Understanding the biochemical impact of nontarget clinical drugs on insect models provides critical insights into xenobiotic toxicity. In this study, we investigated the biochemical effects of dietary AZR on the hemolymph of seventh-instar Galleria mellonella (Lepidoptera: Pyralidae) larvae. First-instar larvae of the insect were reared under laboratory conditions until the seventh-instar larvae. The larvae were fed an artificial diet supplemented with azithromycin (AZR) at different concentrations: 0.0012, 0.0072, 0.0432, 0.2592, 0.7776, and 1.0368%. Our results demonstrated that dietary AZR exposure significantly induced oxidative damage and impacted the defense system of the insect's hemolymph. At a low concentration of AZR (0.0072%), a statistically significant increase in MDA (from 0.065 ± 0.001 to 0.094 ± 0.002 nmol/mg protein) and PCO (from 327.462 ± 13.4 to 432.648 ± 41.17 nmol/mg protein) content was detected. The highest concentration of the antibiotic significantly increased CYP450 enzyme activity from 57.75 ± 5.61 to 113.1 ± 5.53 U/mg protein by about twofold. However, at this same concentration, GST activity decreased from 277.34 ± 15.13 to 172.34 ± 12.51 nmol/mg protein/min. Compared with the control, a statistically significant decrease in TP contents was observed in all treatment groups, except for the 0.0432% concentration. These findings suggest that dietary AZR triggers significant oxidative stress and disrupts the detoxification balance in G. mellonella hemolymph. Consequently, the current data demonstrate hemolymph biochemical stress responses to AZR exposure in G. mellonella.
Methotrexate is a widely used chemotherapeutic agent associated with significant cytotoxic side effects, including xerostomia and salivary gland dysfunction. Exosomes have recently emerged as prospective therapeutic agents owing to their capacity to transfer bioactive compounds, including nucleic acids, proteins, and lipids. Therefore, this study was conducted to evaluate the effect of systemic injection of bone marrow mesenchymal stem cell-derived exosomes on submandibular glands of rats receiving Methotrexate. In this study, 36 adult albino rats were randomly divided into three groups (n = 12): Group I received phosphate-buffered saline (PBS); Group II received intraperitoneal Methotrexate (40 mg/kg); and Group III received Methotrexate followed by intravenous injection of BMMSC-derived exosomes (100-μg/kg/dose suspended in 0.2-mL PBS) via the tail vein after 7 days. After 5 weeks, rats were sacrificed, and submandibular glands were dissected out and prepared for histological and immunohistochemical examination. Statistical analysis was performed on the outcomes. Histological evaluation showed that BMMSC-derived exosomes markedly restored the normal glandular architecture and repaired most of the distortion created by Methotrexate. Immunohistochemically, BCL-2 expression was significantly upregulated, whereas TNF-α expression was significantly downregulated in the treated group. Our results concluded that systemically administrated BMMSC-derived exosomes exhibit therapeutic potential against Methotrexate-induced cytotoxicity in the submandibular salivary glands.
