Genetic Toxicity Research Articles

Metformin Exhibits an Attractive Antineoplastic Effect on Human Endometrial Cancer by Regulating the Hippo Signaling Pathway.

Metformin, the first-line oral antidiabetic medicine, has shown great antineoplastic potential in various cancer types, despite an unclear mechanism. This study aimed to elucidate the possible mechanism of metformin as a chemotherapy agent with less reproductive and genetic toxicity in human endometrial cancer. The type I endometrial carcinoma cell lines Ishikawa and RL95-2 were treated with metformin. Cell functions, such as proliferation, migration, and invasion, were analyzed. Flow cytometry was performed for cell cycle and apoptosis analyses. Simultaneously, RT-qPCR and western blotting were performed to explore the possible mechanism. Moreover, YAP1 knockout Ishikawa cells were established via lentivirus to demonstrate the underlying mechanism. The results showed that metformin mediated Ishikawa and RL95-2 cell growth inhibition in a dose- and time-dependent manner. The IC50 values of metformin in Ishikawa and RL95-2 cells were 10 mM and 8 mM, respectively. The migration and invasion abilities were also inhibited in the metformin-treated group using wound healing assays and transwell migration and invasion assays, and Ishikawa and RL95-2 cells were arrested in the G1 or G2 phase, respectively. Moreover, the cell proportions of cells in both early and late apoptosis stages were dramatically elevated when treated with metformin, as was the ratio of Bax/Bcl-2 expression. Additionally, the expression levels of YAP1 mRNA and protein in the treatment group were much lower than those in the control group. The cellular behaviors of YAP1 knockout Ishikawa cells were similar to those in the metformin-treated group. Our results demonstrated that it is an attractive alternative to cytotoxic chemotherapy in human endometrial cancer, and YAP of the Hippo pathway may be a potential molecular target. This study provides novel ideas for the adjuvant therapy of endometrial cancer patients, especially for women with strong fertility desires and demands.

Ecotoxicity of Heteroaggregates of Polystyrene Nanospheres in Chironomidae and Amphibian.

Due to their various properties as polymeric materials, plastics have been produced, used and ultimately discharged into the environment. Although some studies have shown their negative impacts on the marine environment, the effects of plastics on freshwater organisms are still poorly studied, while they could be widely in contact with this pollution. The current work aimed to better elucidate the impact and the toxicity mechanisms of two kinds of commercial functionalized nanoplastics, i.e., carboxylated polystyrene microspheres of, respectively, 350 and 50 nm (PS350 and PS50), and heteroaggregated PS50 with humic acid with an apparent size of 350 nm (PSHA), all used at environmental concentrations (0.1 to 100 µg L−1). For this purpose, two relevant biological and aquatic models—amphibian larvae, Xenopus laevis, and dipters, Chironomus riparius—were used under normalized exposure conditions. The acute, chronic, and genetic toxicity parameters were examined and discussed with regard to the fundamental characterization in media exposures and, especially, the aggregation state of the nanoplastics. The size of PS350 and PSHA remained similar in the Xenopus and Chironomus exposure media. Inversely, PS50 aggregated in both exposition media and finally appeared to be micrometric during the exposition tests. Interestingly, this work highlighted that PS350 has no significant effect on the tested species, while PS50 is the most prone to alter the growth of Xenopus but not of Chironomus. Finally, PSHA induced a significant genotoxicity in Xenopus.

Benzo(a)pyrene and cardiovascular diseases: An overview of pre-clinical studies focused on the underlying molecular mechanism

Benzo(a)pyrene (BaP) is a highly toxic and carcinogenic polycyclic aromatic hydrocarbon (PAH) whose toxicological effects in the vessel-wall cells have been recognized. Many lines of evidence suggest that tobacco smoking and foodborne BaP exposure play a pivotal role in the dysfunctions of vessel-wall cells, such as vascular endothelial cell and vascular smooth muscle cells, which contribute to the formation and worsening of cardiovascular diseases (CVDs). To clarify the underlying molecular mechanism of BaP-evoked CVDs, the present study mainly focused on both cellular and animal reports whose keywords include BaP and atherosclerosis, abdominal aortic aneurysm, hypertension, or myocardial injury. This review demonstrated the aryl hydrocarbon receptor (AhR) and its relative signal transduction pathway exert a dominant role in the oxidative stress, inflammation response, and genetic toxicity of vessel-wall cells. Furthermore, antagonists and synergists of BaP are also discussed to better understand its mechanism of action on toxic pathways.

