PMID- 37348686 OWN - NLM STAT- MEDLINE DCOM- 20230724 LR - 20230724 IS - 1095-9947 (Electronic) IS - 1050-4648 (Linking) VI - 139 DP - 2023 Aug TI - Synthetic phenolic antioxidants evoked hepatoxicity in grass carp (Ctenopharyngodon idella) through modulating the ROS-PI3K/mTOR/AKT pathway: Apoptosis-autophagy crosstalk. PG - 108906 LID - S1050-4648(23)00392-3 [pii] LID - 10.1016/j.fsi.2023.108906 [doi] AB - Synthetic phenolic antioxidants (SPAs) are an environmental concern due to their persistence nature and bioaccumulation. However, the hepatoxicity and mechanisms of SPAs in aquatic organisms remain poorly understood. In this study, grass carp were exposed to two representative SPAs (BHA and BHT) at environmentally relevant levels (0.1 muM) for 30 days. We observed that BHA and BHT exposure significantly increased the levels of serum aminotransferase (ALT) and aspartate aminotransferase (AST) in grass carp, accompanied by mild inflammatory cell infiltration and irregularity in the shape of hepatocytes. Dihydro ethylenediamine staining showed that BHA and BHT exposure resulted in elevated levels of superoxide levels, accompanied by increased antioxidant enzyme activities (T-AOC, SOD, CAT, GSH-PX) and MDA levels, which is suggestive of oxidative stress responses in the liver of grass carp. Besides, BHA and BHT could dock into the pocket of phosphatidylinositol 3-kinases (PI3K) and thereby inhibiting PI3K/mammalian target of rapamycin (mTOR)/protein kinase B (AKT) signaling cascades. Meanwhile, our results clarified that BHA and BHT could promote autophagosome production and increase the expression of key autophagy proteins, likely due to inhibition of PI3K/mTOR/AKT signaling pathway. Moreover, BHA and BHT could induce apoptotic process by upregulating the expression of Bax, Caspase3 and Caspase8 and downregulating Bcl2 expression. Notably, BHT exhibited more hepatoxicity on the indicators of the apoptosis and oxidative stress than BHA. In summary, our findings demonstrated that BHA and BHT exposure could induce liver damage induced via regulating ROS/PI3K-mediated autophagic hyperactivation, which is a crucial step in triggering hepatocyte death. This study provides novel insight into the potential mechanisms underlying liver damage caused by BHA and BHT in aquatic organisms, and offers a new theoretical basis for ecological risk assessment of SPAs. CI - Copyright (c) 2023 Elsevier Ltd. All rights reserved. FAU - Li, Siwen AU - Li S AD - Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, PR China. FAU - Xie, Jiaqi AU - Xie J AD - Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, PR China; Hunan Food and Drug Vocational College, Changsha 410078, Hunan Province, PR China. FAU - Bai, Yiang AU - Bai Y AD - Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, PR China. FAU - Jiang, Zhihao AU - Jiang Z AD - Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, PR China. FAU - Li, Keman AU - Li K AD - Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, PR China. FAU - Wu, Chunling AU - Wu C AD - Gannan Healthcare Vocational College, Ganzhou 341000, Jiangxi Province, PR China; Department of Pathophysiology, College of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan Province, PR China. Electronic address: dlutwcl@163.com. LA - eng PT - Journal Article DEP - 20230620 PL - England TA - Fish Shellfish Immunol JT - Fish & shellfish immunology JID - 9505220 RN - 0 (Antioxidants) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - W36ZG6FT64 (Sirolimus) RN - 0 (Phenols) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - *Antioxidants/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Reactive Oxygen Species/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Sirolimus MH - *Carps/metabolism MH - Phenols MH - Apoptosis MH - Autophagy MH - TOR Serine-Threonine Kinases/metabolism MH - Mammals/metabolism OTO - NOTNLM OT - Apoptosis OT - Hepatoxicity OT - Oxidative stress OT - Phosphatidylinositol 3-kinases (PI3K) OT - Synthetic phenolic antioxidants COIS- Declaration of competing interest The authors declare that they have no conflict of interest. EDAT- 2023/06/23 01:10 MHDA- 2023/07/24 06:43 CRDT- 2023/06/22 19:14 PHST- 2023/05/14 00:00 [received] PHST- 2023/06/12 00:00 [revised] PHST- 2023/06/16 00:00 [accepted] PHST- 2023/07/24 06:43 [medline] PHST- 2023/06/23 01:10 [pubmed] PHST- 2023/06/22 19:14 [entrez] AID - S1050-4648(23)00392-3 [pii] AID - 10.1016/j.fsi.2023.108906 [doi] PST - ppublish SO - Fish Shellfish Immunol. 2023 Aug;139:108906. doi: 10.1016/j.fsi.2023.108906. Epub 2023 Jun 20.