Explore the vast range of titles available.

N -nitrosamine impurities have been increasingly detected in human drugs. This is a safety concern as many nitrosamines are mutagenic in bacteria and carcinogenic in rodent models. Typically, the mutagenic and carcinogenic activity of nitrosamines requires metabolic activation by cytochromes P450 enzymes (CYPs), which in many in vitro models are supplied exogenously using rodent liver homogenates. There are only limited data on the genotoxicity of nitrosamines in human cell systems. In this study, we used metabolically competent human HepaRG cells, whose metabolic capability is comparable to that of primary human hepatocytes, to evaluate the genotoxicity of eight nitrosamines [ N -cyclopentyl-4-nitrosopiperazine (CPNP), N -nitrosodibutylamine (NDBA), N -nitrosodiethylamine (NDEA), N -nitrosodimethylamine (NDMA), N -nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA), N -nitroso- N -methyl-4-aminobutyric acid (NMBA), and N -nitrosomethylphenylamine (NMPA)]. Under the conditions we used to culture HepaRG cells, three-dimensional (3D) spheroids possessed higher levels of CYP activity compared to 2D monolayer cells; thus the genotoxicity of the eight nitrosamines was investigated using 3D HepaRG spheroids in addition to more conventional 2D cultures. Genotoxicity was assessed as DNA damage using the high-throughput CometChip assay and as aneugenicity/clastogenicity in the flow-cytometry-based micronucleus (MN) assay. Following a 24-h treatment, all the nitrosamines induced DNA damage in 3D spheroids, while only three nitrosamines, NDBA, NDEA, and NDMA, produced positive responses in 2D HepaRG cells. In addition, these three nitrosamines also caused significant increases in MN frequency in both 2D and 3D HepaRG models, while NMBA and NMPA were positive only in the 3D HepaRG MN assay. Overall, our results indicate that HepaRG spheroids may provide a sensitive, human-based cell system for evaluating the genotoxicity of nitrosamines.

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 μM and 200 μM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = −0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = −0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere–mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.

3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. As a result of the above, 1 has potential chemotherapeutic application and may be a candidate for developing a new generation of chemotherapeutics. In addition, it has characteristics to be used as a chemotherapy adjuvant in association with cyclophosphamide and cisplatin since it increases the frequency of cell death induced by chemotherapy. We also reported that the chemopreventive effect of 1, in association with cyclophosphamide and cisplatin, can prevent adverse effects (induction of DNA damage in non-tumor cells) without interfering with the mode of action of chemotherapy drugs and, therefore, without reducing the induction of cell death.

Many nitrosamines are recognized as mutagens and potent rodent carcinogens. Over the past few years, nitrosamine impurities have been detected in various drugs leading to drug recalls. Although nitrosamines are included in a ‘cohort of concern’ because of their potential human health risks, most of this concern is based on rodent cancer and bacterial mutagenicity data, and there are little data on their genotoxicity in human-based systems. In this study, we employed human lymphoblastoid TK6 cells transduced with human cytochrome P450 (CYP) 2A6 to evaluate the genotoxicity of six nitrosamines that have been identified as impurities in drug products: N -nitrosodiethylamine (NDEA), N -nitrosoethylisopropylamine (NEIPA), N -nitroso- N -methyl-4-aminobutanoic acid (NMBA), N -nitrosomethylphenylamine (NMPA), N -nitrosodiisopropylamine (NDIPA), and N -nitrosodibutylamine (NDBA). Using flow cytometry-based assays, we found that 24-h treatment with NDEA, NEIPA, NMBA, and NMPA caused concentration-dependent increases in the phosphorylation of histone H2A.X (γH2A.X) in CYP2A6-expressing TK6 cells. Metabolism of these four nitrosamines by CYP2A6 also caused significant increases in micronucleus frequency as well as G2/M phase cell-cycle arrest. In addition, nuclear P53 activation was found in CYP2A6-expressing TK6 cells exposed to NDEA, NEIPA, and NMPA. Overall, the genotoxic potency of the six nitrosamine impurities in our test system was NMPA > NDEA ≈ NEIPA > NMBA > NDBA ≈ NDIPA. This study provides new information on the genotoxic potential of nitrosamines in human cells, complementing test results generated from traditional assays and partially addressing the issue of the relevance of nitrosamine genotoxicity for humans. The metabolically competent human cell system reported here may be a useful model for risk assessment of nitrosamine impurities found in drugs.

