A comprehensive overview of metabolic and structural changes in the kidney associated with chronic BPA exposure is provided and potential links between environmental toxicants and renal metabolic disturbances are highlighted.
Abstract
BPA is a widespread environmental contaminant with endocrine-disrupting properties, but its impact on renal metabolism remains incompletely understood. This study aimed to characterize metabolic alterations in mouse kidney following chronic BPA exposure and to relate these findings to histopathological changes. Mice were exposed to BPA at the lowest observed adverse effect level (50 mg/kg body weight/day) for 3 months, and kidney samples were analyzed using untargeted liquid chromatography-mass spectrometry-based metabolomics. BPA exposure was associated with distinct changes in renal metabolic profiles, particularly in pathways related to lipid metabolism, fatty acid oxidation, steroid metabolism, and xenobiotic biotransformation. Altered levels of polyunsaturated fatty acids and lysophospholipids suggested disruption of lipid homeostasis and membrane composition. Changes in acylcarnitine profiles were consistent with alterations in energy metabolism, while shifts in steroid metabolites indicated perturbations in steroidogenic pathways. Increased levels of conjugated metabolites suggested activation of phase II detoxification processes. Histopathological analysis revealed structural abnormalities, including tubular epithelial damage and glomerular alterations. Together, these findings provide a comprehensive overview of metabolic and structural changes in the kidney associated with chronic BPA exposure and highlight potential links between environmental toxicants and renal metabolic disturbances.
Bisphenol A (BPA) is a widely distributed endocrine-disrupting chemical with documented metabolic effects in experimental models. Although hepatic transcriptional alterations following BPA exposure have been reported, the extent to which these changes translate into functional metabolic remodeling remains unclear. This study aimed to characterize global hepatic metabolomic alterations following chronic exposure to BPA at the lowest observed adverse effect level (LOAEL) in mice and to determine whether the affected metabolic networks overlap with pathways implicated in non-alcoholic fatty liver disease (NAFLD) progression and early events associated with hepatocarcinogenic susceptibility. Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics was performed on liver samples from BPA-exposed (n = 8) and control (n = 6) mice. Differential metabolite analysis and pathway enrichment analysis were conducted to identify significantly altered metabolites and metabolic pathways. BPA exposure induced marked hepatic metabolic remodeling involving polyunsaturated fatty acids, arachidonic acid-derived eicosanoids, lysophospholipids, retinoid metabolism, and phase II detoxification pathways. Dysregulation of omega-3 and omega-6 fatty acids and altered prostaglandin and thromboxane derivatives indicated disruption of inflammatory lipid mediator balance. Changes in retinol- and retinoic acid-related metabolites suggested impaired differentiation-associated signaling, while increased sulfated and glucuronidated metabolites reflected enhanced xenobiotic metabolism. Pathway enrichment analysis highlighted biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and retinol metabolism as significantly affected pathways. Chronic BPA exposure at a LOAEL dose induces coordinated hepatic metabolic reprogramming characterized by pro-inflammatory lipid remodeling, disruption of retinoid signaling, and activation of detoxification mechanisms. These alterations may represent metabolic features associated with pathways relevant to NAFLD progression and hepatocarcinogenic susceptibility.
E. Lepiarczyk, Marta Wiszpolska, M. Maździarz et al.· Metabolomics· 0 citations
Accumulating evidence reveals that bisphenol A (BPA) exposure triggered maternal lipid metabolism disorders and pregnancy complications, but the molecular regulatory networks driving metabolic reprogramming remain to be fully elucidated. This study employed an integrated multi-omics approach based on BPA-exposed animal and cell models to systematically explore the molecular mechanisms underlying gestational BPA-induced metabolic dysfunction and macrophage inflammatory activation. Untargeted metabolomics revealed elevated cholesterol abundance in gestational BPA-exposed mice, indicating that gestational BPA exposure induced synergistic abnormalities in aromatic amino acid and lipid metabolism. The molecular regulatory mechanisms of BPA toxicity during pregnancy were investigated via transcriptomic analysis. Interestingly, the multifunctional lipid receptor CD36 has been regarded as the sole key gene at the intersection of macrophage inflammation and cholesterol metabolism. Gestational BPA-induced downregulation of CD36 impairs tissue repair and disrupts anti-inflammatory negative feedback loops in macrophages. Conclusion Gestational BPA exposure induces chronic inflammation accompanied by CD36 downregulation and abnormal cholesterol metabolism, revealing an inflammation-metabolic disorder axis in macrophage reprogramming. This study provides evidence for the role of BPA in the pathogenesis of cholesterol metabolic reprogramming, and illustrates the advantages of integrative analysis for investigating the mechanisms of pregnancy complications triggered by gestational BPA exposure.
