Search Results (8)

The metalloid arsenic (As) and the metals lead (Pb) and mercury (Hg), which together we call the “Toxic Triad”, are among the pollutants of greatest global concern, harming the health of millions of people and contributing to biodiversity loss. The widespread distribution of As, Pb and Hg facilitates the exposure of humans and other species to these elements simultaneously, potentially amplifying their individual toxic effects. While As, Pb and Hg are well established as toxic elements, the mechanisms by which they interact with genetic material and impact the health of various species remain incompletely understood. This is particularly true regarding the combined effects of these three elements. In this context, the objective of this work was to perform a toxicogenomic analysis of As, Pb and Hg to highlight multiple aspects of element-gene interactions, in addition to revisiting information on the genotoxicity and carcinogenicity of the Toxic Triad. By using The Comparative Toxicogenomics Database, it was possible to identify that As interacts with 7666 genes across various species, while Pb influences 3525 genes, and Hg affects 692 genes. Removing duplicate gene names, the three elements interact with 9763 genes across multiple species. Considering the top-20 As/Pb/Hg-interacting genes, catalase (CAT), NFE2 like bZIP transcription factor 2 (NFE2L2), caspase 3 (CASP3), heme oxygenase (HMOX1), tumor necrosis factor (TNF), NAD(P)H quinone dehydrogenase 1 (NQO1) and interleukin 6 (IL6) were the most frequently observed. In total, 172 genes have the potential to interact with the three elements. Gene ontology analysis based on those genes evidenced that the Toxic Triad affects several cellular compartments and molecular functions, highlighting its effect on stimulation of toxic stress mechanisms. These 172 genes are also associated with various diseases, especially those of the urogenital tract, as well as being related to biological pathways involved in infectious diseases caused by viruses, bacteria and parasites. Arsenic was the element with the best-substantiated genotoxic and carcinogenic activity. This article details, through a toxicogenomic approach, the genetic bases that underlie the toxic effects of As, Pb and Hg. Full article

Background/Objectives: β-Lapachone (β-lap) is an o-naphthoquinone with potent antitumor activity. However, its clinical application is hindered by poor solubility and toxicity. Thiosemicarbazone derivatives of β-lap (BV3 and BV5) have demonstrated enhanced selectivity and anticancer efficacy in leukemia cells. Therefore, this study aimed to evaluate the therapeutic potential of these derivatives in solid tumors. Furthermore, the mechanism of tumor cell death, the involvement of protein kinase inhibition, and the toxicogenetic safety of BV3 and BV5 were investigated. Methods: The cytotoxic effects of BV3 and BV5 were assessed in cancer cell lines and a non-cancerous cell line. The compounds were most effective against HeLa (human cervical adenocarcinoma) cells. For that reason, this type of cell was chosen to study how the compounds might cause cell death, using flow cytometry. Kinase inhibition assays were conducted in vitro and in silico, followed by genotoxicity assessments to determine toxicogenetic safety. Results: BV3 and BV5 derivatives significantly inhibited cancer cell proliferation after 72 h, with IC₅₀ values ranging from 2.8 to 36.9 µM. BV3 demonstrated superior selectivity (selectivity index: 15.6) when compared to β-lap (selectivity index: 1.9) in HeLa cells. Morphological changes and flow cytometry analysis revealed features of apoptosis and/or necrosis in HeLa cells treated with the compounds BV3 and BV5. Furthermore, among the kinases tested, BV3 and BV5 were more effective in inhibiting the activity of the protein kinases JAK3 and GSK3β. This result was also confirmed by the in silico studies. Additionally, genotoxicity assays indicated an overall favorable toxicogenetic safety profile; however, BV5 exhibited potential genotoxicity at high concentrations. Conclusions: The findings underscore the anticancer potential of BV3 and BV5 in solid tumors and highlight their mechanism of action, which involves protein kinases. The findings also show that the drugs are selective and relatively safe. Full article