Gomphrena celosioides is a native Brazilian plant found in the State of Mato Grosso do Sul. It is used in folk medicine to treat kidney diseases, skin diseases, infections, rheumatism, gastrointestinal diseases, and respiratory diseases. It is also used as an abortifacient. To evaluate the effects of the ethanolic extract of Gomphrena celosioides (EEGc) on reproductive performance, embryo development, and chromosome stability, Swiss mice were randomly divided into experimental groups (n = 10). The animals in the control group received the vehicle Tween 80–1% in the proportion of 0.1 mL/10 g of body weight orally, from the first to the 18th gestational day. The animals in the treatment groups received the EEGc (100, 1000, and 2000 mg/kg) from the first to the 18th gestational day. The animals underwent evaluations of their reproductive performance and embryofetal development. The results showed that the EEGc did not change the animals’ final weight, weight gain, uterine weight, or net weight gain. The evaluation showed that the absolute and relative organs’ weights did not vary between the different experimental groups. In addition, the EEGc did not change the numbers of implants, live fetuses, dead fetuses, or fetal resorptions. There were no differences in post-operative loss rates, implantations, or resorptions, nor were there differences in fetal viability or sex ratio. The use of the EEGc did not result in different frequencies of malformations. In addition, the EEGc did not alter the frequency of chromosomal damage or frequency of micronuclei. Based on our findings, we considered the extract of Gomphrena celosioides to be safe for use during pregnancy, although some parameters indicated caution in its use.

Abstract Chicken (Gallus gallus domesticus) is one of the primary sources of animal protein for the Brazilian population. Thus, the safety of this food is highly relevant. This study was based on the evidence of severe contamination of these animals by metals such as lead in Santo Amaro, Bahia. This exploratory study aimed to evaluate associations between lead levels in blood of chicken exposed to a contaminated area with the occurrence of chromosomal alterations, evidencing genotoxic effects. Serum lead analysis was performed by GF-AAS after dilution with a matrix modifier solution (Triton X-100 0.2% v/v and HNO3 0.1% v/v), while chromosomal damage was evaluated using the comet assay. The results showed genotoxic effects (positive comet assay) only for the specimen sample with higher serum lead concentrations (33.9 µg dL-1), suggesting the occurrence of toxic effects at this level of exposure. This work evaluated a relationship between the reduction of serum lead levels in chicken and increased distance from the primary polluting source - a lead processing plant (COBRAC). It also showed that lead is bioavailable in this territory, contaminating chicken and causing genotoxic effects in these animals, further expanding the concern with the local biota and the health of the residents of Santo Amaro. Resumo O frango (Gallus gallus domesticus) é uma das principais fontes de proteína animal para população brasileira, sendo que a segurança deste alimento é extremamente relevante. Assim, evidências de severa contaminação dessas aves, por metais como chumbo no município de Santo Amaro - BA, estimularam a realização deste estudo. O objetivo deste estudo exploratório foi avaliar associações entre os níveis de chumbo no sangue de frangos expostos a área contaminada com a ocorrência de alterações cromossômicas, evidenciando efeitos genotóxicos. As análises de chumbo sérico foram realizadas por GF-AAS após diluição em uma solução modificadora de matriz (Triton X-100 0,2% v/v e HNO3 0,1% v/v), enquanto os danos cromossômicos foram avaliados empregando o teste cometa. Os resultados obtidos evidenciaram efeitos genotóxicos (teste cometa positivo) apenas para amostra do espécime que apresentou concentrações séricas de chumbo mais elevadas (33.9 µg dL-1), sugerindo a ocorrência de efeitos tóxicos neste nível de exposição. Neste trabalho foi possível avaliar claramente uma relação entre a redução dos níveis séricos de chumbo no frango com o aumento da distância da principal fonte poluidora - uma fábrica de processamento de chumbo (COBRAC). O presente estudo evidenciou que neste território o chumbo está biodisponível, contaminando aves de criação e acarretando em efeitos genotóxicos nestes animais, ampliando ainda mais a preocupação com a biota local e com a saúde dos moradores de Santo Amaro.

