Aug 2026· International Journal of Molecular Sciences· Vol 27, pp. 7460· 0 citations· 141 references
Medicine
TL;DR
It is argued that antimicrobial stewardship discussions should consider host genome integrity alongside resistance, while remaining mindful that the mechanistic case currently outpaces clinical-endpoint validation.
Abstract
Global antibiotic consumption continues to rise across pediatric and adult populations, while the genotoxic consequences of host eukaryotic exposure remain less systematically characterized than the parallel problem of antimicrobial resistance. Several lines of evidence, from molecular cytogenetics, redox biology, and systems toxicology, now permit a more mechanistically resolved synthesis of antibiotic-induced genome stress than was previously possible, although a substantial fraction of this evidence is preclinical and warrants cautious clinical extrapolation. This narrative review evaluates the molecular mechanisms, cytogenetic biomarkers, and translational implications of antibiotic-induced genotoxicity, with a primary focus on six clinically prominent classes (fluoroquinolones, nitroimidazoles, aminoglycosides, macrolides, β-lactams, and tetracyclines) and a brief extension to glycopeptides and glycylcyclines. We organize the evidence around three convergent mechanistic axes rather than around individual drugs. Accumulating evidence supports three intersecting off-target axes: (i) eukaryotic topoisomerase II interference, principally documented for fluoroquinolones; (ii) mitochondrial dysfunction, reflecting the evolutionary kinship between the mitoribosome and bacterial ribosomes; and (iii) inflammation-coupled redox stress, often amplified by microbiome perturbation. These pathways converge on a common spectrum of DNA lesions—including double-strand breaks, oxidatively modified bases, replication-fork stalling, and chromosomal mis-segregation) detected by complementary assays (CBMN-Cyt, comet, γH2AX, and oxidative and mitochondrial biomarkers). Pediatric, pregnant, geriatric, and oncology populations may represent biologically distinct susceptibility strata, although direct human evidence for several of these inferences remains limited. Causal inference is constrained by infection as a confounder, frequent use of supratherapeutic in vitro concentrations, reliance on immortalized cell lines that may not recapitulate primary-cell repair capacity, inter-laboratory variability across cytogenetic assays, and a marked scarcity of pediatric and pregnancy biomonitoring data. Most existing positive signals derive from preclinical models; clinically validated long-term outcomes, particularly carcinogenic endpoints, remain inconsistently demonstrated for most antibiotic classes outside metronidazole. Antibiotic-induced genotoxicity appears to be a measurable and mechanistically tractable dimension of drug safety, though its clinical magnitude in real-world exposure scenarios requires further investigation. Integrating multi-omics, microphysiological systems, single-cell genotoxicology, and AI-assisted prediction may improve risk resolution, particularly in vulnerable populations. We argue that antimicrobial stewardship discussions should consider host genome integrity alongside resistance, while remaining mindful that the mechanistic case currently outpaces clinical-endpoint validation.
This critical narrative review integrates evidence on major environmental genotoxin classes, exposure routes, molecular mechanisms, human biomonitoring, disease associations and risk-assessment practice for well-established and less mature evidence domains.
Omoighele F. Akhigbe, O. Abutu, N. Y. Wike et al.· Asian Journal of Research in...· 0 citations
Doxorubicin is an effective anthracycline used against solid and haematological malignancies, but dose-dependent multi-organ toxicity limits its clinical use. Oxidative stress is a major mechanism underlying this injury and produces measurable changes in redox biomarkers. This review synthesises evidence on mechanisms of doxorubicin-induced oxidative stress, major biomarkers, organ-specific patterns, clinical relevance and protective strategies. PubMed/MEDLINE, targeted Google Scholar searching and backward reference-list searching were used to identify literature from January 2010 to 10 August 2026. Relevant human, animal and in-vitro studies were considered, with seminal pre-2010 studies retained selectively for mechanistic context. Doxorubicin generally increases oxidative-damage markers, particularly malondialdehyde and 8-hydroxy-2′-deoxyguanosine, while reducing superoxide dismutase, catalase, glutathione peroxidase and glutathione. Evidence is strongest for cardiotoxicity, whereas clinical validation for non-cardiac organs is limited. Dexrazoxane and liposomal doxorubicin have stronger clinical evidence for cardioprotection, while many antioxidant and nanocarrier approaches remain preclinical. Oxidative-stress biomarkers are mechanistically informative but lack sufficient standardisation and prospective validation for routine predictive use. Integrated biomarker approaches require further clinical evaluation.
