Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.

Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.

The Use of Multiple Biomarkers to Assess the Health of Anuran Amphibians in the Brazilian Cerrado Savanna: An Ecotoxicological Approach.

Changes in the natural landscape and the indiscriminate use of pesticides can have a major impact on aquatic environments and have contributed to the worldwide decline of amphibian populations. In the present study, we sampled tadpoles of three anuran amphibians (Boana albopunctata, Physalaemus cuvieri, and Dendropsophus minutus) from ponds in six different agricultural landscapes of the Brazilian Cerrado savanna and evaluated whether and to what extent genotoxic and mutagenic damage was related to land use (the amount of forest and agricultural remnants, and related physicochemical factors) and the presence of pesticides in the water of the study ponds. We also evaluated the hepatotoxicity in P. cuvieri, which was the most abundant species at five of the six sampling points. Clomazone and atrazine were the most common pesticides found in the ponds. The B. albopunctata and P. cuvieri tadpoles presented similar patterns of DNA damage among the sampling points. The least DNA damage was found in the D. minutus tadpoles, although this species was present in only one of the study ponds. More binucleated and anucleated cells were observed in B. albopunctata, but there was no significant variation among species in terms of the number of micronuclei or other erythrocytic nuclear abnormalities. Land use and physicochemical factors did not explain the variation in the DNA damage observed in the three anurans. The hepatotoxicity analyses of P. cuvieri revealed the presence of a series of alterations, including the enlargement of the sinusoids, vacuolization of the hepatocytes, the infiltration of inflammatory cells, hepatic steatosis, and dilation of the blood vessels. The interaction between physicochemical factors and the biomarkers analyzed in the present study is complex. In particular, it will be important to better elucidate which factors are contributing, either directly or indirectly, to the decline of anuran amphibian populations, especially in threatened biomes, such as the Brazilian Cerrado. In this case, we would encourage further in situ studies that assess the ecotoxicology of the landscape, together with the systematic monitoring of aquatic environments, to guarantee the long-term integrity of amphibian populations, and those of other organisms that play an essential functional role in the ecosystem. Environ Toxicol Chem 2023;42:2422-2439. © 2023 SETAC.

Cancer and occupational exposure to pesticides: a bibliometric study of the past 10 years.

Occupational exposure to pesticides has been identified as a major trigger of the development of cancer. Pesticides can cause intoxication in the individuals who manipulate them through either inhalation, ingestion, or dermal contact. Given this, we investigated the association between the incidence of cancer and occupational exposure to pesticides through a bibliometric analysis of the studies published between 2011 and 2020, based on 62 papers selected from the Scopus database. The results indicated an exponential increase in the number of studies published over the past decade, with most of the research being conducted in the USA, France, India, and Brazil, although a further 17 nations were also involved in the research on the association between cancer and pesticides. The principal classes of pesticides investigated in relation to their role in intoxication and cancer were insecticides, herbicides, and fungicides. The types of cancer reported most frequently were multiple myeloma, bladder cancer, non-Hodgkin's lymphoma, prostate cancer, leukemia, and breast cancer. Despite the known association between pesticides and cancer, studies are still relatively scarce in comparison with the global scale of the use of these xenobiotic substances, which is related to the increasing demand for agricultural products throughout the world.

Farmers exposed to pesticides have almost five times more DNA damage: a meta-analysis study.

We carried out a meta-analytical review of possible DNA damage resulting from occupational exposure to pesticides in farmers in the scientific literature. After the search, screening, and eligibility criteria steps, we included 42 studies to analyze random effect calculation. DNA damage in farmers occupationally exposed to pesticides represents an effect of SMD 4.63 [CI 95% 3.94-5.32; p <0.001]. We observed a high heterogeneity rate between the studies and an asymmetry of the bias analysis results. We performed a meta-regression on the parameters. The Olive Tail Moment (OTM) was the most effective comet assay parameter in the evaluated studies. The Damage Index (DI) was more conservative and highlighted the variability between studies caused by distinct methodologies that showed more significant effects and greater deviations. An analysis of confounding factors demonstrated a slight DNA damage in smokers who were occupationally exposed to pesticides compared to nonsmokers, indicating genotoxicity but smaller than the pesticide effect. The present study shows the greater risk that occupationally exposed rural workers have of developing related diseases due to pesticides' genotoxic effect.

Evaluation of genotoxicity in bat species found on agricultural landscapes of the Cerrado savanna, central Brazil.

Habitat loss and fragmentation together represent the most significant threat to the world's biodiversity. In order to guarantee the survival of this diversity, the monitoring of bioindicators can provide important insights into the health of a natural environment. In this context, we used the comet assay and micronucleus test to evaluate the genotoxic susceptibility of 126 bats of eight species captured in soybean and sugarcane plantation areas, together with a control area (conservation unit) in the Cerrado savanna of central Brazil. No significant differences were found between the specimens captured in the sugarcane and control areas in the frequency of micronuclei and DNA damage (comet assay). However, the omnivore Phyllostomus hastatus had a higher frequency of nuclear abnormalities than the frugivore Carollia perspicillata in the sugarcane area. Insectivorous and frugivorous bats presented a higher frequency of genotoxic damage than the nectarivores in the soybean area. In general, DNA damage and micronuclei were significantly more frequent in agricultural environments than in the control area. While agricultural development is an economic necessity in developing countries, the impacts on the natural landscape may result in genotoxic damage to the local fauna, such as bats. Over the medium to long term, then DNA damage may have an increasingly negative impact on the wellbeing of the local species.