In this study, the toxic effects of paraquat, one of the most commercially sold herbicides in the world, and the protective role of green tea leaf extract (GTLE) against these effects were investigated. Allium cepa L. bulbs ( n  = 16) were used as test material. One hundred milligrams per liter dose of paraquat and 190 and 380 mg/L doses of GTLE were preferred. Paraquat toxicity was investigated with the help of physiological (percent germination, root length, and weight gain), cytogenetic (mitotic index = MI, micronucleus = MN, and chromosomal damages = CAs), biochemical (superoxide dismutase = SOD, catalase = CAT, malondialdehyde = MDA), and anatomical (meristematic cell damages) parameters. A. cepa bulbs were divided into 6 groups as 1 control and 5 applications. The control group was germinated with tap water, and the application groups were germinated with paraquat and two different doses of GTLE. Germination was carried out at room temperature for 72 h. At the end of the period, A. cepa bulbs were prepared for physiological, cytogenetic, biochemical, and anatomical analyzes using routine preparation techniques. As a result, paraquat application caused a decrease in physiological parameters and an increase in cytogenetic (except MI) and biochemical parameters. Compared to the control (group I), the germination percentage decreased by 38%, root length 12.5 times, and weight gain 5 times decreased in group IV treated with paraquat. MDA level increased 2.58 times, SOD activity 2.48 times, and CAT activity 4.51 times increased. Paraquat application caused a decrease in the percentage of MI and an increase in the number of MN and CAs. Paraquat application caused CAs in the form of fragment, sticky chromosome, unequal distribution of chromatin, bridge, nucleus with vacuoles, nucleus bud, and reverse polarization. In the meristematic cells of the root tips applied paraquat, unclearly vascular tissue, flattened cell nucleus, epidermis, and cortex cell deformation were observed. The application of GTLE together with paraquat caused an increase in the physiological parameter values and a decrease in the cytogenetic (except MI) and biochemical parameter values. An improvement in the severity of damages induced by paraquat was also observed in root tip meristematic cells. It was determined that the improvements observed in all these parameters were related to the dose of GTLE applied. The 380 mg/L dose of GTLE provided more protection than the 190 mg/L dose. Compared to group IV in which paraquat was applied, the germination percentage increased by 21%, root length 5.83 times, and weight gain 2.92 times increased in group VI administered 380 mg/L dose of GTLE. In addition, MDA level decreased 1.78 times, SOD activity 1.59 times and CAT activity 1.65 times. In conclusion, paraquat administration at a dose of 100 mg/L caused physiological, cytogenetic, biochemical, and anatomical toxicity in A. cepa bulbs. GTLE application, on the other hand, resulted in improvements in the severity of this toxicity induced by paraquat, depending on the dose. Therefore, GTLE can be used as an effective nutritional supplement to reduce or prevent the toxicity caused by environmental agents such as pesticides.

Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited.

This study aimed to investigate air pollutant exposure at five primary schools in Terengganu, Malaysia, and to assess the chromosomal damage among the students by evaluating 176 school children aged 10–11 years. Members of the exposed group lived close to the industrial zone, whereas those of the comparative group lived far from it. The parameters for the indoor air monitoring included suspended particulate matter, gaseous pollutants (NO 2 and SO 2 ), and physical variables (temperature, relative humidity, and air velocity). Respiratory symptoms were assessed through questionnaires ( n = 176), and a micronucleus assay was conducted on the buccal epithelial cells of 91 children. The findings showed that the air pollutant levels at the schools of the exposed group were significantly higher ( p < 0.05) than those of the comparative group. The highest concentrations of PM 1 , PM 2.5 , and PM 10 recorded at the exposed schools were 43.30, 44.83, and 60.83 µg m –3 , respectively. Coughing was the most significant recurring respiratory symptom among the children with a 2.52 odds ratio ( p < 0.05). An average micronucleus frequency of 5.02 ± 3.43 MN per 1000 cells was displayed by children in the exposed group vs. 2.00 ± 1.56 MN per 1000 cells for the comparative group. After controlling for all possible confounding factors, these results strongly suggest that exposure to industrial air pollutants significantly influences the formation of micronuclei and increases the prevalence of respiratory symptoms among children living in proximity to an industrial area. Our study provides baseline data for genotoxic damage among such children in South East Asia specifically.

Objectives Structural chromosomal aberrations in blood lymphocytes represent a biomarker for cellular damage caused by genotoxic carcinogens and are an indicator of increased cancer risk. We evaluated the association between frequencies of total chromosomal aberrations, chromatid- and chromosome-type aberrations, and occupational exposures to volatile anesthetics, antineoplastic agents, and formaldehyde among 601 medical professionals. Methods Chromosomal damage among exposed individuals and unexposed controls was determined by conventional cytogenetic analysis. We used binary logistic regression to evaluate the effects of workplace exposures and major confounders on chromosomal damage. Results Significantly higher frequencies of total chromosomal, chromatid-type and chromosome-type aberrations were observed among subjects occupationally exposed to volatile anesthetics, antineoplastic agents, and formaldehyde compared to age- and sex-matched controls (P<0.0001). The risk of an increased frequency of chromosomal aberrations was associated with exposure to anesthetics [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 2.7—5.8], cytostatics (OR 2.7, 95% CI 1.9—3.9), and formaldehyde (OR 1.7, 95% CI 1.1—2.7). No other covariate contributed significantly to the model. Chromatid- and chromosome-type aberrations were associated with exposure to anesthetics and cytostatics without any contribution of other variables. Stratified data analysis showed the risk of increased chromosomal aberrations among non-smoking female nurses and physicians exposed to anesthetics, cytostatics and, partially, formaldehyde. Chromatid and chromosome exchanges were significantly higher in the exposed groups than among controls. Conclusion Our findings indicate that the presence of genotoxic compounds in operating rooms, oncological units, and pathological departments results in a significant increase of chromosomal damage (impair of chromosomal integrity) among medical workers employed in these facilities.