Protective Effects of Fig and Olive Extracts on 2-Nitropropane Testicular...

[Full title: Protective Effects of Fig and Olive Extracts on 2-Nitropropane Testicular Toxicity in Mice]

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OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2024.217.228 Research Article Protective Effects of Fig and Olive Extracts on 2-Nitropropane Testicular Toxicity in Mice 1 Bassam Abdulaziz Alahmadi, 2 Ahlam Abdulaziz Alahmadi, 3 Neveen El Nesr, 4 Soad Shaker Ali and 5 Elham Abdelsabour Abd-Allah 1 Department of Biology, College of Science, Taibah University, Medina 41311, Saudi Arabia 2 Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21442, Saudi Arabia 3 Department of Pathology, Animal Health Research Institute, Assiut 71684, Egypt 4 Department of Histology, Faculty of Medicine, King Abdul Aziz University, Jeddah 21442, Saudi Arabia 5 Department of Zoology, Faculty of Science, New Valley University, El-Kharga 72511, Egypt Abstract Background and Objective: Figs and olives have antioxidant and anti-inflammatory properties, while 2-Nitropropane (2-NP), a solvent in industrial processes, has been linked to adverse health effects, including liver, kidney, nervous system and reproductive organ toxicity. The protective effects of figs and/or olive extracts against testicular dysfunction induced by (2-NP) were investigated Materials and Methods: An 8-week dose of 2-NP was administered 3 times weekly. Group I, intraperitoneally injected (i.i) with 0.9% NaCl, II (i.i) with 2-NP (100 mg/kg b.wt.), III (i.i) with 2-NP and with fig (300 mg/kg), IV (i.i) with 2-NP and with olive (100 mg/kg) and V (i.i) with 2-NP and with a mixture of fig and olive (1:1). The measured parameters were lipid peroxidation (LPO), Glucose 6 Phosphate Dehydrogenase (G 6 PD), Glutathione (GSH), glutathione reductase (GSH-Px), Glutathione S-Transferase (GSH-ST), the activity of superoxide dismutase (SOD), catalase (CAT) and plasma testosterone level. The expression of PCNA and Cas-3 was also detected. GraphPad software version 0.7, with One-way Variance Analysis (ANOVA) was used as a statistical method. Results: Results indicated an elevation in testes (LPO), a decrease in (G 6 PD), (GSH), (GSH-Px), (GSH-ST) levels, the activity of (SOD), (CAT) and testosterone levels, with degeneration of testicular architecture tissue. Supplementation with fig and/or olive extractions may ameliorate these changes. Concerning immunohistochemical analysis, concentrations of testosterone in fig, olive or the combination along with 2-NP increased significantly. Caspase-3 marker showed moderate to strong reactions, all groups exhibited weak reactions with (PCNA) Conclusion: Dietary supplementation of fig and/or olive extracts may offer protection against testicular toxicity induced by 2-NP Key words: 2-Nitropropane, testicular toxicity, fig, olive, oxidative stress Citation: Alahmadi, B.A., A.A. Alahmadi, N. El Nesr, S.S. Ali and E.A. Abd-Allah, 2024. Protective effects of fig and olive extracts on 2-nitropropane testicular toxicity in mice. Int. J. Pharmacol., 20: 217-228 Corresponding Author: Elham Abdelsabour Abd-Allah, Department of Zoology, Faculty of Science, New Valley University, El-Kharga 72511, Egypt Tel: +2-01065614779 Copyright: © 2024 Bassam Abdulaziz Alahmadi et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