The study aimed to evaluate the antitumor and toxicogenetic effects of liposomal nanoformulations containing citrinin in animal breast carcinoma induced by 7,12-dimethylbenzanthracene (DMBA). Mus musculus virgin females were divided into six groups treated with (1) olive oil (10 mL/kg); (2) 7,12-DMBA (6 mg/kg); (3) citrinin, CIT (2 mg/kg), (4) cyclophosphamide, CPA (25 mg/kg), (5) liposomal citrinin, LP-CIT (2 μg/kg), and (6) LP-CIT (6 µg/kg). Metabolic, behavioral, hematological, biochemical, histopathological, and toxicogenetic tests were performed. DMBA and cyclophosphamide induced behavioral changes, not observed for free and liposomal citrinin. No hematological or biochemical changes were observed for LP-CIT. However, free citrinin reduced monocytes and caused hepatotoxicity. During treatment, significant differences were observed regarding the weight of the right and left breasts treated with DMBA compared to negative controls. Treatment with CPA, CIT, and LP-CIT reduced the weight of both breasts, with better results for liposomal citrinin. Furthermore, CPA, CIT, and LP-CIT presented genotoxic effects for tumor, blood, bone marrow, and liver cells, although less DNA damage was observed for LP-CIT compared to CIT and CPA. Healthy cell damage induced by LP-CIT was repaired during treatment, unlike CPA, which caused clastogenic effects. Thus, LP-CIT showed advantages for its use as a model of nanosystems for antitumor studies. Full article

In toxicogenetics, an integrative approach including the prediction of phenotype based on post-mortem genotyping of drug-metabolising enzymes might help explain the cause of death (CoD) and manner of death (MoD). The use of concomitant drugs, however, might lead to phenoconversion, a mismatch between the phenotype based on the genotype and the metabolic profile actually observed after phenoconversion. The aim of our study was to evaluate the phenoconversion of CYP2D6, CYP2C9, CYP2C19, and CYP2B6 drug-metabolising enzymes in a series of autopsy cases tested positive for drugs that are substrates, inducers, or inhibitors of these enzymes. Our results showed a high rate of phenoconversion for all enzymes and a statistically significant higher frequency of poor and intermediate metabolisers for CYP2D6, CYP2C9, and CYP2C19 after phenoconversion. No association was found between phenotypes and CoD or MoD, suggesting that, although phenoconversion might be useful for a forensic toxicogenetics approach, more research is needed to overcome the challenges arising from the post-mortem setting. Full article

Background: Colorectal cancer is a highly prevalent disease, requiring effective strategies for prevention and treatment. The present research aimed to formulate a natural fiber-rich food product (NFRFP) and to evaluate its safety, toxicogenetics, and effects on aberrant crypt foci induced by 1,2-dimethyl-hydrazine in a preclinical model. Methods: A total of 78 male Wistar rats were distributed in six experimental groups: negative control, positive control (1,2-Dimethylhydrazine—40 mg/Kg), and four groups fed with 10% NFRFP: NFRFP, pre-treatment protocol, simultaneous treatment, and post-treatment protocol. Results: The NFRFP was shown to be a good source of fibers and did not change biometric, biochemical, hematological, and inflammatory parameters, and did not induce signs of toxicity and genotoxicity/carcinogenicity. NFRFP exhibited a chemopreventive effect, in all protocols, with damage reduction (% DR) of 75% in the comet test. NFRFP reduced the incidence of aberrant crypt outbreaks by 49.36% in the post-treatment protocol. Conclusions: The results suggest the applicability of NFRFP in the human diet due to potential production at an industrial scale and easy technological application in different products, since it could be incorporated in food without altering or causing small changes in final product sensory characteristics. Full article

Clostridium perfringens is a Gram-positive bacterium that possess seven toxinotypes (A, B, C, D, E, F, and G) that are responsible for the production of six major toxins, i.e., α, β, ε, ι, CPE, and NetB. The aim of this study is to find out the occurrence of toxinotypes in buffalo and cattle of Punjab province in Pakistan and their corresponding toxin-encoding genes from the isolated toxinotypes. To accomplish this aim, six districts in Punjab province were selected (i.e., Lahore, Sahiwal, Cheecha Watni, Bhakkar, Dera Ghazi Khan, and Bahawalpur) and a total of 240 buffalo and 240 cattle were selected for the collection of samples. From isolation and molecular analysis (16S rRNA), it was observed that out of seven toxinotypes (A–G), two toxinotypes (A and D) were found at most, whereas other toxinotypes, i.e., B, C, E, F, and G, were not found. The most frequently occurring toxinotype was type A (buffalo: 149/240; cattle: 157/240) whereas type D (buffalo: 8/240 cattle: 7/240) was found to occur the least. Genes encoding toxinotypes A and D were cpa and etx, respectively, whereas genes encoding other toxinotypes were not observed. The occurrence of isolated toxinotypes was studied using response surface methodology, which suggested a considerable occurrence of the isolated toxinotypes (A and D) in both buffalo and cattle. Association between type A and type D was found to be significant among the isolated toxinotypes in both buffalo and cattle (p ≤ 0.05). Correlation was also found to be positive and significant between type A and type D. C. perfringens exhibits a range of toxinotypes that can be diagnosed via genotyping, which is more reliable than classical toxinotyping. Full article

