Mechanisms of chromium-induced toxicity DesMarias, Thomas Liborio; Costa, Max
Current opinion in toxicology,
April 2019, 2019-04-00, 20190401, Volume:
14
Journal Article
Peer reviewed
Open access
Chromium is a pervasive environmental contaminant that is of great importance because of its toxicity. Hexavalent chromium is a classified group 1 carcinogen with multiple complex mechanisms by which ...it triggers cancer development. Increased levels of oxidative stress, chromosome breaks, and DNA adduct formation are some of the major mechanisms by which Cr(VI) causes cellular damage. Trivalent chromium is another species of chromium that is described as a nonessential metal and is used in nutritional supplementation. Evidence on nutritional benefit is conflicting, which could suggest that humans absorb enough Cr(III) from diet alone and that extra supplementation is not necessary. This review highlights the differences between Cr(VI) and Cr(III) from a chemical and toxicological perspective, describes shortcomings in nutritional research of Cr(III), and explains the multiple mechanisms by which Cr(VI) is involved in the process of carcinogenesis.
Multidrug resistance of the pathogenic microorganisms to the antimicrobial drugs has become a major impediment toward successful diagnosis and management of infectious diseases. Recent advancements ...in nanotechnology-based medicines have opened new horizons for combating multidrug resistance in microorganisms. In particular, the use of silver nanoparticles (AgNPs) as a potent antibacterial agent has received much attention. The most critical physico-chemical parameters that affect the antimicrobial potential of AgNPs include size, shape, surface charge, concentration and colloidal state. AgNPs exhibits their antimicrobial potential through multifaceted mechanisms. AgNPs adhesion to microbial cells, penetration inside the cells, ROS and free radical generation, and modulation of microbial signal transduction pathways have been recognized as the most prominent modes of antimicrobial action. On the other side, AgNPs exposure to human cells induces cytotoxicity, genotoxicity, and inflammatory response in human cells in a cell-type dependent manner. This has raised concerns regarding use of AgNPs in therapeutics and drug delivery. We have summarized the emerging endeavors that address current challenges in relation to safe use of AgNPs in therapeutics and drug delivery platforms. Based on research done so far, we believe that AgNPs can be engineered so as to increase their efficacy, stability, specificity, biosafety and biocompatibility. In this regard, three perspectives research directions have been suggested that include (1) synthesizing AgNPs with controlled physico-chemical properties, (2) examining microbial development of resistance toward AgNPs, and (3) ascertaining the susceptibility of cytoxicity, genotoxicity, and inflammatory response to human cells upon AgNPs exposure.
Toxic contaminants, including pesticides, microplastics, and heavy metals, have a significant impact on aquatic life and other aquatic species. These pollutants come from anthropogenic sources such ...as crop growing, industrial operations, effluent, residential wastewater, and leaching, as well as environmental events like storms, floods, and seismic processes. Pesticides, particularly pesticides, have been shown to have detrimental effects on aquatic ecology, causing decreased growth, restricted larvae and embryo development, and dysfunction in primary organs like the gill, liver, kidney, and gonad. Genotoxicity from pesticide exposure raises safety concerns, as prolonged exposure can lead to oxidative stress, mutagenicity, and cellular apoptosis. Pesticide exposure can lead to elevated levels, even without measurable concentrations in biological matrices. The toxicity of pesticides directly affects aquatic life, leading to high mortality rates or the complete elimination of species that serve as their food source.To maintain the well-being of aquatic organisms, particularly fish, and protect aquatic ecosystems, it is crucial to investigate safe, acceptable, and efficient alternatives to pesticides. In this study, we focuses on the hematological, biochemical, and histopathological changes induced by pesticide exposure and highlights strategies for mitigating the adverse impacts of pesticides on fish. Further investigation is needed to determine species suitability for toxicity detection, an essential aspect of monitoring aquatic environments for agricultural pesticides.