Multi-biomarker responses to pesticides in an agricultural population from Central Brazil.

We evaluated farmworkers exposed to pesticides and individuals with no history of occupational exposure to pesticides. It was performed the comet assay to evaluate DNA damage. The immunophenotyping of TCD4+ lymphocyte subpopulations in peripheral blood was performed by flow cytometry. The single nucleotide polymorphisms (SNPs) in PON1, XRCC1, IL6, IL6R, TNF-α, and MIR137 genes were evaluated by real-time PCR. The exposed group was composed mostly by males (69.44%), with direct exposure to pesticides (56%) and with an average age range of 46 ± 13.89 years, being that 58.3% of farmworkers directly exposed to pesticides and reported the full use of personal protective equipment (PPE). DNA damage was greater in the exposed group (p < 0.05), reinforced by the use of PPE to denote a lower degree of DNA damage (p = 0.002). In this context, in the exposed group, we demonstrated that the use of PPE, age, gender and intoxication events were the variables that most contributed to increase DNA damage (p < 0.0001). Besides, the exposed group showed a significant increase in the subpopulations of T lymphocytes CD3+CD4+ (p < 0.05) and CD3+CD4+CD25+ (p < 0.0001) and a significant decrease in CD3+CD4+CD25-FOXP3+ (p < 0.05). SNPs in the TNF-α (rs361525) gene presented a difference in the genotype distribution between the groups (p = 0.002). The genotype distribution of TNF-α (rs361525) was also positively correlated with the DNA damage of the exposed group (r = 0.19; p = 0.01), demonstrating a higher risk of DNA damage in the farmworkers presenting the A mutated allele. Our findings demonstrate that pesticides can exert various deleterious effects on human health by damaging the DNA as well as by influencing the immune system in the case of both direct or indirect exposure and these issues are associated to age, gender, intoxication and the nonuse of PPE.

Evaluating genotoxic risks in Brazilian public health agents occupationally exposed to pesticides: a multi-biomarker approach.

This is the first study demonstrating genotoxic effects and whole transcriptome analysis on community health agents (CHAs) occupationally exposed to pesticides in Central Brazil. For the transcriptome analysis, we found some genes related to Alzheimer's disease (LRP1), an insulin-like growth factor receptor (IGF2R), immunity genes (IGL family and IGJ), two genes related to inflammatory reaction (CXCL5 and CCL3), one gene related to maintenance of cellular morphology (NHS), one gene considered to be a strong apoptosis inductor (LGALS14), and several transcripts of the neuroblastoma breakpoint family (NBPF). Related to comet assay, we demonstrated a significant increase in DNA damage, measured by the olive tail moment (OTM), in the exposed group compared to the control group. Moreover, we also observed a statistically significant difference in OTM values depending on GSTM1 genotypes. Therefore, Brazilian epidemiological surveillance, an organization responsible for the assessment and management of health risks associated to pesticide exposure to CHA, needs to be more proactive and considers the implications of pesticide exposure for CHA procedures and processes.

DNA damage in peripheral blood lymphocytes and association with polymorphisms in the promoter region of the CYP2E1 gene in alcoholics from Central Brazil.

DNA damage caused by the accumulation of bio-products generated in the biotransformation of ethanol to acetaldehyde mediated by the CYP2E1 enzyme has been studied. To evaluate DNA damage in peripheral blood lymphocytes and the possible association with polymorphisms in the promoter region of the CYP2E1 gene, we performed a case-control study including 75 alcoholics and 59 individuals who consume alcohol socially. Alcoholics were previously diagnosed by the Psychosocial Care Center - Alcohol and Drugs (CAPS A/D) in the city of Goiania, Goias state, Central Brazil. DNA damage was evaluated by comet assay. The analysis of the rs3813867, rs2031920, and rs2031921 polymorphisms in the promoter region of CYP2E1 gene was performed by Sanger sequencing. Men older than 35 years old were the most common alcoholics. We found increased DNA damage in the case group, compared to the control group (p < 0.001). Alcoholics who were heterozygous in the rs3813867, rs2031920, and rs2031921 polymorphisms showed higher DNA damage (tail length and olive tail moment), compared to individuals with the homozygous non-mutated allele. Previous studies have shown that polymorphisms in the promoter region of the CYP2E1 gene could cause higher CYP2E1 transcriptional activity, increasing enzyme activity compared with nondrinkers, indicating that the presence of the mutated allele (heterozygous or homozygous) may be associated with higher alcohol metabolic rates and therefore show increased acetaldehyde levels after alcohol consumption, which then can exert its carcinogenic effect.