Occurrence of cytogenetic effects under the action of epimutagen in winter wheat

Research on studying the features of 0.01%, 0.05%, 0.10% and 0.50% epimutagen Triton-X-305 impact at the cellular level, which means the way of identifying the viability of pollen in plants of the first generation, and cytological analysis of chromosomal aberrations in the cells of the primary meristem of germinal roots during germination of bread winter wheat seeds have been conducted. Research in this direction allows us to significantly improve the monitoring of same type of substances in the environment and to forecast the nature of their action at the DNA-level. Genotypes Podolyanka and Spivanka created by Ukrainian selection and varieties of French selection Altigo, Courtot, Lyrik, Flamenko have been studied. These genotypes were selected in order to characterize possible genotype-mutagenic interactions for a compound of complex hereditary pattern for a range of concentrations with maximum contrast taking into account the possible high site-specific effect. The main purpose of this research was to identify the specificity of impact of the agent Triton X-305 at the cellular level and identify parameters fully showing the effect of this substance on the subsequent induction of biodiversity and the enhancement of hereditary variability at the cellular level. Such indicators as pollen sterility effected by various concentrations, the total frequency of chromosomal rearrangements, the spectrum of chromosomal rearrangements, including fragments and double fragments, single and double bridges, micronuclei and lagging chromosomes have been investigated. The ratio of fragments to bridges as an indicator of the active factor nature, the number of cells with two or more rearrangements as an indicator of genetic toxicity of this substance has been established. As a result, a significantly weaker effect of the epimutagen on the overall frequency of chromosomal rearrangement has been shown unlike other factors of a mutagenic nature, at the same time changing the ratio of the obtained aberrations in favour of micronuclei and lagging chromosomes. In addition, other parameters are determined as more meaningful for identifying a specific agent of impact, and the differences in concentrations are less contrasting. There is also a less significantly decreasing fertility, however, this parameter is highly dependent on the source material. In the future, we intend to assess the variability, primarily of a hereditary nature, by the way of a visual analysis of the obtained material in subsequent generations, as well as through biochemical analysis, yield qualities analysis and morphometry of the obtained material.

Biological responses of alga Euglena gracilis to triclosan and galaxolide and the regulation of humic acid

Although the toxicity of triclosan (TCS) and galaxolide (HHCB) in freshwater has been reported, little study is shed light on their molecular toxicity mechanism and the regulation of humic acid (HA). In this work, freshwater algae E. gracilis was selected to explore these processes, and the molecular toxicity mechanism was analyzed by metabolomics. TCS was more toxic to E. gracilis than HHCB at 1 d exposure with the EC50 value of 0.76 mg L−1, but HHCB showed a higher toxicity as the exposure time prolonged. HA could alleviate the toxicity of TCS and HHCB, mainly due to the inhibition of TCS uptake and oxidative stress, respectively. The perturbations on a number of antioxidant defense-related metabolites in response to TCS or HHCB also indicated oxidative stress was a main toxicity mechanism. However, the exposure to HHCB resulted in more pronounced perturbations in the purine metabolism than TCS, implying that HHCB may pose a genetic toxicity on algae. It may explain the higher toxicity of HHCB to algae as the exposure time increased. These findings provide a comprehensive understanding on the ecological risks of TCS or HHCB in natural waters.

