Epigenetic processes involved in response to pesticide exposure in human populations: a systematic review and meta-analysis.

In recent decades, the use of pesticides in agriculture has increased dramatically. This has resulted in these substances being widely dispersed in the environment, contaminating both exposed workers and communities living near agricultural areas and via contaminated foodstuffs. In addition to acute poisoning, chronic exposure to pesticides can lead to molecular changes that are becoming better understood. Therefore, the aim of this study was to assess, through a systematic review of the literature, what epigenetic alterations are associated with pesticide exposure. We performed a systematic review and meta-analysis including case-control, cohort and cross-sectional observational epidemiological studies to verify the epigenetic changes, such as DNA methylation, histone modification and differential microRNA expression, in humans who had been exposed to any type of pesticide. Articles published between the years 2005 and 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI software. Post-completion, the data of selected articles were extracted and analyzed. Most of the 28 articles included evaluated global DNA methylation levels, and the most commonly reported epigenetic modification in response to pesticide exposure was global DNA hypomethylation. Meta-analysis revealed a significant negative correlation between Alu methylation levels and ß-hexachlorocyclohexane, p,p'-dichlorodiphenyldichloroethane and p,p'-dichlorodiphenylethylene levels. In addition, some specific genes were reported to be hypermethylated in promoter regions, such as CDKN2AIGF2, WRAP53α and CDH1, while CDKN2B and H19 were hypomethylated due to pesticide exposure. The expression of microRNAs was also altered in response to pesticides, as miR-223, miR-518d-3p, miR-597, miR-517b and miR-133b that are associated with many human diseases. Therefore, this study provides evidence that pesticide exposure could lead to epigenetic modifications, possibly altering global and gene-specific methylation levels, epigenome-wide methylation and microRNA differential expression.

Hazard assessment of antineoplastic drugs and metabolites using cytotoxicity and genotoxicity assays.

Antineoplastic drugs are among the most toxic pharmaceuticals. Their release into the aquatic ecosystems has been reported, giving rise to concerns about the adverse effects, including cytotoxicity and genotoxicity, that they may have on exposed organisms. In this study, we analyzed the cytotoxicity and genotoxicity of 5-fluorouracil (5-FU) and its metabolite alpha-fluoro-beta-alanine (3-NH2-F); gemcitabine (GEM) and its metabolite 2'-deoxy-2',2'-difluorouridine (2-DOH-DiF); as well as cyclophosphamide (CP) on the HepG2 cell line. Drug concentrations were based on those previously observed in the effluent of a major cancer hospital in Brazil. The study found that GEM, 2-DOH-DiF and 5-FU resulted in reduced cell viability. No reduction in cell viability was observed for CP and 3-NH2-F. Genotoxic assessment revealed damage in the form of nucleoplasmic bridges for CP and 3-NH2-F. The tested concentrations of all compounds resulted in significantly increased MNi and NBUDs. The results showed that these compounds induced cytotoxic and genotoxic effects in HepG2 cells at concentrations found in the environment. To the best of our knowledge, this study is the first to report on the cytogenotoxic impacts of the metabolites 3-NH2-F and 2-DOH-DiF in HepG2 cells. These findings may help in the development of public policies that could minimize potential environmental contamination.

In vitro evaluation of the cytotoxic and genotoxic effects of Al and Mn in ambient concentrations detected in groundwater intended for human consumption.

Environmental exposure to metals can induce cytotoxic and genotoxic effects in cells and affect the health of the exposed population. To investigate the effects of aluminum (Al) and manganese (Mn), we evaluated their cytogenotoxicity using peripheral blood mononuclear cells (PBMCs) exposed to these metals at previously quantified concentrations in groundwater intended for human consumption. The cell viability, membrane integrity, nuclear division index (NDI), oxidative stress, cell death, cell cycle, and DNA damage were analyzed in PBMCs exposed to Al (0.2, 0.6, and 0.8 mg/L) and Mn (0.1, 0.3, 1.0, and 1.5 for 48 h. We found that Al induced late apoptosis; decreased cell viability, NDI, membrane integrity; and increased DNA damage. However, no significant alterations in the early apoptosis, cell cycle, and reactive oxygen species levels were observed. In contrast, exposure to Mn altered all evaluated parameters related to cytogenotoxicity. Our data show that even concentrations allowed by the Brazilian legislation for Al and Mn in groundwater intended for human consumption cause cytotoxic and genotoxic effects in PBMCs. Therefore, in view of the results found, a comprehensive approach through in vivo investigations is needed to give robustness and validity to the results obtained, thus broadening the understanding of the impacts of metals on the health of environmentally exposed people.