Cannabidiol (CBD), a naturally occurring cyclic terpenoid found in Cannabis sativa L., is renowned for its diverse pharmacological benefits. Marketed as a remedy for various health issues, CBD ...products are utilized by patients as a supplementary therapy or post-treatment failure, as well as by healthy individuals seeking promised advantages. Despite its widespread use, information regarding potential adverse effects, especially genotoxic properties, is limited. The present study is focused on the mutagenic and genotoxic activity of a CBD isolate (99.4 % CBD content) and CBD-rich Cannabis sativa L extract (63.6 % CBD content) in vitro. Both CBD samples were non-mutagenic, as determined by the AMES test (OECD 471) but exhibited cytotoxicity for HepG2 cells (∼IC50(4 h) 26 µg/ml, ∼IC50(24 h) 6–8 µg/ml, MTT assay). Noncytotoxic concentrations induced upregulation of genes encoding metabolic enzymes involved in CBD metabolism, and CBD oxidative as well as glucuronide metabolites were found in cell culture media, demonstrating the ability of HepG2 cells to metabolize CBD. In this study, the CBD samples were found non-genotoxic. No DNA damage was observed with the comet assay, and no influence on genomic instability was observed with the cytokinesis block micronucleus and the γH2AX and p-H3 assays. Furthermore, no changes in the expression of genes involved in genotoxic stress response were detected in the toxicogenomic analysis, after 4 and 24 h of exposure. Our comprehensive study contributes valuable insights into CBD's safety profile, paving the way for further exploration of CBD's therapeutic applications and potential adverse effects.
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•At non-cytotoxic concentrations CBD samples upregulated genes involved in CBD metabolism (CYP1A1, CYP3A4 and UGT1A3).•CBD oxidative, as well as glucuronide metabolites, were found in cell culture media.•CBD samples exhibited cytotoxicity, with IC50 values of 26 µg/ml, and 6–8 µg/ml after 4 and 24 h of exposure, respectively.•The tested CBD samples were found to be non-mutagenic in the Ames test (OECD 471).•CBD samples were non-genotoxic, with negative results in the comet, CBMN, γH2AX, and p-H3 assays, and toxicogenomics.
Opioids such as morphine are the first choice in acute and chronic pain treatment. However, they lead to addiction. Several studies have searched (i) to find a molecule that can replace morphine use ...or (ii) to reduce its adverse effects. This work aimed to evaluate whether (–)-Borneol (–)-BOR, a bicyclic monoterpene, in doses of 25, 50, and 100 mg/kg (i.p.), has an antiaddictive effect on morphine (5 mg/kg, i.p.) and reduces its withdrawal symptoms precipitated by naloxone (8 mg/kg, i.p.) in Swiss mice. Furthermore, the (–)-BOR genotoxic potential was also investigated by the comet assay. The antiaddictive effect of (–)-BOR was evaluated by the conditioned preference place (CPP). The CPP was induced by morphine administration during the conditioning phase. The effects of (–)-BOR on the rewarding characteristics of morphine were tested in mice with the administration of (–)-BOR, naloxone, or vehicle (NaCl 0.9%), 30 min before morphine. This work also investigated the (–)-BOR effect on morphine withdrawal symptoms precipitated by naloxone. Morphine withdrawal symptoms were induced by administering morphine twice daily for 5 days, precipitated by naloxone administration on the sixth day. The effect of (–)-BOR on reducing morphine withdrawal symptoms was evaluated in mice that received (–)-BOR before daily morphine administration. Finally, the comet assay was performed to assess the DNA damage degree caused by the (–)-BOR (100 mg/kg, i.p.) administration. The comet assay was performed on peripheral blood taken from the tail of each animal. Cyclophosphamide (50 mg/kg, i.p.) was used to induce DNA damage. After starting the protocol, analyses were performed for 4 h (acute effect) and 24 h (repair effect). The (–)-BOR (100 mg/kg, i.p.) significantly attenuated (*** p < 0.001) the acquisition of morphine-induced CPP and reduced only the jumping behavior in the morphine withdrawal model. The best-studied dose was 100 mg/kg, being evaluated, then, in the comet assay. (–)-BOR at 100 mg/kg did not show the genotoxic effect when compared with the cyclophosphamide group (CYCLO, 50 mg/kg, i.p.) after 4 h or 24 h, a period that corresponded to the repair time of DNA fragmentation. The study showed that (–)-BOR attenuated the acquisition of CPP by morphine and made opioid withdrawal milder. In the comet assay, although (–)-BOR caused DNA damage, this damage was significantly less than the damage by CYCLO, at either 4 h or 24 h after the treatments.
•Artemia spp. displays a low sensitivity in several ecotoxicological assessments.•Morphological endpoints are widely employed for detecting acute/chronic toxicity.•New emerging pollutants and trace ...metals are the most tested compounds.•NGS provide additional tools to evaluate the molecular response of Artemia spp.•Genotoxicity is suggested as a novel endpoint in Artemia spp. models.