Research Progress of Safety of Zearalenone: A Review

Zearalenone, a mycotoxin produced by fungi of the genus Fusarium, widely exists in animal feed and human food. The structure of zearalenone is similar to estrogen, so it mainly has estrogenic effects on various organisms. Products contaminated with zearalenone can pose risks to animals and humans. Therefore, it is imperative to carry out toxicological research on zearalenone and evaluate its risk to human health. This paper briefly introduces the production, physical, and chemical properties of zearalenone and the research progress of its toxicity kinetics, focusing on its genetic toxicity, reproductive toxicity, hepatotoxicity, immunotoxicity, carcinogenicity, endocrine interference, and its impact on intestinal health. Finally, the progress of the risk assessment of human exposure is summarized to provide a reference for the follow-up study of zearalenone.

The hydrogen storage nanomaterial MgH2 improves irradiation-induced male fertility impairment by suppressing oxidative stress

ObjectiveThis study aimed to reveal the protective effect of hydrogen storage nanomaterial MgH2 on radiation-induced male fertility impairment.MethodsThe characterization of MgH2 were analyzed by scanning electron microscopy (SEM) and particle size analyzer. The safety of MgH2 were evaluated in vivo and in vitro. The radioprotective effect of MgH2 on the reproductive system were analyzed in mice, including sperm quality, genetic effect, spermatogenesis, and hormone secretion. ESR, flow cytometry and western blotting assay were used to reveal the underlying mechanisms.ResultsMgH2 had an irregular spherical morphology and a particle size of approximately 463.2 nm, and the content of Mg reached 71.46%. MgH2 was safe and nontoxic in mice and cells. After irradiation, MgH2 treatment significantly protected testicular structure, increased sperm density, improved sperm motility, reduced deformity rates, and reduced the genetic toxicity. Particularly, the sperm motility were consistent with those in MH mice and human semen samples. Furthermore, MgH2 treatment could maintain hormone secretion and testicular spermatogenesis, especially the generation of Sertoli cells, spermatogonia and round sperm cells. In vitro, MgH2 eliminated the [·OH], suppressed the irradiation-induced increase in ROS production, and effectively alleviated the increase in MDA contents. Moreover, MgH2 significantly ameliorated apoptosis in testes and cells and reversed the G2/M phase cell cycle arrest induced by irradiation. In addition, MgH2 inhibited the activation of radiation-induced inflammation and pyroptosis.ConclusionMgH2 improved irradiation-induced male fertility impairment by eliminating hydroxyl free radicals.Graphical abstractMice fertility and function were evaluated with or without MgH2 treatment after 5 Gy irradiation. MgH2 had the ability of hydroxyl radicals scavenging and MDA suppressing in testicular tissue induced by irradiation. Further, MgH2 could participate in spermatogenesis and protect sperm development in three stages: the generation of Sertoli cells (Sox-9+), spermatogonia (Stra8+) and round sperm cells (Crem+). Moreover, MgH2 alleviated the decrease of testosterone secreted by interstitial cells after irradiation. In addition, MgH2 suppressed apoptosis, pyroptosis and inflammatory response and alleviated cell cycle arrest by mediating IR-induced ROS.

The role of ginger’s extract and N-acetylcysteine against docetaxel-induced oxidative stress and genetic disorder

Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 μM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel.

Toxicological Assessments of a Proprietary Blend of Punica granatum Fruit Rind and Theobroma cacao Seed Extracts: Acute, Subchronic, and Genetic Toxicity Studies.

LN18178 (Tesnor®) is a standardized, proprietary composition of aqueous ethanol extracts of Punica granatum fruit rind and Theobroma cacao seeds. The present study demonstrates a broad-spectrum toxicological evaluation of LN18178 utilizing in vitro and in vivo preclinical models following the Organization for Economic Cooperation and Development (OECD) guidelines for testing chemicals. Wistar rats did not show any clinical signs of toxicity and morbidity in acute oral and dermal toxicity tests with the median lethal dose (LD50) values of at least 5000 mg/kg and 2000 mg/kg body weight, respectively. LN18178 was nonirritating to the skin and eyes of the treated rabbits. In a ninety-day subchronic repeated oral dose toxicity study, the LN18178-treated Wistar rats did not show dose-related signs of toxicity on their body weight, food consumption, organ weights, hematology, and clinical chemistry parameters. The estimated no-observed-adverse-effect level (NOAEL) of LN18178 in male and female rats was 2500 mg/kg body weight. The observations from the bacterial reverse mutation test, in vitro chromosomal aberration assay, micronucleus assay in mouse bone marrow erythrocytes, and in vitro mouse lymphoma TK+/− gene mutation assay suggest that LN18178 is neither mutagenic nor clastogenic. In summary, the present study demonstrates that oral consumption of the herbal blend LN18178 does not show signs of toxicity; also it does not elicit genetic toxicity in the standard preclinical models.