Occupational Exposures and Risks of Non-Hodgkin Lymphoma: A Meta-Analysis.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group with different types of diseases. It remains unclear as to what has led to an increase in incidences of NHL, however, chemical substance exposure is known to be one of the risk factors for the disease. Therefore, we performed a systematic review and meta-analysis including case-control, cohort, and cross-sectional observational epidemiological studies to verify the association between occupational exposure to carcinogens and NHL risk. Articles between the years 2000 and 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI web app. Post-completion, the selected articles were extracted and analyzed via the RedCap platform. Our review resulted in 2719 articles, of which 51 were included in the meta-analysis, resulting in an overall OR of 1.27 (95% CI 1.04-1.55). Furthermore, it was observed that the main occupation associated with the increased risk of NHL was that in which workers are exposed to pesticides. We therefore conclude that the evidence synthesis of the epidemiological literature supports an increased risk for NHL, regardless of subtype, considering occupational exposure to certain chemical compounds, mainly pesticides, benzene, and trichlorethylene, and certain classes of work, primarily in the field of agriculture.

Acute Toxic and Genotoxic Effects of Aluminum and Manganese Using In Vitro Models.

The objective of this study was to use the same concentrations of aluminum (Al) and manganese (Mn) detected previously in groundwater above those permitted by Brazilian law and assess their cytotoxic and genotoxic effects in hamster ovary cell lines and their mutagenic effects through the Salmonella microsome assay. Chinese hamster ovary (CHO) and CHO-XRS5 cells were treated with different concentrations of Al and Mn (0.2 to 2.0 mg/L and 0.1 to 3.0 mg/L, respectively). The Ames test was used to analyze the concentrations of Al and Mn ranging from 0.025 to 1.0 mg/L and 0.0125 to 1.5 mg/L, respectively. Both metals showed cytotoxic effects on both cell lines and two bacterial strains (TA98 and TA100). The genotoxic effects of the highest concentrations of Al and Mn in cell lines showed nuclear buds, micronuclei, and DNA damage; however, none of the concentrations showed a positive mutagenic response in the Ames test. This is one of the few studies to demonstrate the cytotoxic effects of Al and Mn through the Ames test. In addition, the metals caused genomic instability in cell lines. Therefore, this study may help hasten the review of established regulatory standards for human consumption of groundwater.

DNA methylation changes in promoter region of CDKN2A gene in workers exposed in construction environment.

PURPOSE: Construction workers are exposed to a mixture of substances in the workplace considered carcinogenic. This study aimed to characterise gene-specific changes in DNA methylation over the workweek in this population as this type of environmental exposure has not been studied extensively. MATERIALS AND METHODS: We evaluated their DNA methylation in 4 gene-promoter regions (CDKN2A, RASSF1A, MLH1 and APC) and 2 repeat elements (ALU and LINE-1) in blood samples obtained on the first and fifth day of the same workweek of a group of 39 male construction workers. DNA methylation was measured by bisulphite-PCR-Pyrosequencing. We also measured the levels of trace elements in the whole blood by ICP-MS. RESULTS: Only the CDKN2A gene had significant differences in the average methylation level between the first and fifth day of the workweek. We also observed that the levels of Cu, Pb, Se, Mn, and Ti decreased during the fifth day of exposure, and only lead, titanium and copper showed a low significant correlation with the methylation level mean for three specific CpG sites of the CDKN2A. CONCLUSIONS: In summary, the data suggest that altered levels of CDKN2A methylation in construction workers may be a potential biomarker of recent exposure in this environment.

Metals and emerging contaminants in groundwater and human health risk assessment.