Artemia spp. represent models species widely used in ecotoxicological studies due to its simple and fast manipulation in laboratory conditions that makes this crustacean well adaptable to several methodological approaches. Although cysts hatching, swimming behavior, reproductive success and mortality are the main endpoints used for the determination of toxicity, the detection of slight alterations induced by certain substances found at low concentrations in the environment may require more sensitive biomarkers. For this reason, the identification of DNA or chromosomal damages has been proposed as an additional and appreciable endpoint for the ecotoxicological assessment of environmental chemicals. Concerning Artemia models, only few studies indicated that the exposure to organic and inorganic compounds (i.e. pesticides, nanoparticles, bacterial products or heavy metals) can reduce the survival and fitness through the onset of DNA breaks or the dysregulation of key genes. In contrast, literature research revealed a lot of works primarily focusing on the mortality and hatching rates of Artemia nauplii and cysts despite the well-known low sensitivity of these species.
The present review reports the current state of knowledge concerning the effects induced by various chemicals, including organic and inorganic compounds, on the common parameters and genotoxicity in both Artemia franciscana and Artemia salina. Advantages and limitations of Artemia spp. models in eco-toxicological investigations together with the most used classes of compounds are briefly discussed. Moreover, a mention is also addressed to scarce availability of literature data focusing on genotoxic effects and the great reliability of molecular approaches observed in this poorly sensitive model organism. Thus, the opportunity to take advantage of genotoxic analyses has also been highlighted, by suggesting this approach as a novel endpoint to be used for the eco-toxicological assessment of several stressors.
Epidemiological studies have demonstrated that metformin (a cornerstone of diabetes treatment) has anticancer activity, but the underlying mechanism remains elusive. We aimed to investigate whether ...metformin elicits anticancer activity via increasing genotoxic stress, a state of increased genome damage that becomes tumor-suppressing if it goes beyond an intolerable threshold. We found that metformin (1–16 mM) suppressed proliferation and colony formation in a panel of cancer cell lines (HeLa, A375, A549 and QGY). Metformin induced a dose-dependent increase of genotoxic stress (including micronucleus, nucleoplasmic bridge and nuclear bud) and the increase of genotoxic stress correlated well with metformin's anticancer potential. Metformin deregulated the expression of BUBR1 and MAD2, two core genes of spindle assembly checkpoint (SAC) that surveillances chromosome segregation. Metformin had weakened antiproliferative effect and a corresponding attenuated genotoxic effect in HeLa cells cultured in high glucose (16 mg/ml). Meanwhile, metformin significantly increased genotoxicity in non-cancer cells (NCM460 and HUVECs). Metformin became non-genotoxic to HUVECs in high-glucose (8 and 16 mg/ml) conditions and reduced the genotoxicity of high glucose. Overall, these results infer a new mechanism of high-dose metformin, whereby low-glucose dependent genotoxic stress derived from SAC dysfunction might mediate some of the anticancer effect of this drug.
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•Metformin elicits short- and long-term effects to inhibit the growth of cancer cells.•Metformin causes significant genotoxic stress in cancer cells.•Metformin de-regulates the expression of core SAC genes.•Metformin is genotoxic to non-cancer cells.•The genotoxic and anti-genotoxic effects of metformin depend on glucose availability.
The in vitro micronucleus (MN) assay is a component of most test batteries used in assessing potential genotoxicity. Our previous study adapted metabolically competent HepaRG cells to the ...high-throughput (HT) flow-cytometry-based MN assay for genotoxicity assessment (Guo et al. in J Toxicol Environ Health A 83:702–717, 2020b,
https://doi.org/10.1080/15287394.2020.1822972
). We also demonstrated that, compared to HepaRG cells grown as two-dimensional (2D) cultures, 3D HepaRG spheroids have increased metabolic capacity and improved sensitivity in detecting DNA damage induced by genotoxicants using the comet assay (Seo et al. in ALTEX 39:583–604, 2022,
https://doi.org/10.14573/altex.22011212022
). In the present study, we have compared the performance of the HT flow-cytometry-based MN assay in HepaRG spheroids and 2D HepaRG cells by testing 34 compounds, including 19 genotoxicants or carcinogens and 15 compounds that show different genotoxic responses in vitro and in vivo. 2D HepaRG cells and spheroids were exposed to the test compounds for 24 h, followed by an additional 3- or 6-day incubation with human epidermal growth factor to stimulate cell division. The results demonstrated that HepaRG spheroids showed generally higher sensitivity in detecting several indirect-acting genotoxicants (require metabolic activation) compared to 2D cultures, with 7,12-dimethylbenzanthracene and
N
-nitrosodimethylamine inducing higher % MN formation along with having significantly lower benchmark dose values for MN induction in 3D spheroids. These data suggest that 3D HepaRG spheroids can be adapted to the HT flow-cytometry-based MN assay for genotoxicity testing. Our findings also indicate that integration of the MN and comet assays improved the sensitivity for detecting genotoxicants that require metabolic activation. These results suggest that HepaRG spheroids may contribute to New Approach Methodologies for genotoxicity assessment.