Indoxacarb is a widely used oxadiazine insecticide that has a unique pro-insecticidal mode of action. It functions by metabolic activation to a sodium channel-blocking metabolite, leading to disruption of neuronal signalling and insect mortality. However, increasing evidence highlights that, beyond its target specificity, indoxacarb exerts diverse biological and environmental effects. This review provides an integrated framework linking the physicochemical properties and mode of action of indoxacarb with its toxicity, resistance development, environmental transformation and degradation while identifying key knowledge gaps and future research priorities. Indoxacarb exhibited substantial toxicity across target and non-target organisms, with reported acute LC₅₀ values ranging from 0.0521 mg/L in Labeo rohita to 5.13 μg/mL in Artemia sp., while sublethal exposure induced developmental, reproductive, behavioural, metabolic and oxidative effects. Resistance has evolved across several major pest species, with resistance levels reaching approximately 58-fold in Spodoptera litura, 472-fold in Spodoptera frugiperda, 750-fold in Plutella xylostella and 1794-fold in Tuta absoluta through mechanisms involving enhanced metabolic detoxification, reduced bioactivation, target-site mutations, sequestration and regulatory adaptations. Indoxacarb undergoes microbial, soil, plant, hydrolytic and photolytic transformation, with microbial degradation efficiencies reaching up to 95.7%-100% in some actinomycetes and approximately 68% degradation within 24 h by Priestia aryabhattai DPX-1. However, transformation does not always result in detoxification, as some metabolites, such as IN-KG433, exhibit greater toxicity than the parent compound. Overall, the evidence indicates that indoxacarb has high insecticidal efficacy with considerable ecological and resistance-related concerns. Despite extensive research, several important knowledge gaps exist, which include limited availability of field-scale data on indoxacarb degradation and remediation efficiency, insufficient information on chronic toxicity thresholds for pollinators and the absence of standardized approaches for monitoring and comparing indoxacarb resistance across pest populations. In addition, the complete molecular mechanisms underlying microbial degradation remain insufficiently characterized, particularly with respect to the genes and enzymes involved.
Cosmetic and quasi-drug ingredients intended for daily use require reliable skin irritation assessment. However, restrictions on animal testing, including the European Union marketing ban for cosmetics tested on animals, have prompted the adoption of reconstructed human epidermis (RhE) assays, such as Organization for Economic Co-operation and Development (OECD) Test Guideline 439 (TG439). Although TG439 identifies Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Category 2 irritants and No Category (non-irritant) chemicals as an alternative to the 4-h rabbit skin irritation test, its ability to predict human responses to 24-h exposure and mild irritation remains limited. This study evaluated the reproducibility of TG439 across six laboratories using LabCyte EPI-MODEL24 and a standardized stepwise dilution design. TG439 was used to determine a "TG439 non-irritant concentration" for 17 test substances. Human 24-h closed patch tests were then performed using stepwise escalation to one-quarter and one-half of this concentration, with predefined stopping criteria to ensure subject safety. Inter-laboratory control results confirmed TG439 reproducibility. Most test substances exhibited Sugai's Irritation Index (S.I.I.) values within the "Safe" or "Acceptable" categories at both test concentrations. However, selected surfactants, cationic preservatives, and hair dye intermediates produced elevated S.I.I. values, requiring discontinuation of concentration escalation and highlighting the importance of predefined stopping criteria. These findings support TG439 as a practical starting point for human irritation testing when combined with a stepwise concentration approach and predefined safety criteria, enabling the ethical translation of in vitro findings to human testing and extending TG439-based evaluation beyond "harmless ingredients."
The rapid advancement of nanotechnology has outpaced the development of adequate toxicity assessment methods, necessitating innovative analytical frameworks for evaluating emerging nano-contaminants. The zebrafish (Danio rerio) has emerged as a versatile vertebrate model that enables a comprehensive evaluation of molecular, physiological and developmental responses to nano-contaminant exposure. This minireview synthesises recent advances in zebrafish-based nanotoxicology, emphasising the integration of physicochemical characterisation with biological responses to improve predictive toxicity assessment. Current evidence identifies oxidative stress as one of the most extensively characterised molecular initiating events, activating interconnected pathways involving mitochondrial dysfunction, inflammation and apoptosis, ultimately driving organ-specific and developmental toxicities. Combining physicochemical characterisation with multi-omics approaches, high-throughput phenotypic analyses and computational modelling enables a quantitative linkage between nanoparticle properties and toxicological outcomes within systems-level and adverse outcome pathway (AOP)-oriented frameworks. Together, these complementary approaches strengthen predictive toxicology while improving the mechanistic understanding of nanoparticle-induced toxicity across diverse classes of emerging nano-contaminants. Despite these advances, important challenges remain, including the lack of standardised protocols for nanoparticle characterisation and exposure, uncertainty in selecting appropriate exposure metrics and environmentally relevant experimental models. Addressing these limitations is essential for improving reproducibility, prediction accuracy and translational relevance. Overall, zebrafish-based analytical toxicology provides a comprehensive framework for advancing predictive nanotoxicology thereby supporting safer-by-design nanomaterial development and evidence-based risk assessment of emerging nano-contaminants.
