Systems toxicogenomics of prenatal low-dose BPA exposure on liver metabolic pathways, gut microbiota, and metabolic health in mice

Diamante, Graciel; Cely, Ingrid; Zamora, Zacary; Ding, Jessica; Blencowe, Montgomery; Lang, Jennifer M.; Bline, Abigail; Singh, Maya; Lusis, Aldons J.; Yang, Xia

doi:10.1016/j.envint.2020.106260

Cited by 57 publications

(39 citation statements)

References 92 publications

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“…Samples were stored in −80°C until lipid analysis. TG, TC, unesterified cholesterol (UC), and phospholipid levels in lipid extractions from cells and from culture media were measured separately using a colorimetric assay at the UCLA GTM Mouse Transfer Core ( 56 ). Intracellular lipids were normalized to the cellular protein amount measured by BCA protein assay kit (Pierce, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis

Blencowe

Ahn

Saleem

et al. 2021

Journal of Lipid Research

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Genome-wide association studies (GWASs) have implicated ∼380 genetic loci for plasma lipid regulation. However, these loci only explain 17–27% of the trait variance, and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely, total cholesterol, high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides, from GWASs were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in “interferon signaling,” “autoimmune/immune activation,” “visual transduction,” and “protein catabolism” were significantly associated with all lipid traits. In addition, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL; glutathione metabolism for HDL; valine, leucine, and isoleucine biosynthesis for total cholesterol; and insulin signaling and complement pathways for triglyceride. Finally, by using gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g., APOH , APOA4 , and ABCA1 ) and novel (e.g., F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (coagulation factor II, thrombin) in 3T3-L1 and C3H10T1/2 adipocytes altered gene expression of Abcb11 , Apoa5 , Apof , Fabp1 , Lipc , and Cd36 ; reduced intracellular adipocyte lipid content; and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.

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Section: Methodsmentioning

confidence: 99%

Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis

Blencowe

Ahn

Saleem

et al. 2021

Journal of Lipid Research

Self Cite

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“…Resveratrol (RSV) has been demonstrated to be involved in a variety of bioactivities and functions, such as the reduction of oxidative damage and inflammation, neuroprotection, chemoprevention, anti-obesity effects, and anti-aging effects [ 13 , 14 , 15 , 16 , 17 , 18 ]. Previous research has also shown that perinatal BPA exposure increases the risk of cardiometabolic diseases [ 19 ] and liver injury [ 20 ] in mouse offspring, and affects hypothalamic neuronal growth and appetite in rat offspring [ 21 ]. Supplementation with RSV during the perinatal period influences the physiology and health of the offspring [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota

Liao

Chen

Shih

et al. 2021

IJMS

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Resveratrol can affect the physiology or biochemistry of offspring in the maternal–fetal animal model. However, it exhibits low bioavailability in humans and animals. Fifteen-week SD pregnant female rats were orally administered bisphenol A (BPA) and/or resveratrol butyrate ester (RBE), and the male offspring rats (n = 4–8 per group) were evaluated. The results show that RBE treatment (BPA + R30) compared with the BPA group can reduce the damage caused by BPA (p < 0.05). RBE enhanced the expression of selected genes and induced extramedullary hematopoiesis and mononuclear cell infiltration. RBE increased the abundance of S24-7 and Adlercreutzia in the intestines of the male offspring rats, as well as the concentrations of short-chain fatty acids (SCFAs) in the feces. RBE also increased the antioxidant capacity of the liver by inducing Nrf2, promoting the expression of HO-1, SOD, and CAT. It also increased the concentration of intestinal SCFAs, enhancing the barrier formed by intestinal cells, thereby preventing BPA-induced metabolic disruption in the male offspring rats, and reduced liver inflammation. This study identified a potential mechanism underlying the protective effects of RBE against the liver damage caused by BPA exposure during the peri-pregnancy period, and the influence of the gut microbiota on the gut–liver axis in the offspring.

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“…The RNAs in the CCN of one T47D cell were significantly enriched in the up-regulated genes after MALAT1 KO ( Figure S5A ). Functional enrichment results implied that RNAs in the CCN participated in the pathway of “fatty acid metabolism”, which has also been reported to be associated with BPA exposure, mainly driven by RNAs including MALAT1 ( 22 ). This provides evidence for the functional inference of lncRNA via the CCN.…”

Section: Discussionmentioning

confidence: 89%

“…The “fatty acid metabolism” has also been reported to be enriched by DEGs between BPA exposure and control in mouse liver. Several DEGs were key drivers, such as Apoa2 , Akr1c12 , and Malat1 ( 22 ). This provides additional support for the function inference of lncRNAs via the CCN.…”

Section: Resultsmentioning

confidence: 99%

Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer

Chen

Zeng

et al. 2021

Front. Oncol.

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Single-cell RNA sequencing is a powerful tool to explore the heterogeneity of breast cancer. The identification of the cell subtype that responds to estrogen has profound significance in breast cancer research and treatment. The transcriptional regulation of estrogen is an intricate network involving crosstalk between protein-coding and non-coding RNAs, which is still largely unknown, particularly at the single cell level. Therefore, we proposed a novel strategy to specify cell subtypes based on a cell-specific ceRNA network (CCN). The CCN was constructed by integrating a cell-specific RNA-RNA co-expression network (RCN) with an existing ceRNA network. The cell-specific RCN was built based on single cell expression profiles with predefined reference cells. Heterogeneous cell subtypes were inferred by enriching RNAs in CCN to the estrogen response hallmark. Edge biomarkers were identified in the early estrogen response subtype. Topological analysis revealed that NEAT1 was a hub lncRNA for the early response subtype, and its ceRNAs could predict patient survival. Another hub lncRNA, DLEU2, could potentially be involved in GPCR signaling, based on CCN. The CCN method that we proposed here facilitates the inference of cell subtypes from a network perspective and explores the function of hub lncRNAs, which are promising targets for RNA-based therapeutics.

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Systems toxicogenomics of prenatal low-dose BPA exposure on liver metabolic pathways, gut microbiota, and metabolic health in mice

Cited by 57 publications

References 92 publications

Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis

Gene networks and pathways for plasma lipid traits via multitissue multiomics systems analysis

Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota

Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer

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