Isaac S. Iquot, Ifabunmi Osonuga, O. Akano et al.· FUDMA Journal of Sciences· 0 citations
Colorectal cancer (CRC) is a multifactorial disease influenced by genetic, environmental, and microbial factors. Among gut microbiota, pks+Escherichia coli has emerged as a key contributor to colorectal carcinogenesis through the production of colibactin, a genotoxic secondary metabolite. Colibactin induces DNA damage by forming interstrand crosslinks and promoting replication-associated double-strand breaks, thereby triggering host DNA damage response pathways and genomic instability. Recent advances in genomic profiling have identified distinct mutational signatures, such as SBS88 and ID18, in colorectal tumors, providing molecular evidence of prior colibactin exposure. Notably, emerging data suggest that these signatures are enriched in early-onset CRC, highlighting a potential role for bacterial genotoxins in tumor initiation at younger ages. In parallel, interactions between pks+E. coli and the tumor microenvironment, including inflammation and microbiota dysbiosis, further modulate disease progression. In addition to mechanistic insights, growing attention has focused on translational applications, including the use of microbial markers, exosomes, and miRNA profiles as potential diagnostic and prognostic tools. However, significant challenges remain, including the high prevalence of pks+E. coli among healthy individuals, population variability, and the difficulty of establishing causality from associative data. This review summarizes current evidence on the role of colibactin-producing bacteria in CRC pathogenesis, integrates recent genomic findings, and discusses emerging diagnostic and therapeutic perspectives, while highlighting key limitations and future research directions.
Sina Nasrollahian, M. Halaji, Parisa Honarvar Bakeshloo et al.· Infection, Genetics and Evol...· 0 citations
Drug- and metal-induced liver damage (DILI/MILI) continues to be a predominant cause of acute hepatic failure globally, with two clinically significant but mechanistically underexplored triggers being the metalloid antimony (Sb) and non-steroidal anti-inflammatory medications (NSAIDs). This review consolidates current molecular findings about the convergence of Sb(III)/Sb(V) species and NSAID reactive metabolites on a common hepatotoxic framework. Hepatic organic anion-transporting polypeptides and multidrug-resistance proteins regulate the sinusoidal uptake and canalicular efflux of both substances, while cytochrome P450 2C9/3A4/2E1-mediated bioactivation of NSAIDs and thiol-reactive Sb species produces reactive oxygen species (ROS), diminishes reduced glutathione (GSH) levels, disrupts mitochondrial membrane potential and initiates PERK-eIF2α-ATF4-CHOP-mediated endoplasmic reticulum stress. These insults target nuclear factor-kappa B, mitogen-activated protein kinase and NLRP3 inflammasome signalling, resulting in apoptotic, necroptotic, pyroptotic and ferroptotic hepatocyte death. We conduct a comprehensive assessment of the multi-target hepatoprotective effects of polyphenols (curcumin, resveratrol, quercetin), flavonoids, terpenoids, alkaloids and extracts from medicinal plants, focusing on the activation of the Nrf2/Keap1/ARE antioxidant pathway, inhibition of NF-κB and NLRP3, AMPK-SIRT1-PGC-1α-mediated mitochondrial biogenesis, PI3K/Akt cytoprotective signalling and PINK1/Parkin-dependent mitophagy. We ultimately examine translational prospects, including omics-derived hepatotoxicity biomarkers, network pharmacology, artificial intelligence-facilitated natural product discovery, nanocarrier-mediated hepatoprotective administration and precision medicine strategies for the prevention of drug-induced liver injury (DILI). The intersection of antimony- and NSAID-induced damage at a limited number of druggable targets supports the use of multi-target natural therapies as logical complements to traditional hepatoprotection. However, the strength of evidence supporting this convergence is heterogeneous: Several downstream mechanisms-particularly NLRP3 inflammasome activation, ferroptosis, pyroptosis and necroptosis in antimony-induced hepatotoxicity-are supported mainly by in vitro and animal data rather than confirmed human evidence, and are treated in this review as emerging or hypothetical rather than established. As this is a narrative rather than a systematic review, the literature search strategy, evidence-grading approach and limitations are described explicitly to aid transparent interpretation.