Contractility analysis of human engineered 3D heart tissues by an automatic tracking technique using a standalone application.

The use of Engineered Heart Tissues (EHT) as in vitro model for disease modeling and drug screening has increased, as they provide important insight into the genetic mechanisms, cardiac toxicity or drug responses. Consequently, this has highlighted the need for a standardized, unbiased, robust and automatic way to analyze hallmark physiological features of EHTs. In this study we described and validated a standalone application to analyze physiological features of EHTs in an automatic, robust, and unbiased way, using low computational time. The standalone application “EHT Analysis” contains two analysis modes (automatic and manual) to analyzes the contractile properties and the contraction kinetics of EHTs from high speed bright field videos. As output data, the graphs of displacement, contraction force and contraction kinetics per file will be generated together with the raw data. Additionally, it also generates a summary file containing all the data from the analyzed files, which facilitates and speeds up the post analysis. From our study we highlight the importance of analyzing the axial stress which is the force per surface area (μN/mm2). This allows to have a readout overtime of tissue compaction, axial stress and leave the option to calculate at the end point of an experiment the physiological cross-section area (PSCA). We demonstrated the utility of this tool by analyzing contractile properties and compaction over time of EHTs made out of a double reporter human pluripotent stem cell (hPSC) line (NKX2.5EGFP/+-COUP-TFIImCherry/+) and different ratios of human adult cardiac fibroblasts (HCF). Our standalone application “EHT Analysis” can be applied for different studies where the physiological features of EHTs needs to be analyzed under the effect of a drug compound or in a disease model.

Safety evaluation of carbon tetrafluoride as an inert hyperbaric breathing gas in Sprague-Dawley rats

Carbon tetrafluoride (CF4) is an inert gas with higher molecular weight and lower water solubility than commonly used hyperbaric breathing gases. These inert gas properties decrease time required to decompress and avoid decompression sickness after deep dives. To assess CF4 toxicity, Sprague-Dawley rats were exposed to 8 atm absolute (ATA) air (10 males, 10 females) or 8 ATA 79% CF4/21% O2 (25 males, 25 females). Exposures were 30 min daily for 5 days. Rat behavior was normal throughout the testing period. There were no gross or microscopic pathology abnormalities following repeat dose exposure. Male body weight trends were similar between groups. Female body weight trends were 0.5 ± 0.8% day−1 for hyperbaric air exposure and − 0.2 ± 0.8% day−1 for hyperbaric CF4 exposure (P = 0.01) but remained within literature cited norms. Organ weights and hematologic indices remained within or near literature normal ranges. Clinical chemistry panels showed no signs of toxicity in renal or hepatic biomarkers. Polychromatic erythrocyte micronucleus frequency showed no chromosomal damage. Comet assay showed no DNA damage in lung tissue. Females exposed to CF4 had 2.5 times greater percent tail DNA in liver tissue than controls (P = 0.009). However this result remained within the normal range of local negative controls. A bacterial reverse mutation assay with exposure to 1 ATA 79% CF4/21% O2 for 72 h was nonmutagenic in four strains of Salmonella typhimurium and one strain of Escherichia coli. Overall, there was no evidence that CF4 caused organ toxicity or genetic toxicity.