Aluminum (Al) and copper (Cu) homeostasis is critical for neuronal health. Disruption of their balance contributes to oxidative stress, mitochondrial dysfunction, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Existing studies have reported a positive correlation between aluminum and copper concentrations in specific neuronal models. Such homeostatic imbalance may contribute to the activation of pathways related to apoptosis or cuproptosis through mechanisms including oxidative stress, mitochondrial dysfunction, and glutathione depletion. Aluminum-copper dysregulation is considered to potentially play a significant role in certain neurodegenerative disease studies, suggesting that targeted regulation of trace elements may hold potential therapeutic value. However, the specific mechanisms by which maintaining aluminum-copper homeostasis prevents neurodegenerative diseases remain incompletely understood, and further interventional studies focusing on trace elements are urgently needed to validate the causal relationships and clinical application prospects.
Nanotechnology enables the manipulation of materials at dimensions comparable to biomolecules, offering transformative applications across medicine, agriculture, and environmental systems. Among emerging nanomaterials, green-synthesized nanoparticles (GSNPs) have attracted considerable attention due to their eco-friendly production, biogenic surface functionalization, and potential for improved biocompatibility. However, despite reduced process-related toxicity, GSNPs pose unique safety challenges arising from nanoscale properties, dynamic protein corona formation, and complex nano-bio interactions that are inadequately captured by conventional toxicity assays. This review critically evaluates the relevance of nano-omics as a next-generation toxicological tool for hazard identification and risk assessment of emerging nanomaterials, examines the limitations of traditional bioassays, and highlights the growing role of nano-omics approaches, including transcriptomics, proteomics, metabolomics, lipidomics, and epigenomics, in providing systems-level insights into GSNP-induced biological responses. These approaches reveal pathway-level perturbations, such as oxidative stress, immune modulation, metabolic reprogramming, and epigenetic alterations, even at subcytotoxic exposure levels. We further discuss how surface chemistry, protein corona evolution, and intracellular trafficking govern the biological identity and fate of GSNPs. Current limitations in nano-omics, including the lack of standardized protocols, data integration challenges, and regulatory gaps, are critically addressed. An integrative multi-omics framework aligned with FAIR data principles is proposed to support predictive nanosafety assessment and safe-by-design development of green nanomaterials.
Acute hydrogen cyanamide (Dormex) toxicity is associated with hypoxia-mediated cellular injury; however, reliable early biomarkers for assessing toxicity severity remain limited. This study aimed to evaluate serum erythropoietin (EPO) and selected hematological parameters as biomarkers associated with toxicity severity, with a comparative assessment of their diagnostic performance. Forty participants were allocated into four groups: control, mild, moderate, and severe toxicity. Clinical assessment, arterial blood gases, coagulation profile, a complete blood count, random blood sugar, renal function tests, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and serum EPO level, were performed upon admission. Radiological evaluation using computed tomography of the brain was conducted, with magnetic resonance imaging performed when indicated. Significant differences were observed among the studied groups in white blood cell count, neutrophil count, and NLR at admission. Serum EPO levels showed a highly significant increase with increasing severity of toxicity. Strong positive correlations were identified between serum EPO, NLR, and severity of toxicity, whereas significant negative correlations were found with Glasgow Coma Scale scores. Receiver operating characteristic (ROC) analysis demonstrated that serum EPO had the highest discriminative ability for assessing toxicity severity, with superior sensitivity, specificity, and overall accuracy compared to the evaluated hematological indices in the present cohort. However, given the relatively small study population, particularly the limited number of patients with severe toxicity (n = 8), and the absence of external validation, the observed discriminative performance should be interpreted cautiously and validated in larger independent multicenter studies. Serum EPO and selected hematological indices, particularly NLR, are valuable biomarkers for early assessment of severity in acute Dormex toxicity. EPO, in particular, represents a promising early biomarker for assessing the severity of acute hydrogen cyanamide poisoning, reflecting underlying hypoxia-driven pathophysiology and outperforming traditional hematological indices such as NLR and PLR.
