PMID- 36863164 OWN - NLM STAT- MEDLINE DCOM- 20230323 LR - 20230323 IS - 1873-6750 (Electronic) IS - 0160-4120 (Linking) VI - 173 DP - 2023 Mar TI - Metabolic perturbations in pregnant rats exposed to low-dose perfluorooctanesulfonic acid: An integrated multi-omics analysis. PG - 107851 LID - S0160-4120(23)00124-1 [pii] LID - 10.1016/j.envint.2023.107851 [doi] AB - Emerging epidemiological evidence has linked per- and polyfluoroalkyl substances (PFAS) exposure could be linked to the disturbance of gestational glucolipid metabolism, but the toxicological mechanism is unclear, especially when the exposure is at a low level. This study examined the glucolipid metabolic changes in pregnant rats treated with relatively low dose perfluorooctanesulfonic acid (PFOS) through oral gavage during pregnancy [gestational day (GD): 1-18]. We explored the molecular mechanisms underlying the metabolic perturbation. Oral glucose tolerance test (OGTT) and biochemical tests were performed to assess the glucose homeostasis and serum lipid profiles in pregnant Sprague-Dawley (SD) rats randomly assigned to starch, 0.03 and 0.3 mg/kg.bw.d groups. Transcriptome sequencing combined with non-targeted metabolomic assays were further performed to identify differentially altered genes and metabolites in the liver of maternal rats, and to determine their correlation with the maternal metabolic phenotypes. Results of transcriptome showed that differentially expressed genes at 0.03 and 0.3 mg/kg.bw.d PFOS exposure were related to several metabolic pathways, such as peroxisome proliferator-activated receptors (PPARs) signaling, ovarian steroid synthesis, arachidonic acid metabolism, insulin resistance, cholesterol metabolism, unsaturated fatty acid synthesis, bile acid secretion. The untargeted metabolomics identified 164 and 158 differential metabolites in 0.03 and 0.3 mg/kg.bw.d exposure groups, respectively under negative ion mode of Electrospray Ionization (ESI-), which could be enriched in metabolic pathways such as alpha-linolenic acid metabolism, glycolysis/gluconeogenesis, glycerolipid metabolism, glucagon signaling pathway, glycine, serine and threonine metabolism. Co-enrichment analysis indicated that PFOS exposure may disturb the metabolism pathways of glycerolipid, glycolysis/gluconeogenesis, linoleic acid, steroid biosynthesis, glycine, serine and threonine. The key involved genes included down-regulated Ppp1r3c and Abcd2, and up-regulated Ogdhland Ppp1r3g, and the key metabolites such as increased glycerol 3-phosphate and lactosylceramide were further identified. Both of them were significantly associated with maternal fasting blood glucose (FBG) level. Our findings may provide mechanistic clues for clarifying metabolic toxicity of PFOS in human, especially for susceptible population such as pregnant women. CI - Copyright (c) 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Yu, Guoqi AU - Yu G AD - Ministry of Education -Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. FAU - Wang, Jinguo AU - Wang J AD - School of Public Health, Guilin Medical University, Guilin 541001, China. FAU - Liu, Yongjie AU - Liu Y AD - Ministry of Education -Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. FAU - Luo, Tingyu AU - Luo T AD - School of Public Health, Guilin Medical University, Guilin 541001, China. FAU - Meng, Xi AU - Meng X AD - Ministry of Education -Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. FAU - Zhang, Ruiyuan AU - Zhang R AD - Ministry of Education -Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. FAU - Huang, Bo AU - Huang B AD - School of Public Health, Guilin Medical University, Guilin 541001, China. FAU - Sun, Yan AU - Sun Y AD - School of Public Health, Guilin Medical University, Guilin 541001, China. Electronic address: 13946167049@163.com. FAU - Zhang, Jun AU - Zhang J AD - Ministry of Education -Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: junjimzhang@sina.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230226 PL - Netherlands TA - Environ Int JT - Environment international JID - 7807270 RN - 0 (Fluorocarbons) RN - TE7660XO1C (Glycine) RN - 9H2MAI21CL (perfluorooctane sulfonic acid) RN - 452VLY9402 (Serine) RN - 0 (Steroids) RN - 2ZD004190S (Threonine) SB - IM MH - Animals MH - Female MH - Pregnancy MH - Rats MH - *Fluorocarbons/toxicity MH - Glycine MH - *Multiomics MH - Rats, Sprague-Dawley MH - Serine MH - Steroids MH - Threonine OTO - NOTNLM OT - Glycolipid metabolism OT - Metabolome OT - Perfluorooctanesulfonic acid OT - Pregnancy OT - Transcriptome COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/03/03 06:00 MHDA- 2023/03/22 06:00 CRDT- 2023/03/02 18:12 PHST- 2022/11/27 00:00 [received] PHST- 2023/01/22 00:00 [revised] PHST- 2023/02/22 00:00 [accepted] PHST- 2023/03/03 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2023/03/02 18:12 [entrez] AID - S0160-4120(23)00124-1 [pii] AID - 10.1016/j.envint.2023.107851 [doi] PST - ppublish SO - Environ Int. 2023 Mar;173:107851. doi: 10.1016/j.envint.2023.107851. Epub 2023 Feb 26.