It is stated in studies that fungicides are effective on liver enzymes. To illustrate, it is reported that the levels of ALT and AST, the liver function enzymes, increase in the sera of mice and rats administered with mancozeb (Sakr & Saber, 2007; Sakr et al. 2005). In addition, Lavric et al. (1990) reported that bithionol sulfoxide causes hepatotoxicity at high doses, including an increase in serum AST level. As in our study, it was also found that AST, ALT and ALP values increased with Pyra administration, and that Res, which is known to have antioxidant activity, decreased these values depending on increase in dose. It is reported that Pyra causes oxidative stress effects in adult zebrafish liver and embryos and increases SOD, CAT and MDA levels depending on the dose and inhibits GSH activity (Mao et al., 2020; Li et al. 2018). Jiang et al. (2019) It is reported that tebuconazole, a different fungicide, increases SOD, CAT and GPx activities and decreases GSH levels in rats (Othmène et al. 2020). Consistent with the other studies conducted, it was determined in this study that Pyra caused an increase in MDA levels and a decrease in glutathione and antioxidant enzyme activities due to the formation of reactive oxygen species, whereas Res improved these values due to its antioxidant activity.
Prya (30 mg/kg) produced noticeable histopathological changes in the liver and kidney of the rats. Ibtissem et al (2017) reported that administration of methyl-thiophanate, a fungicide, to rats caused necrosis, infiltration of inflammatory leukocyte cells and hepatocyte vacuolization in the liver, narrowing the Bowman's capsule in the kidneys and causing occlusion of the vessels in the glomeruli and between the tubules. Selmanoğlu et al. (2001) stated in their study that the administration of fungicide carbendazim to rats caused congestion in the liver, enlargement of the sinusoids, an increase in the number of Kupffer cells, mononuclear cell infiltration and hydropic degeneration, and obstruction in the kidney tissue, mononuclear cell infiltration, tubular degeneration and fibrosis. It is reported that hypertrophy, separation of epithelium from lamellae, lamellar fusion and epithelial cell necrosis were observed in the tissues of rainbow trout exposed to captan fungicide, and organs affected the most were gills, kidneys and liver (Boran et al. 2012). Similarly, it is determined in this study that deterioration of the remark cord structure in liver tissue, degenerative changes in hepatocytes in pericentral regions and formations of binucleated hepatocyte increased in rats administered with Pyra and that vacuolization formations in the glomeruli, degenerative changes in tubular epithelial cells and enlargement of the Bowman capsule in the glomeruli in the kidney tissue were increased. In the other words, Res, administered using a dose-dependent approach, protected the liver and kidney tissue of the rats against Prya-induced cellular damage due to the protective effect on cell and tissue.
An excess of pro-apoptotic proteins in the cell indicates that the cell is prone to apoptosis, whereas an excess of anti-apoptotic proteins indicates that the cell is less prone to apoptosis (Adams & Cory, 2001). Similarly to this study, conducted on zebrafish (Danio rerio) by Kumar et al. (2020), it was observed that Pyra increased caspase-9, p53 and BAX gene expression. In addition, it is reported that during the development of zebrafish embryo, Pyra causes immunotoxicity by changing the innate immune system-related TNF-α, IL-1b, C1C and IL-8 gene expression levels (Li et al. 2018). It is revealed that tebuconazole fungicide also decreased bcl-2 gene expression in male rat kidney tissues and increased BAX and caspase-3 gene expression, which trigger apoptosis via Bax/Bcl-2 and caspase pathway (Othmène et al. 2020). In a study conducted with metalaxyl fungicide, it is revealed that it increases NFκB, TNF-α and caspase-8 gene expression levels and caused DNA damage in liver tissue; on the other hand, ginger administration is effective in protecting rats against metalaxyl-induced liver damage with an anti-inflammatory mechanism (Hassa et al. 2018). It was observed that azoxystrobin and Pyra increased the CYP24A1 gene expression level in zebrafish embryos (Kim et al. 2021). Similarly, it was found in this study that it increased the gene expression levels of BAX, CYP2E1, caspase-3, caspase-8, caspase-9, NFκB and p53 in groups administered with Pyra when compared to the control group and decreased the bcl-2 gene expression level, and that Res administration, which is known to be protective against this, reversed these values. In another study, Res was observed to be protective against Cadmium chloride (CdCl2)-induced toxicity in rat testicles. CdCl2 was down-regulated the anti-apoptotic gene Bcl-2 and up-regulated the expression of the pro-apoptotic genes p53 and Bax. Res was protected against and partially reversed CdCl2 testicular toxicity through upregulation of Bcl-2 and downregulation of p53 and Bax gene expression (Eleawa et al. 2014) The protective effects of Res against UVB-induced photoaging in HaCaT cells were investigated, and Res upregulated the expression of HSP27, decreased the production of pro-apoptotic proteins such as p65, Bax and cleaved caspase-3, and promoted the expression of the anti-apoptotic protein Bcl-2. It has been shown to inhibit UVB-induced apoptosis (Zhou et al. 2018). As in our study, it has also been reported that resveratrol suppresses the expression of antiapoptotic gene products (eg Bcl-2, Bcl-XL, XIAP and survivin), and inhibits the expression of cell cycle regulatory genes (eg p53, Rb, PTEN, cyclins and CDKs) (Harikumar et al. 2008). With all these studies, the expectations for clinical use of Res are increasing rapidly. Our review explains Res's potential for protective effects against Prya at the various gene level.
In the study, it was found that Pyra caused DNA damage, whereas the administration of Res, which is known to have antioxidant activity, reduced this damage. Similarly, it is reported some studies that Pyra causes DNA damage in worms (Eisenia fetida), leukocytes isolated from whole blood, and aquatic algae (Chlorella vulgaris) (Ma et al. 2019; Cobanoglu et al. 2019; Liu et al. 2018). When studies on different fungicides are examined, it is emphasized, for example, that monceren, a commercial fungicide, causes DNA damage in zebrafish embryos and azoxystrobin (AZX) causes DNA damage in fish (Australoheros facetus) (Ku-Centurión et al. 2016; Crupkin et al. 2021). In another study, it was shown that resveratrol can prevent ROS accumulation, oxidative DNA damage and accumulation of DNA breaks in cell lines exposed to oxidative agents such as the particulate phase of cigarette tobacco smoke (TAR) (Sgambato et al. 2001). Cryopreservation of human sperm can cause DNA damage that compromises fertilization and normal embryo development. Res has also been shown to prevent these harms in both fertile and infertile men (Branco et al. 2010). The study by Quincozes-Santos et al. supports that Res prevents DNA damage and is important in health and disease in protecting against DNA damage against oxidative stress caused by hydrogen peroxide in C6 glioma cells (Quincozes-Santos et al. 2007). In this study, Res administered with a dose-dependent approach protected the rats against Prya-induced DNA damage.