In vitro genotoxicity testing that employs metabolically active human cells may be better suited for evaluating human in vivo genotoxicity than current bacterial or non-metabolically active mammalian ...cell systems. In the current study, 28 compounds, known to have different genotoxicity and carcinogenicity modes of action (MoAs), were evaluated over a wide range of concentrations for the ability to induce DNA damage in human HepG2 and HepaRG cells. DNA damage dose–responses in both cell lines were quantified using a combination of high-throughput high-content (HTHC) CometChip technology and benchmark dose (BMD) quantitative approaches. Assays of metabolic activity indicated that differentiated HepaRG cells had much higher levels of cytochromes P450 activity than did HepG2 cells. DNA damage was observed for four and two out of five indirect-acting genotoxic carcinogens in HepaRG and HepG2 cells, respectively. Four out of seven direct-acting carcinogens were positive in both cell lines, with two of the three negatives being genotoxic mainly through aneugenicity. The four chemicals positive in both cell lines generated HTHC Comet data in HepaRG and HepG2 cells with comparable BMD values. All the non-genotoxic compounds, including six non-genotoxic carcinogens, were negative in HepaRG cells; five genotoxic non-carcinogens also were negative. Our results indicate that the HTHC CometChip assay detects a greater proportion of genotoxic carcinogens requiring metabolic activation (i.e., indirect carcinogens) when conducted with HepaRG cells than with HepG2 cells. In addition, BMD genotoxicity potency estimate is useful for quantitatively evaluating CometChip assay data in a scientifically rigorous manner.
Realgar (As2S2 or As4S4) is a traditional Chinese medicine (TCM) containing arsenic. Existing studies have shown that it has genotoxicity under long-term use with large doses. Niuhuang Jiedu (NHJD) ...is a Chinese medicine prescription containing realgar and seven other TCMs. Whether the multiple TCMs combination in NHJD can reduce the genotoxicity induced by realgar in equivalent doses is still unknown.
To research the effect of NHJD on realgar's genotoxicity and the possible mechanism involved based on the arsenic methylation metabolic pathway.
Six groups (control, realgar (0.8 g/kg), NHJD (12.48 g/kg), as well as Glycyrrhiza uralensis Fisch (GU), Scutellaria baicalensis Georg (SB), Rheum palmatum L (RP) plus equivalent doses of realgar, respectively) were set up. ICR mice were intragastric administered for 12 weeks. First, genotoxicology tests were conducted to evaluate the effect of NHJD, GU, SB, and RP on reducing realgar's genotoxicity. The inorganic arsenic (iAs), dimethyl arsenic acid (DMA), and monomethyl arsenic acid (MMA) were determined by HPLC-AFS, and the iAs%, MMA%, DMA%, primary methylation index (PMI), etc. Were calculated. Meanwhile, the S-adenosyl methionine (SAM) and arsenate reductase (ARR) levels, the arsenic (+3)methyltransferase (As3MT), purine-nucleoside phosphorylase (PNP), glutathione S-transfer omega1 (GSTO1) gene expression were detected, aimed to explore the possible alleviation mechanisms of NHJD.
The combination of multiple TCMs in NHJD decreased the levels of MN‰, SPA%, and DNA damage caused by realgar, with similar effects observed when SB, RP, and GU were used separately with realgar. Notably, the iAs% significantly decreased, while DMA% and PMI notably increased in the NHJD and realgar + SB (or RP) groups compared to the realgar-only group (P < 0.05). Increases in SAM and ARR levels were observed across various groups, but only the ARR increase in the NHJD group was statistically significant. Moreover, significant increases in As3MT mRNA and GSTO1 mRNA were noted in the NHJD group, and PNP mRNA levels significantly rose in the realgar + SB group.
This study revealed that NHJD could attenuate the genotoxic effects of realgar. The botanicals SB, RP, and GU within NHJD may be key contributors to this effect. Enhancements in arsenic methylation capabilities through increased levels of SAM and ARR and elevated gene expressions of As3MT, PNP, and GSTO1 suggest potential mechanisms behind these findings.
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•NHJD reduces the increment of MN‰, SPA%, and DNA damage caused by realgar.•NHJD increases arsenic methylation capacity compared to equivalent doses of realgar.•SAM and ARR proteins may play roles in NHJD's alleviating realgar genotoxicity.•As3MT, PNP, and GSTO1 genes may be involved in the detoxification mechanisms of NHJD.•Nine chemical compounds were identified in the prepared NHJD decoction.
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