The safety of bisphenol analogs as alternatives to bisphenol A (BPA) is increasingly concerning. This study investigated the hepatotoxic effects of bisphenol M (BPM), a widely used BPA substitute, in 6-week-old female BALB/c mice exposed to 2.5, 5, and 10 mg/kg/day intraperitoneally for 14 days. Hepatic changes were assessed via histopathology, ultrastructure, biochemistry, and molecular analyses. BPM caused dose-dependent liver damage, including hydropic degeneration, necrosis, apoptosis, sinusoidal dilatation, and fibrotic remodeling. Masson's trichrome staining indicated increased collagen deposition, especially in medium- and high-dose groups. TUNEL assay confirmed elevated hepatocyte apoptosis, and immunohistochemistry showed dose-dependent TGF-β1 upregulation in hepatocytes, portal areas, and inflammatory regions. Transmission electron microscopy identified mitochondria and endoplasmic reticulum as primary targets, showing mitochondrial swelling, cristae disruption, membrane rupture, myelin figure formation, ribosomal loss, and rough ER disorganization. Biochemically, TNF-α and IL-6 increased significantly, while tissue sspartate aminotransferase (AST) and alanine aminotransferase (ALT) remained unchanged. Molecular analysis revealed upregulation of p53, Bax, caspase-3, and cytochrome c, indicating activation of the intrinsic mitochondrial apoptotic pathway. Concurrent Bcl-2 upregulation suggested compensatory anti-apoptotic responses under severe stress. In summary, BPM induces dose-dependent hepatotoxicity associated with mitochondrial, inflammatory, and apoptotic alterations, which may not be reflected by changes in conventional liver enzyme markers, including AST and ALT. These findings raise concerns regarding the safety of BPA alternatives and emphasize the need for careful evaluation of BPM-related health risks.
Saccharin is one of the oldest and most extensively used nonnutritive sweeteners, valued for its intense sweetness, chemical stability and negligible caloric contribution. Since its discovery in 1879, it has been widely incorporated into foods, beverages, pharmaceuticals and personal care products, while its safety has remained the subject of considerable scientific and regulatory debate. Early experimental studies linking saccharin to bladder tumour formation in rodents raised concerns regarding its carcinogenic potential; however, subsequent mechanistic investigations, epidemiological evidence and comprehensive risk assessments have demonstrated that these findings are species-specific and not directly applicable to humans. This review provides a comprehensive and critical synthesis of current knowledge on saccharin, encompassing its chemical characteristics, physicochemical properties, industrial and pharmaceutical applications, absorption, metabolism, excretion and toxicological profile. Particular emphasis is placed on evaluating evidence related to carcinogenicity, genotoxicity, metabolic effects, oxidative stress, gut microbiota interactions and other emerging health concerns through the integration of experimental, clinical and population-based studies. In addition, the review examines the scientific basis of international regulatory decisions, discusses the challenges of translating animal toxicology findings into human health risk assessment and identifies persistent knowledge gaps requiring further investigation. Current evidence consistently supports the safety of saccharin when consumed within established acceptable daily intake limits established by international regulatory agencies. Nevertheless, well-designed long-term human studies and mechanistic investigations remain necessary to better define its potential effects on metabolic health, the gut microbiome and susceptible populations. By integrating historical evidence with contemporary advances in toxicology and regulatory science, this review provides an updated framework for understanding the safety, biological effects and public health implications of saccharin consumption.