Groundwaters are normally consumed without previous treatment and therefore the monitoring of contaminants in order to guarantee its safety is necessary. Thus, we aimed to evaluate the groundwater contamination by metals and emerging contaminants, seeking to understand the relationship between their presence in the groundwater and the use and land cover profile of Itaporã and Caarapó. In addition, the contaminant concentrations observed were compared with maximum permitted values (MPV) and/or with calculated water quality criteria (WQC) for human consumption to investigate possible human health risks due to the groundwater intake. We collected one groundwater sample from each of the 12 wells located in Itaporã and 11 wells located in Caarapó. The metals were analyzed using ICP-OES and the emerging contaminants using LC-MS/MS. At least 1 of the 9 metals analyzed was found in each of the samples. In 12 samples, the metal concentrations verified exceeded the MPV or calculated WQC. A risk to human health has been observed for metals Co, Mn, Cr, and Ni. The emerging contaminant concentrations found in some samples were low (ng/L) and probably did not pose health risks, but their presence in the groundwater showed the impact of agriculture and the inadequate disposal of domestic sewage in the wells of both cities.

Influence of Land Use and Cover on Toxicogenetic Potential of Surface Water from Central-West Brazilian Rivers.

The objective of this study was to evaluate toxicogenetic potential of surface water samples from rivers of center-west Brazil and analyze the influence of land use and cover and physicochemical parameters in genetic damage. Samples were collected during winter (June) and summer (November) at sampling sites from Dourados and Brilhante Rivers (Mato Grosso do Sul/Brazil). The toxicogenetic variables, including chromosomal alterations, micronuclei, and mitotic index, were analyzed in meristematic cells of Allium cepa; and micronuclei, nuclear abnormalities, and DNA strand breaks (arbitrary units, AUT) were analyzed in erythrocytes of Astyanax lacustris. The rivers presented physicochemical values outside the Brazilian laws, which can be a characteristic of human pollution (domestic sewage and local agriculture). The results of A. cepa test suggest that the water samples from Dourados and Brilhante rivers exerted significant (p < 0.05) cytotoxic and genotoxic effects, in both periods of collection, especially alterations in mitotic index. In blood cells of A. lacustris, genotoxic effect of the water samples from the rivers also was observed as significant nuclear abnormalities, DNA breaks (UAT), in both sampling periods, compared with the negative control. Spearman correlation analyses revealed that data of land use and cover and physicochemical parameters were statistically correlated with DNA damages in bioassays. This study demonstrates toxicogenetic potential of water samples from Dourados and Brilhante rivers; furthermore, the type of land use and land cover and physicochemical parameters were revealed to have influence on toxicogenetic damage.

Toxicological properties of an aqueous extract of Aristolochia triangularis leaves, using the brine shrimp lethality and Allium cepa bioassays / Propriedades toxicológicas de um extrato aquoso de folhas de Aristolochia triangularis utilizando os bioensaios de letalidade com Artemia salina e Allium cepa

ABSTRACT: The aqueous extract of Aristolochia triangularis leaves showed activity against Artemia salina larvae, with an LD50 of 370.6 µg/mL. In experiments with Allium cepa seeds, the extract caused a 51.26% reduction in the germination index, inhibited mean root growth, and was cytotoxic at concentrations of 668 and 2,000 µg/mL. Its antioxidant activity was additionally assessed in this research and the ferric reducing antioxidant power value was found to be 391.2 µM/g. Such health-beneficial property can be attributed partly to the total phenolic content, spectrophotometrically determined as 52.67 mg/g. The occurrence of cytotoxicity suggested caution when consuming teas from A. triangularis leaves for medicinal purposes, and equally reveals the need for further studies to investigate their adverse effects.

RESUMO: O extrato aquoso de folhas de Aristolochia triangularis mostrou atividade sobre larvas de Artemia salina, com um DL50 de 370,6 µg/mL. Em experimentos com sementes de Allium cepa, o extrato provocou uma redução de 51,26% no índice de germinação, inibiu o crescimento radicular médio e foi citotóxico nas concentrações de 668 e 2.000 µg/mL. Sua atividade antioxidante foi adicionalmente avaliada nesta pesquisa e o valor de poder redutor de íons férrico foi de 391,2 µM/g. Tal propriedade benéfica para a saúde pode ser parcialmente atribuída ao conteúdo de compostos fenólicos totais, espectrofotometricamente determinada como 52,67 mg/g. A ocorrência de citotoxicidade sugeriu cautela ao consumir chás de folhas de A. triangularis para propósitos medicinais, e igualmente revela a necessidade por estudos adicionais para investigar os efeitos adversos deles.