Genetic instability of lung induced by carbon black nanoparticles is related with Plk1 signals changes

As a possible carcinogen, carbon black has threatened public health. However, the evidences are insufficient and the mechanism of carcinogenesis is still not specified. Thirty rats were randomly divided into 3 groups, namely 0, 5 and 30 mg/m3 Carbon Black nanoparticles (CBNPs) groups, respectively. Rats were treated with CBNPs by nose-only inhalation for 28 days, 6 h/day. The human bronchial epithelial (16HBE) cells were treated with 0, 50, 100 and 200 μg/mL CBNPs for 24 h. Polo-like kinase 1 (PLK1) overexpression cell line was established by pcDNA3.1-PLK1 stable transfection. Our results showed that CBNPs exposure could induce DNA damage and genetic changes as well as apoptosis in vivo and in vitro. The DNA repair ability increased after CBNPs exposure. Cell cycle process was retarded at the G2/M phases in 16HBE cells after CBNPs treatment. The PLK1, ChK2 GADD45α and XRCC1 expression levels changed in rat lung and 16HBE cells after CBNPs treatment. Compared with NC 16HBE cells, DNA damage and repair, numbers of apoptotic cells and micronucleus (MN) rates, as well as the ChK2, GADD45α, XRCC1 expression levels decreased, whereas cytokinesis block proliferation index (CBPI) and replicative index (RI) increase in PLK overexpression (PLK+/+) cells after CBNPs treatment. This study highlighted that PLK1 related with the genetic toxicity of CBNPs in vitro and in vivo. Our results provided evidences supporting reclassification of carbon black as a human possible carcinogen.

Safety and the probiotic potential of Bifidobacterium animalis CP-9.

Bifidobacterium animalis CP-9 was a commensal strain isolated from human breast milk. In this study, genetic and 90-day oral toxicity were assessed in rodents for its safety. Ames test as well as in vivo bone marrow micronucleus and spermatocyte chromosomal aberration were surveyed in mice. B. animalis CP-9 exhibited no mutagenic activity in the Ames test at the highest tested dosage (5000µg/plate) with or without metabolic activation. No evidence of in vivo genetic toxicity was observed at the maximum tested dosage of 10g/kg body weight (BW). Furthermore, there was no statistically significant difference of the biochemical and histological parameters in the rats administrated with B. animalis CP-9 at dosages of 0, 0.25, 0.5, or 1.5g/kg BW/day. No indication of concern for pathogenicity was exhibited during evaluation of Bifidobacterium ssp. generally, or B. animalis specifically. It was noted that B. animalis CP-9 was able to survive in gastric acid-like and high bile salt environment, and showed strong adhesion to the intestinal epithelial cells, Caco-2. Intriguingly, B. animalis CP-9 decreased olic acid-induced triglyceral (TG) accumulation in the Caco-2 cells, and viable B. animalis CP-9 had a better bacteriostatic activity compared to another well-documented B. animalis ssp. lactis, BB-12. Based on the present study, B. animalis CP-9 can be a safe probiotic supplement and may improve the health of host. PRACTICAL APPLICATION: Although the health benefits of probiotics are well known, the safety of a probiotic product is acquired particularly for a long-term consumption. We conduct the safety of B. animalis CP-9 isolated from human breast milk, and demonstrate no toxicity concern in vitro and in vivo. Hence, B. animalis CP-9 powder can be used as a commercial and safe probiotic supplement with some health benefits.

Screening of Pig-Derived Zearalenone-Degrading Bacteria through the Zearalenone Challenge Model, and Their Degradation Characteristics.

Zearalenone (ZEN) is widely found in food and feed. Its cytotoxicity, reproductive toxicity, genetic toxicity, immunotoxicity and hepatorenal toxicity have serious impacts on human and animal health. In order to help animals avoid ZEN poisoning in feed, ZEN-degrading bacterial strains were screened from fecal samples through a zearalenone challenge pig model, and their degradation characteristics were researched. Through the optimization of parameters such as the culture time, pH value, temperature, and strain concentration, the optimal conditions for the ZEN-degrading ability of these strains were preliminarily determined, and the active site of the ZEN degradation was explored. In this study, three strains (SY-3, SY-14, SY-20) with high ZEN degradation capacities were obtained. SY-3 was identified as Proteus mirabilis, and its main degrading component was the supernatant. SY-14 and SY-20 were identified as Bacillus subtilis. Their main degrading components were the intracellular fluid of SY-14, and the intracellular fluid and cell wall of SY-20. The above results showed that the ZEN challenge model was an effective way to screen ZEN-degrading bacteria.