Electronic-waste (e-waste) recycling is an important source of occupational exposure to complex mixtures of heavy metals, yet the broader metabolic consequences remain insufficiently characterized. Untargeted metabolomics provides a hypothesis-generating approach for identifying systemic biochemical alterations associated with such exposure. A cross-sectional serum metabolomics study was performed using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) in negative electrospray ionization mode, including 30 e-waste recycling workers and 46 non-exposed controls. After preprocessing, 2305 metabolic features were retained. Multivariate analysis indicated separation between exposed workers and controls. Univariate filtering identified 44 putatively annotated discriminatory features (p < 0.05, fold change > 1.5), of which 20 also showed VIP scores > 1.0. Steroid-related metabolites (pregnenolone, 17-hydroxyprogesterone, corticosterone, and tetrahydrocorticosterone) and eicosanoid/oxylipin-related features (thromboxane B2, prostaglandin H2, prostaglandin B2, 15-HETE, and 5,6-DHET) were among the main contributors to group discrimination. Pathway analysis indicated steroid-related metabolism as the strongest pathway-level signal, whereas arachidonic acid metabolism and several additional pathways showed exploratory trends. Overall, no statistically significant associations between individual blood metal levels and discriminatory metabolites remained after correction for multiple testing. These findings indicate that the observed metabolic differences are more appropriately characterized as exposure group associated rather than directly attributable to any single measured metal. Occupational e-waste exposure was associated with a distinct serum metabolic profile, with the strongest differences involving steroid-related metabolites and additional variation in eicosanoid/oxylipin-related features. These findings support the utility of untargeted metabolomics for characterizing exposure-associated metabolic signatures and provide a basis for future targeted and longitudinal studies.
6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD, causes acute mortality in several salmonid species, but its toxicity varies markedly among fish species. Disruption of vascular-barrier integrity and inflammatory signaling has been proposed as a key mechanism of 6PPD-Q toxicity. However, it remains unclear whether related transcriptional responses are specific to lethal effects. In this study, juvenile Japanese medaka (Oryzias latipes) aged 30-35 days post-hatch, an insensitive species, were exposed to 6PPD-Q at 31-500 μg/L to examine acute lethality and the expression of selected genes related to tight-junction function, inflammation, antioxidant defense, and neurotoxicity. No mortality or abnormal behavior was observed after 48 h of exposure at nominal concentrations up to 500 μg/L. After 24 h of exposure, the tight-junction-related genes cldn7, cldn15, and zo1 generally showed concentration-dependent increases at concentrations ranging from 62.5 to 500 μg/L. In contrast, the inflammation-related gene il1b was downregulated, whereas il8 was unaffected. Antioxidant- and neurotoxicity-related genes showed modest or nonmonotonic responses, including decreases in cat, gpx1, and ache. These results demonstrate that 6PPD-Q can alter tight-junction- and epithelial-barrier-related genes and other stress-response genes in medaka without causing overt acute toxicity. Thus, transcriptional changes in these genes alone are not sufficient predictors of acute lethality, although functional vascular-barrier disruption may remain a critical key event in sensitive salmonids.
The invasive fall armyworm, Spodoptera frugiperda (J.E. Smith), poses a serious threat to global maize production due to its high reproductive potential and rapid evolution of insecticide resistance. Although chlorantraniliprole is widely used for its management, information on the transgenerational effects of parental exposure to sublethal and median-lethal concentrations of chlorantraniliprole in Indian populations of S. frugiperda remains limited. This study evaluated the toxicity of chlorantraniliprole and its effects on the biology and age-stage, two-sex life-table parameters of S. frugiperda following exposure to LC10, LC25 and the median-lethal concentration (LC50). Chlorantraniliprole exhibited high toxicity, with LC10, LC25 and LC50 values of 0.0047, 0.0354 and 0.3274 mg L-1, respectively. In the directly exposed F1 parental generation, chlorantraniliprole prolonged larval and pupal development, increased female longevity and significantly reduced fecundity. In the F2 progeny, parental exposure prolonged pre-adult development but reduced pupal duration, adult longevity, fecundity and population growth potential. Age-stage, two-sex life-table analysis showed significant reductions in the intrinsic rate of increase (r), finite rate of increase ( λ ), net reproductive rate ( R 0 ) and gross reproductive rate (GRR), accompanied by prolonged mean generation time (T) and doubling time (DT). Age stage-specific survival rate (Sxj), life expectancy (exj), reproductive value (vxj) and age-specific maternity (lxmx) were also reduced following parental exposure. Furthermore, population projection analysis demonstrated substantial long-term suppression of population growth, particularly under LC25 and LC50, owing to delayed development, reduced survival and impaired reproductive performance. These findings demonstrate that chlorantraniliprole exerts significant direct and transgenerational effects on S. frugiperda and emphasize the importance of considering these responses for the systematic evaluation and optimal use of insecticides under field condition.