Yu-jiao Chen, Yifan Liu, Meng Zhang et al.· Food and Chemical Toxicology· 0 citations
Nonylphenol (NP) is an alkylphenol environmental contaminant with endocrine-disrupting activity and potential hepatotoxicity. However, the molecular responses associated with different NP exposure durations remain insufficiently characterized. In this study, male Kunming mice were exposed to NP through drinking water at 500 μg/L for 10 days (NP-S) or 90 days (NP-L) (n = 8/group), and hepatic toxicological alterations were evaluated using biochemical, histopathological, transcriptomic, metabolomic, and integrative analyses. Network toxicology analysis was first applied as a hypothesis-generating approach to identify candidate NP-associated hepatotoxicity targets. Most candidate targets had corresponding mouse orthologs. Compared with control mice, short-term NP exposure induced substantial transcriptional and metabolic alterations without significant changes in serum aminotransferases, oxidative stress markers, or liver histopathology. In contrast, long-term NP exposure was associated with increased ALT and AST activities, reduced SOD and GSH-Px activities, increased MDA levels, elevated IL-6 and IL-1β levels, and histopathological liver injury. Multi-omics analysis revealed that NP exposure affected pathways related to xenobiotic metabolism, glutathione metabolism, retinol metabolism, lipid remodeling, arachidonic acid metabolism, and inflammatory signaling. WGCNA identified exposure-associated co-expression modules, including an NP-L-associated module correlated with liver injury-related phenotypes. Targeted transcriptomic analysis further indicated coordinated alterations in estrogen receptor/nuclear receptor-related genes, CYP-mediated phase I metabolism, and GST/UGT-mediated phase II detoxification. Integrated transcriptome-metabolome analysis suggested coordinated remodeling of xenobiotic metabolism, oxidative stress, lipid metabolism, and inflammatory responses. Overall, under the present single-dose mouse exposure design, short- and long-term NP exposure were associated with distinct hepatic molecular and toxicological profiles. These findings suggest that early molecular reprogramming may precede overt hepatic injury, whereas prolonged exposure is associated with broader metabolic disturbance and more evident liver toxicity.
Xiaohang Yang, Yao-Dong Zhang, Jinlong Liu et al.· Ecotoxicology and Environmen...· 0 citations
Diazepam (DZP), one of the most widely prescribed benzodiazepines (BZDs), is commonly used clinically to treat anxiety and epilepsy by reducing neuronal excitability. However, its potential ecological toxicity remains poorly understood. In this study, adult female zebrafish were exposed to environmentally relevant concentrations of DZP for 28 days, and hepatic responses were evaluated through integrated biochemical, transcriptional, and untargeted metabolomics analyses. DZP exposure altered antioxidant enzyme activities and increased oxidative stress markers, indicating disruption of hepatic redox homeostasis. Significant alterations were also observed in triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu). These physiological alternations were accompanied by modified expression of genes associated with glucose and lipid metabolism. Untargeted metabolomics analysis further revealed extensive metabolic reprogramming after DZP exposure. KEGG enrichment analysis indicated significant disturbances in energy and amino acid metabolism, with histidine metabolism identified the most prominently affected pathway. Alterations in metabolites associated with glutathione synthesis, membrane phospholipids, and purine metabolism further suggested widespread metabolic dysregulation in the liver following DZP exposure. Collectively, these findings demonstrate that environmentally relevant DZP exposure disrupts hepatic metabolism and induces oxidative stress in zebrafish, providing new insights into the ecotoxicological effects of DZP on aquatic organisms.
Yihong Huang, Ting Xu, Ting Luo et al.· Food and Chemical Toxicology· 0 citations
Aluminum (Al) is a widespread environmental contaminant with multi-organ toxicity. Although aluminum-induced testicular toxicity has been reported in male rats, its underlying mechanism remains unclear. Different from conventional single-model or single-omics research, this study integrated in vitro and in vivo experiments, network toxicology, and multi-omics approaches to investigate aluminum-induced testicular toxicity and its underlying mechanisms. In vitro, aluminum reduced the viability of TM3 and TM4 cells in a concentration-dependent manner. In vivo, rats administered AlCl3·6H2O for 15 days showed decreased body weight and testicular index, testicular histopathological damage, and increased sperm abnormalities. Network toxicology analysis suggested that inflammation, oxidative stress, apoptosis, and the PI3K-Akt signaling pathway are suggested to be key pathways. Transcriptomics and metabolomics identified 287 differentially expressed genes and 39 metabolites, which were mainly involved in glycerophospholipid and amino acid metabolism. Multi-omics integration revealed disrupted amino acid, lipid, and energy metabolism, with significant enrichment of the PI3K-Akt signaling pathway, which was validated using qRT-PCR. These findings provide novel insights into aluminum-induced testicular toxicity and prevention of male reproductive dysfunction.
Siyu Liao, Liqing Huang, Yusi Zhou et al.· Food and Chemical Toxicology· 0 citations
BACKGROUND
Titanium dioxide (TiO2) is widely present in a variety of food and personal care products, leading to frequent human exposure primarily via oral ingestion. Although the oral bioavailability of TiO2 nanoparticles is generally considered low, the gastrointestinal tract represents the primary site of exposure and may undergo local molecular and metabolic disturbances following repeated contact.
METHODS
In this study, we investigated the impact of TiO2 exposure on gene expression and cellular metabolism in intestinal epithelial cells using integrated transcriptomic and metabolomic approaches.
RESULTS
Transcriptomic analysis identified differentially expressed genes associated with disruptions in cellular components, molecular functions, and biological processes, collectively pointing to mechanisms underlying TiO2-induced cytotoxicity. Metabolomic profiling further revealed that TiO2 exposure perturbed key metabolic pathways, as evidenced by significant alterations in critical metabolites-including acetylcholine, glutathione, cytosine, deoxyadenosine, and pantothenic acid-indicative of broad metabolic dysfunction. Notably, integrative correlation analysis demonstrated that TiO2 disrupts lipid metabolism, amino acid metabolism, nucleotide metabolism, energy metabolism, and redox homeostasis.
CONCLUSIONS
In conclusion, our findings elucidate the metabolic mechanisms driving TiO2-induced intestinal toxicity. Moreover, this work underscores the power of integrated transcriptomic-metabolomic analysis as a robust strategy for mechanistic toxicological evaluation and risk assessment of nanomaterial exposure.
