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Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring

Di-(2-Ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) present significant environmental endocrine-disrupting chemical properties. Although studies have implied reproductive impairment from exposure to BPA and DEHP, no study to date has shown the effect and mechanism of hepatic function after gest...

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Autores principales: Wang, Minghan, Wang, Yu, Han, Junyuan, Duan, Zhiwen, Yin, Jiye, Ding, Rigao, Wang, Quanjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058277/
https://www.ncbi.nlm.nih.gov/pubmed/36976981
http://dx.doi.org/10.3390/toxics11030216
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author Wang, Minghan
Wang, Yu
Han, Junyuan
Duan, Zhiwen
Yin, Jiye
Ding, Rigao
Wang, Quanjun
author_facet Wang, Minghan
Wang, Yu
Han, Junyuan
Duan, Zhiwen
Yin, Jiye
Ding, Rigao
Wang, Quanjun
author_sort Wang, Minghan
collection PubMed
description Di-(2-Ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) present significant environmental endocrine-disrupting chemical properties. Although studies have implied reproductive impairment from exposure to BPA and DEHP, no study to date has shown the effect and mechanism of hepatic function after gestational and lactational co-exposure to DEHP and BPA in offspring. A total of 36 perinatal rats were randomly divided into four groups, DEHP (600 mg/kg/day), BPA (80 mg/kg/day), DEHP combined with BPA (600 mg/kg/day + 80 mg/kg/day), and control. Notably, 11 chemical targets were screened after identifying eight substances associated with chemically-induced hepatic damage. Molecular docking simulations revealed a high-scoring combination of eight metabolic components and targets of the PI3K/AKT/FOXO1 signaling pathway. The DEHP and BPA combination disrupted hepatic steatosis, ultimately affecting systemic the glucose and the lipid metabolic homeostasis with significant toxicity. Mechanistically, co-exposure to DEHP and BPA causes liver dysfunction and hepatic insulin resistance via PI3K/AKT/FOXO1 pathway in offspring. This is the first study of the hepatic function and mechanism of co-exposure to DEHP and BPA that combines metabolomics, molecular docking, and traditional toxicity assessment methods.
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spelling pubmed-100582772023-03-30 Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring Wang, Minghan Wang, Yu Han, Junyuan Duan, Zhiwen Yin, Jiye Ding, Rigao Wang, Quanjun Toxics Article Di-(2-Ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) present significant environmental endocrine-disrupting chemical properties. Although studies have implied reproductive impairment from exposure to BPA and DEHP, no study to date has shown the effect and mechanism of hepatic function after gestational and lactational co-exposure to DEHP and BPA in offspring. A total of 36 perinatal rats were randomly divided into four groups, DEHP (600 mg/kg/day), BPA (80 mg/kg/day), DEHP combined with BPA (600 mg/kg/day + 80 mg/kg/day), and control. Notably, 11 chemical targets were screened after identifying eight substances associated with chemically-induced hepatic damage. Molecular docking simulations revealed a high-scoring combination of eight metabolic components and targets of the PI3K/AKT/FOXO1 signaling pathway. The DEHP and BPA combination disrupted hepatic steatosis, ultimately affecting systemic the glucose and the lipid metabolic homeostasis with significant toxicity. Mechanistically, co-exposure to DEHP and BPA causes liver dysfunction and hepatic insulin resistance via PI3K/AKT/FOXO1 pathway in offspring. This is the first study of the hepatic function and mechanism of co-exposure to DEHP and BPA that combines metabolomics, molecular docking, and traditional toxicity assessment methods. MDPI 2023-02-24 /pmc/articles/PMC10058277/ /pubmed/36976981 http://dx.doi.org/10.3390/toxics11030216 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Minghan
Wang, Yu
Han, Junyuan
Duan, Zhiwen
Yin, Jiye
Ding, Rigao
Wang, Quanjun
Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title_full Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title_fullStr Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title_full_unstemmed Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title_short Gestational and Lactational Co-Exposure to DEHP and BPA Impairs Hepatic Function via PI3K/AKT/FOXO1 Pathway in Offspring
title_sort gestational and lactational co-exposure to dehp and bpa impairs hepatic function via pi3k/akt/foxo1 pathway in offspring
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058277/
https://www.ncbi.nlm.nih.gov/pubmed/36976981
http://dx.doi.org/10.3390/toxics11030216
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