This study evaluated both the acute and sublethal effects of pyriproxyfen in Cyprinus carpio using an integrated multibiomarker approach. The 96-h LC50 value was calculated as 4.525 mg/L. Following 14 days of sublethal exposure, pyriproxyfen caused clear, dose-dependent changes across hematological, biochemical, genotoxic, and molecular parameters. Hemoglobin and hematocrit levels declined progressively with increasing concentration, pointing to the development of anemia-like conditions. Biochemical analyses revealed a biphasic response pattern: Several parameters initially increased at lower concentrations but declined at higher doses, suggesting a shift from adaptive metabolic responses to hepatic impairment. DNA damage, assessed by the comet assay, increased significantly in all exposed groups, indicating genotoxic effects even at relatively low concentrations. At the molecular level, antioxidant and proinflammatory genes were upregulated at low to moderate doses, reflecting an early defense response. However, their expression was suppressed at higher concentrations, implying exhaustion of protective mechanisms. In contrast, HSP70 expression increased steadily with dose, highlighting the intensification of cellular stress and protein damage. Overall, the findings demonstrate that pyriproxyfen exposure triggers an initial adaptive response that progressively transitions into physiological dysfunction at higher concentrations, underscoring its potential ecological risk to aquatic organisms.
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.
Organophosphate esters (OPEs) are environmental contaminants widely released during electronic waste dismantling and pose potential threats to human health. Compared to adults, fetuses have weaker detoxification capabilities, making them more susceptible to the effects of these pollutants. This study aims to investigate how prenatal OPE exposure relates to neonatal birth outcomes in a Chinese e-waste recycling area. We collected blood samples from 183 pregnant women during late pregnancy and measured the concentrations of 13 OPEs in these samples using programmed-temperature vaporization gas chromatography-mass spectrometry (PTV-GC/MS). Linear regression analysis was employed to examine the association between seven OPEs and neonatal birth outcomes. Additionally, we utilized the quantile g-computation model to evaluate the effects of mixed exposure to multiple OPEs on birth outcomes. The concentrations of triphenyl phosphate (TPHP) in maternal blood were positively correlated with birth weight (β = 30.38; 95% CI [2.56, 58.20]). The concentrations of 2-ethylhexyl diphenyl phosphate (EHDPP) and TPHP in maternal blood were positively correlated with birth length (β = 0.05; 95% CI [0.01, 0.09]; β = 0.04; 95% CI [0.01, 0.08]). Furthermore, our quantile g-computation analysis showed that mixed exposure to contaminants was associated with increased birth length (β = 0.25; 95% CI [0.02, 0.47]), and the weight distribution plot indicated that EHDPP and TPHP were the major contributors to the observed increase in birth length. This study revealed that maternal exposure to OPEs in e-waste recycling areas contributes to increased neonatal birth weight and length, which may elevate the risk of overweight or obesity during later growth.