Shakir Siddiqui, N. William, B. Aggarwal· Journal of Applied Toxicolog...· 0 citations
Background: Environmental toxicants, including heavy metals, pesticides, particulate air pollutants, per- and polyfluoroalkyl substances (PFAS), and microplastics, are increasingly recognized as major contributors to hematological disorders. Although oxidative stress has traditionally been regarded as the principal mechanism underlying environmental toxicant-induced hematotoxicity, emerging evidence suggests that additional molecular pathways contribute substantially to hematopoietic injury. This review examines the evolving molecular mechanisms of environmental toxicant-induced hematotoxicity beyond the conventional oxidative stress paradigm and explores their translational implications. Methods: Literature was retrieved from PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar and synthesized through a structured narrative review. Evidence published primarily between 2020 and 2026 was critically evaluated and organized into thematic areas including oxidative stress, mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, hematopoietic stem-cell dysfunction, biomarker discovery, multi-omics technologies, artificial intelligence, and precision hematology. Findings: Environmental toxicant-induced hematotoxicity is mediated by a complex network of interacting molecular pathways rather than oxidative stress alone. Emerging evidence highlights important roles for mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, and hematopoietic stem-cell (HSC) impairment in regulating blood-cell homeostasis and bone marrow integrity. These pathways interact extensively with oxidative stress and contribute to disease heterogeneity, chronic toxicity, and variable clinical outcomes. Advances in multi-omics technologies and artificial intelligence further provide opportunities for biomarker discovery, improved risk assessment, and early disease detection. Conclusion: Environmental toxicant-induced hematotoxicity should be viewed as a systems-level disorder arising from coordinated interactions among multiple molecular pathways. Integrating mechanistic insights with multi-omics technologies, artificial intelligence (AI), and precision hematology may improve disease prediction, biomarker development, early diagnosis, and targeted intervention strategies. Novelty/Originality of this article: This review moves beyond the traditional oxidative stress paradigm by integrating emerging molecular mechanisms into a systems hematotoxicology framework for understanding environmental toxicant-induced hematological injury. It synthesizes evidence on mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, and hematopoietic stem-cell dysfunction while highlighting their translational relevance for biomarker discovery, multi-omics research, artificial intelligence, and precision hematology. This integrated perspective remains largely absent from conventional reviews that examine these mechanisms independently.
Esther Uyoyooghene Olokede, Favour Oluwadamilola Agboola, Jane Ifeyinwa Anatuanya et al.· Asian Journal of Toxicology,...· 0 citations
Background Caffeine toxicity represents a growing public health challenge due to the widespread availability of highly potent formulations. Ingestions of 3–10 g can be fatal, with serious toxicity occurring at plasma concentrations 15 mg/L or greater. This review provides a framework explaining its diverse clinical consequences. Methods A comprehensive literature search was conducted across PubMed, Scopus, and Google Scholar using AI-assisted tools, prioritizing clinical, forensic, toxicokinetic, and molecular mechanism studies while excluding chronic moderate consumption. Results Caffeine toxicity is dose-dependent, progressing from adenosine receptor antagonism to phosphodiesterase inhibition, intracellular calcium release, and GABA-A antagonism. In overdose, these mechanisms interact synergistically to cause severe neurological, cardiovascular, and metabolic complications. Furthermore, the CYP1A2 metabolic system becomes saturated, prolonging the elimination half-life up to 27 h and causing a disproportionate rise in plasma concentrations. Interactions with drugs like mexiletine drastically reduce clearance. Conclusion Severe poisoning stems from complex, synergistic molecular interactions. Hypokalemia serves as a promising, actionable clinical biomarker for severity assessment. When massive ingestions saturate endogenous detoxification, hemodialysis becomes essential for survival. Unregulated markets for pure caffeine require stricter regulatory interventions and intensified clinical surveillance.
Antonia Socias, Rafael Blancas· Frontiers in Toxicology· 0 citations
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