. Furthermore, the carboxyl and ester groups of MBP have influences on the charge distribution of MBP, leading to change of electrostatic interactions between MBP and GR by calculations on electronic properties. Both hydrophobic and hydrogen bonding interactions play a crucial role in the stabilization between MBP and GR conducted by molecular docking and dynamics simulation. This work confirms that GR could remain stable upon binding to MBP. In conclusion, dexamethasone and MBP could synergistically activate GR, resulting in synergetic enhancement of subsequent GR-mediated endocrine disrupting effect. Highlights: Metabolites of plasticizers were evaluated for GR-mediated toxic effects in vitro. MBP but no other metabolites of plasticizers could synergistically activate GR in presence of dexamethasone. Induction of the glucocorticoid-responsive gene by dexamethasone was synergistically enhanced by MBP. GR could remain stable upon binding to MBP.