The consumption of green tea (Camellia sinensis (L.) Kuntze) in the form of encapsulated dietary supplements has increased substantially in recent years; however, data supporting toxicological risk assessment of inorganic contaminants in these products remain limited. Unlike traditional tea infusions, encapsulated supplements deliver concentrated plant material in fixed daily doses, requiring exposure-based rather than concentration-based toxicological evaluation. In this study, arsenic (As), cadmium (Cd), and lead (Pb) were quantified in 11 batches of commercially available encapsulated green tea supplements from six brands marketed in Southeast Brazil. Elemental analysis was performed using graphite furnace atomic absorption spectrometry (GF AAS), and measured concentrations (mg·kg-1) were converted into estimated daily intake (EDI, μg/day) based on the maximum labeled intake. Toxicological relevance was primarily assessed using permitted daily exposure (PDE) limits established in United States Pharmacopeia (USP) Chapter <2232>, with complementary interpretation based on estimated weekly intake (EWI) and provisional tolerable weekly intake (PTWI) reference values. Estimated daily exposures to arsenic, conservatively assumed as inorganic arsenic, and cadmium remained below their respective PDE values in all analyzed batches. In contrast, lead exposure exceeded the USP <2232> PDE of 5 μg/day in two batches, revealing batch dependent noncompliance under an exposure-based regulatory framework. These findings demonstrate that dietary supplements may act as concentrated sources of elemental exposure and highlight the importance of dose-normalized assessment for accurate risk characterization. The integration of PDE with complementary exposure metrics strengthens the evaluation of toxicological risk and supports more robust, exposure-based regulatory approaches for the safety assessment of botanical dietary supplements.
Aquatic ecosystems are gradually being threatened by intensive agricultural practices, especially the extensive application of pesticides. Although pesticides such as organophosphates, carbamates, pyrethroids, phenylpyrazoles, and neonicotinoids are extensively used in agriculture for pest control, their entry into aquatic environments through runoff, leaching, and atmospheric deposition poses significant risks to nontarget organisms, including fish. This study provides a comprehensive understanding of pesticide-induced toxicity in fish, with particular emphasis on histopathological modifications and genetic alterations in the liver as critical biomarkers of cellular dysfunction, tissue injury, and toxicological responses. At the molecular level, the principal pathways affected included apoptosis (bcl2, caspase 3, 8, and 9), necroptosis (mlkl, ripk1, and ripk3), autophagy (atg and lc3), inflammation (cyp19a, nfκb, tnfα, and nox4), and DNA damage response pathways (atm, atr, tp53, and mdm2) indicating severe cellular stress, genomic instability, and tissue dysfunction induced by pesticide exposure. The major histopathological alterations observed in the liver included vacuolization, hemorrhage, vascular congestion, pyknotic nuclei, and inflammatory cell infiltration. This review highlights an integrated understanding of the association between hepatic histopathological manifestations and molecular responses in fish exposed to pesticides, providing insights into the mechanisms of hepatotoxicity and recognizing possible biomarkers for environmental monitoring and ecotoxicological risk assessment. These biomarkers play a crucial role in assessing the extent of aquatic contamination and understanding the implications of pesticide exposure on fish health, biodiversity, and ecosystem stability. Furthermore, this review underscores the urgent need for effective monitoring and mitigation strategies to safeguard aquatic life and maintain environmental integrity.
Combined manganese (Mn) and iron (Fe) exposure is increasingly recognized as a risk factor for neurotoxicity, but the underlying mechanisms and potential interventions remain incompletely understood. Here, PC12 cells and Sprague-Dawley rats were used to investigate neuroinjury induced by combined Mn-Fe exposure and the potential protective effects of sodium para-aminosalicylate (PAS-Na). Cognitive performance was evaluated using the Morris water maze and Y-maze, whereas histopathological changes, regional Mn and Fe accumulation, oxidative-inflammatory injury, Wnt/β-catenin/GSK-3β-related proteins, Tau/Aβ-related alterations, and apoptosis were assessed in PC12 cells and in the hippocampus and cortex of rats. Combined Mn-Fe exposure induced marked neuroinjury, characterized by impaired spatial learning and memory, neuronal damage in the hippocampus and cortex, increased regional brain Mn and Fe burden, enhanced oxidative stress and neuroinflammation, Tau/Aβ-related abnormalities, apoptosis, and alterations in Wnt/β-catenin/GSK-3β-related protein expression. PAS-Na attenuated these alterations, with medium and high doses generally showing more consistent effects than the low dose. PAS-Na treatment was associated with reduced Mn and Fe accumulation in cognition-related brain regions, partial normalization of Wnt/β-catenin/GSK-3β-related protein expression, and attenuation of oxidative-inflammatory injury and neuropathological changes. These novel findings indicate that PAS-Na partially alleviates combined Mn-Fe-induced neuroinjury and is associated with reduced regional metal burden, oxidative-inflammatory injury, apoptosis, and changes in Wnt/β-catenin/GSK-3β-related signaling.