Hepatoprotective activity of Dodonaea viscosa leaf extract nanoparticles against N-nitrosodiethylamine induced tumor initiation in rat liver: Modulation of apoptosis and signaling pathways

Aim: To evaluate the hepatoprotective activity of extract and silver nanoparticles of Dodonaea viscose leaves against hepatocellular carcinoma in male rats. Methodology: Eighty adult Wistar male rats were exposed to N-nitrosodiethylamine to induce hepatocellular carcinoma and allocated in different groups supplemented with 125, 250 and 500 mg kg-1 b.wt. of Dodonaea viscosa (DVLE) and DVLE-AgNPs for 12 weeks. Liver samples of treated groups were used to estimate the activities of alanine transaminase (ALT), aspartate aminotransferase (AST), glutathione peroxidase (GPx) and albumin levels. DNA damage, DNA adducts, ROS generation, apoptosis rate, and the expression analysis of the genes associated with the apoptosis (Bcls, Bax and p53) were also determined. Results: HCC group exhibited alterations in the activities of ALT, AST, GPx and levels of albumin compared with the control group. High rates of DNA damage, DNA adducts and ROS generations as well as changes in the apoptosis rates and the expression levels of Bcls, Bax and p53 genes were observed in HCC-induced rats compared with those in control group. DVLE and DVLE-AgNPs prevented the NDEA action on liver damage in a dose-dependent manner by reducing the alteration in the enzymatic and protein levels, decrease ROS generation, diminish genetic toxicity (DNA damage and DNA adducts), increased the apoptosis rate and suppressed the expression changes of Bcls, Bax and p53 genes. Interpretation: The action mechanism of DVLE and DVLE-AgNPs could probably attribute to the presence of polyphenolic and sesquiterpenes which are considered as potent inhibitors of cancer progression of liver cells.

Comprehensive and functional analyses reveal the genomic diversity and potential toxicity of Microcystis

Microcystis is a cyanobacteria that is widely distributed across the world. It has attracted great attention because it produces the hepatotoxin microcystin (MC) that can inhibit eukaryotic protein phosphatases and pose a great risk to animal and human health. Due to the high diversity of morphospecies and genomes, it is still difficult to classify Microcystis species. In this study, we investigated the pangenome of 23 Microcystis strains to detect the genetic diversity and evolutionary dynamics. Microcystis revealed an open pangenome containing 22,009 gene families and exhibited different functional constraints. The core-genome phylogenetic analysis accurately differentiated the toxic and nontoxic strains and could be used as a taxonomic standard at the genetic level. We also investigated the functions of HGT events, of which were mostly conferred from cyanobacteria and closely related species. In order to detect the potential toxicity of Microcystis, we searched and characterized MC biosynthetic gene clusters and other secondary metabolite gene clusters. Our work provides insights into the genetic diversity, evolutionary dynamics, and potential toxicity of Microcystis, which could benefit the species classification and development of new methods for drinking water quality control and management of bloom formation in the future.

Assessment of the ameliorative effect of curcumin on pendimethalin-induced genetic and biochemical toxicity