The detrimental effects of organophosphates (OPs) on human health are thought to be of systemic, i.e., irreversible inhibition of acetylcholinesterase (AChE) at nerve synapses. However, several studies have shown that AChE inhibition alone cannot explain all the toxicological manifestations in prolonged exposure to OPs. The present study aimed to assess the status of antioxidants malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) (reduced), catalase, and ferric reducing antioxidant power (FRAP) in chronic OP-exposed groups from Cameroon and Pakistan. Molecular analysis of genetic polymorphisms (SNPs) of glutathione transferases (GSTM1, GSTP1, GSTT1), catalase gene (CAT, rs7943316), sirtuin 1 gene (SIRT1, rs10823108), acetylcholinesterase gene (ACHE, rs2571598), and butyrylcholinesterase gene (BCHE, rs3495) were screened in the OP-exposed individuals to find the possible causative association with oxidative stress and toxicity. Cholinesterase and antioxidant activities were measured by colorimetric methods using a spectrophotometer. Salting-out method was employed for DNA extraction from blood followed by restriction fragment length polymorphism (RFLP) for molecular analysis. Cholinergic enzymes were significantly decreased in OP-exposed groups. Catalase and SOD were decreased and MDA and FRAP were increased in OP-exposed groups compared to unexposed groups in both groups. GSH was decreased only in Pakistani OPs-exposed group. Molecular analysis of ACHE, BCHE, Catalase, GSTP1, and GSTM1 SNPs revealed a tentative association with their phenotypic expression that is level of antioxidant and cholinergic enzymes. The study concludes that chronic OPs exposure induces oxidative stress which is associated with the related SNP polymorphism. The toxicogenetics of understudied SNPs were examined for the first time to our understanding. The findings may lead to a newer area of investigation on OPs induced health issues and toxicogenetics. Full article

The marine polyether palytoxin (PLTX) is one of the most toxic natural compounds, and is involved in human poisonings after oral, inhalation, skin and/or ocular exposure. Epidemiological and molecular evidence suggest different inter-individual sensitivities to its toxic effects, possibly related to genetic-dependent differences in the expression of Na⁺/K⁺-ATPase, its molecular target. To identify Na⁺/K⁺-ATPase subunits, isoforms correlated with in vitro PLTX cytotoxic potency, sensitivity parameters (EC₅₀: PLTX concentration reducing cell viability by 50%; Emax: maximum effect induced by the highest toxin concentration; 10⁻⁷ M) were assessed in 60 healthy donors’ monocytes by the MTT (methylthiazolyl tetrazolium) assay. Sensitivity parameters, not correlated with donors’ demographic variables (gender, age and blood group), demonstrated a high inter-individual variability (median EC₅₀ = 2.7 × 10⁻¹⁰ M, interquartile range: 0.4–13.2 × 10⁻¹⁰ M; median Emax = 92.0%, interquartile range: 87.5–94.4%). Spearman’s analysis showed significant positive correlations between the β2-encoding ATP1B2 gene expression and Emax values (rho = 0.30; p = 0.025) and between Emax and the ATP1B2/ATP1B3 expression ratio (rho = 0.38; p = 0.004), as well as a significant negative correlation between Emax and the ATP1B1/ATP1B2 expression ratio (rho = −0.30; p = 0.026). This toxicogenetic study represents the first approach to define genetic risk factors that may influence the onset of adverse effects in human PLTX poisonings, suggesting that individuals with high gene expression pattern of the Na⁺/K⁺-ATPase β2 subunit (alone or as β2/β1 and/or β2/β3 ratio) could be highly sensitive to PLTX toxic effects. Full article