This systematic literature review (B-SLR) examines the emerging scholarly consensus on mechanistic linkage between genotoxic exposures and multisystem health dysfunctions. We systematically reviewed 200 peer-reviewed publications from 2021 to 2025 applying SPAR4-SLR protocol with quality appraisal using ROBINS-I adaptation and also performed assessment of publication bias. We have identified trends in genotoxicity research and its causal relationship with reproductive and neurocognitive health outcomes. This novel interdisciplinary approach bridges the traditional siloed research domains of toxicology, genetics, reproductive medicine, and neuroscience. A systematic search strategy using Scopus database and Boolean operators was used at a period of 2020-2025 as well as 2021-2025 to extract articles. SPAR4-SLR protocol was implemented thereby across three stages of assembling, arranging, and assessing. Furthermore, Biblioshiny software (R Language) with quality appraisal (ROBINS-I adapted) and publication bias quantification was performed. This was followed by reporting of thematic mapping, citation network analysis, mechanistic pathway modeling, and validity checks (Scopus vs. Web of Science overlap = 89.5%). This validated coverage adequacy. Bibliometric analysis identified eight major research clusters with distinct maturity profiles: (1) DNA mutations and chromosomal damage (n = 167 papers; h-index 85; mature domain); (2) reprotoxicity and gonadal dysfunction (n = 78; h-index 42; emerging); (3) neurotoxicity and cognitive impairment (n = 89; h-index 51; emerging); (4) transgenerational/epigenetic transmission (n = 34; h-index 28; nascent); (5) bioaccumulation and environmental persistence (n = 96; h-index 59; mature); (6) emerging contaminants (nanoplastics/PFAS/bisphenols) (n = 42; h-index 19; nascent); (7) mechanistic pathway integration (n = 23; h-index 12; nascent); and (8) regulatory and policy applications (n = 8; h-index 4; nascent). A critical knowledge gap was also identified where animal studies dominate, and human epidemiological studies constitute merely 3%. This creates a 20- to 30-year translation lag. The following five high-priority research agendas were identified: (1) comparative potency assessment across emerging contaminants; (2) epigenetic mechanism specificity in transgenerational transmission; (3) mixture/cumulative effects (current literature focuses on single-agent exposures); (4) cost-effective remediation/mitigation strategies; (5) vulnerability characterization for developmentally sensitive populations (gestational windows, critical brain periods, pubertal transition). The research is ready for translation into policy, and the regulatory opportunity closes by 2027-2028. Practical Implications This review provides actionable intelligence for the following five groups: (1) funding agencies-identifies nascent research clusters warranting priority funding; (2) international regulators (OECD, EPA, and EMA)-identifies five critical gaps in current testing guidelines and proposes a unified testing battery, which includes epigenetic endpoints and adverse outcome pathway analysis; (3) occupational health professionals-identifies priority exposure reduction strategies in high-risk sectors; (4) pharmaceutical developers-highlights risk assessment strategies for drug candidates with genotoxic potential; (5) reproductive/pediatric health practitioners-provides evidence synthesis supporting patient counselling on avoidable exposures during critical developmental windows. This integrated mechanistic framework bridges previously siloed research domains to enable coordinated multistakeholder action.