The present study aimed to assess the toxic effects of pendimethalin herbicide and protective role of curcumin using the Allium test on cytological, biochemical and physiological parameters. The effective concentration (EC50) of pendimethalin was determined at 12 mg/L by the root growth inhibition test as the concentration reducing the root length by 50%. The roots of Allium cepa L. was treated with tap water (group I), 5 mg/L curcumin (group II), 10 mg/L curcumin (group III), 12 mg/L pendimethalin (group IV), 12 mg/L pendimethalin + 5 mg/L curcumin (group V) and 12 mg/L pendimethalin + 10 mg/L curcumin (group VI). The cytological (mitotic index, chromosomal abnormalities and DNA damage), physiological (rooting percentage, root length, growth rate and weight gain) and oxidative stress (malondialdehyde level, superoxide dismutase level, catalase level and glutathione reductase level) indicators were determined after 96 h of treatment. The results revealed that pendimethalin treatment reduced rooting percentage, root length, growth rate and weight gain whereas induced chromosomal abnormalities and DNA damage in roots of A. cepa L. Further, pendimethalin exposure elevated malondialdehyde level followed by antioxidant enzymes. The activities of superoxide dismutase and catalase were up-regulated and glutathione reductase was down-regulated. The molecular docking supported the antioxidant enzymes activities result. However, a dose-dependent reduction of pendimethalin toxicity was observed when curcumin was supplied with pendimethalin. The maximum recovery of cytological, physiological and oxidative stress parameters was recorded at 10 mg/L concentration of curcumin. The correlation studies also revealed positive relation of curcumin with rooting percentage, root length, weight gain, mitotic activity and glutathione reductase enzyme level while an inverse correlation was observed with chromosomal abnormalities, DNA damage, superoxide dismutase and catalase enzyme activities, and lipid peroxidation indicating its protective effect.

A toxicological evaluation of 8–28 nm gold nanocrystals

Gold nanocrystals (AuNC) are gold nanoparticles (AuNP) relatively homogenous in size at 8–28 nm with clean surfaces and crystalline structures. There are concerns and a lack of consensus in the scientific literature and major regulatory bodies regarding not only the safety of nanoparticles when consumed by humans, but exactly how to determine their safety and whether evidence from a nanoparticle with one set of physiochemical properties extends to one with a different set. Additionally, there are few general long-term toxicity data on AuNP. To our knowledge, the potential toxicity of AuNC specifically, with the above characteristics, or otherwise, has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test to further explore their safety. AuNC were not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 60-day, repeated-dose oral toxicity study, rats were administered 0, 2.5, 5, or 10 mg/kg bw/day of AuNC by gavage. No toxicity was identified. Therefore, a no observed adverse effect level was determined as 10 mg/kg body weight/day.

Impacts of di-(2-ethylhexyl) phthalate on Folsomia candida (Collembola) assessed with a multi-biomarker approach

Di-(2-ethylhexyl) phthalate (DEHP) is extensively used as an additive to produce plastics, but it may damage non-target organisms in soil. In this study, the effects of DEHP on Folsomia candida in terms of survival, reproduction, enzyme activities, and DNA damage were investigated in spiked artificial soil using a multi-biomarker strategy. The 7-day LC50 (median lethal concentration) and 28-day EC50 (median effect concentration) values of DEHP were 1256.25 and 19.72 mg a.i. (active ingredient) kg-1 dry soil, respectively. Biomarkers involved in antioxidant defense including catalase (CAT-catalase), glutathione S-transferases (GST), detoxifying enzymes including acetylcholinesterase (AChE), Cytochrome P450 (CYP450), and peroxidative damage (LPO-lipid peroxide) were also measured (EC10, EC20, and EC50) after exposure for 2, 4, 7, and 14 days. The Comet assay was also applied to assess the level of genetic damage. The activity of CAT and LPO was drastically enhanced by the highest dose (EC50) of DEHP on day two. The activities of GST and AChE in DEHP treatment groups were found to be blocked. In contrast, the activity of CYP450 was significantly enhanced compared to the respective control groups during the first four days of incubation. The Comet assay in F.candida demonstrated that DEHP (EC50) could induce DNA damage. The obtained multi-biomarker data were analyzed using an integrated biomarker response (IBR) index, indicating that limited-time exposure triggered higher stress than long-term exposure at low concentrations of DEHP. These results demonstrate that DEHP may cause biochemical and genetic toxicity to F. candida, which illustrated the potential risks of DEHP in the soil environment and might affect soil ecosystem processes. Further studies are necessary to elucidate the toxic mechanisms of DEHP on other non-target organisms in soil.

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.