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Int. J. Pharmacol., 20 (2): 217-228, 2024 INTRODUCTION Infertility and late childbearing are the most significant medical troubles of the reproductive period which is common in males 1 . About 13-18% of couples struggle with infertility and accumulating data from clinical and epidemiological studies points to an increase in the prevalence of male reproductive issues 2 . The number of infertile couples worldwide is projected to be 48.5 million (45.0 and 52.6 million) in 2010, making infertility a significant health issue on a global scale, one in every five couples faces this problem 3 . In over half of infertile males, no reason for infertility can be identified and this condition is referred to as unexplained or idiopathic. An excess of seminal ROS, on the other hand, has been documented in 30-80% of infertile males 4 . The 2- Nitropropane (2-NP) has been widely used in industry as a solvent, particularly for paints, inks and varnishes. It has also been found in substantial amounts in cigarette smoke and it is used in a variety of dissolvable structures to contribute desired qualities 5 . Several studies showed that oxidative stress of the testis can result from environmental toxicants, leading to spermatogenesis disruption 6 . Many conditions considered to be destructive to male fertility come on top of all of them, the testicular oxidative stress. It is fully known that 2-NP is a wonderful example of oxidative damage promotion 7 . Studies on unintentionally exposed persons suggest that brief exposure to high concentrations of 2-NP may be detrimental. According to one study, two workers who were painting the inside of a tank were exposed to excessive levels of 2-NP, which caused one of them to pass away and liver damage in the other 8 . A zinc-epoxy paint mixed with 2-NP and ethyl glycol (2-ethoxyethanol) was put to use. Another case reports the fatalities of four individuals who were working in confined spaces with 2-NP-containing paint, surface coating and polyester-based resin materials. All four workers experienced liver injury and hepatocyte destruction. The lack of equilibrium in the generation and removal of reactive oxygen species (ROS) via different types of antioxidants resulted in oxidative stress within any tissue, ROS can be created in major quantities by macrophages and neutrophils, but also by spermatozoa 9 A lot of scientific studies have been performed to explore LPO levels in membranes rich with lipids after 2-NP injection or inhalation. Despite the high toxic impacts of 2-NP at the liver level, intrinsic increases in LPO levels in additional organs may be caused by nitro-alkane 10 . Leaving aside the liver, also the key 2-NP goal, was lung and kidney, Kim et al 11 , revealed that 2-NP significantly raised LPO in liver, lung and kidney. Up to our knowledge, there are no publications regarding the testicular dysfunction resulting from 2-NP These days, antioxidants are broadly used to sever the interaction of the oxidative sequence. Natural medications might be the favored decision in male infertility treatment. The key objective behind their efficiency against infertility may be the presence of antioxidants in the plants 12 . The familiar fig ( Ficus carica ) from the Moraceae family, which is originally cultivated in Western Asia and the Middle East, is one of the plants commonly used because it contains high levels of antioxidants 13 It was identified that this tree is rich with antioxidants present in the leaves, pulp and peels, with high levels of phenols, it has been known that extracts of F. carica are capable of scavenging free radicals, metal-ions of chelate prooxidants and suppressing those active enzymes 14 The tree of olive ( Olea europaea ; Oleaceae family) is a plant that contains phytoestrogen compounds with enormous pharmacological advantages. It is a vastly planted tree in the Mediterranean Region and its products are major food ingredients in the diet of the population there 15 . People of the Mediterranean region utilized the products of olive trees such as olive oil, fruit and leaves as a medication for the treatment of many ailments because of its high content of flavonoids and polyphenols 16 . Moreover, olive leaves have antioxidants because of the presence of phenolic compounds and also have anti-hyperlipidemia with protective effects on the heart, blood vessels and nervous system, Sarbishegi et al 17 , revealed that the administration of olive leaf extract for one month markedly ameliorated the sperm content and quality with the higher antioxidant level of rat testis after exposure to rotenone So, if exposure to chemical compounds is a must, it is important to minimize the harsh oxidative stress associated with its use to protect the reproductive systems from any associated damage. In this context, the testicular protective efficacy of extracts of either figs and/or olives against 2-NPinduced toxicity in mice was investigated MATERIALS AND METHODS Study area: This study was carried out from April to May 2023 in the Animal House at the Faculty of Medicine, Assiut University Preparation of extracts Extraction of crude extracts of olive ( Olea europaea ) fruits (OFE): The fruits of the olives were purchased in full maturity, where the fruits were colored in full black. They were washed, cut into smaller parts and dried in the oven at 40 E C and the flesh was ground. The resulting mixture was blended with five 218

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Int. J. Pharmacol., 20 (2): 217-228, 2024 folds of distilled water. The mixture was then placed in the reflex at 100 E C for three hours. This was followed by filtration to concentrate the output, then placed in a rotary evaporator. The rough product was further dried in an oven at 45 E C. The crude aqueous extract was collected after drying and stored at -20 E C until required Extraction of crude extracts of fig ( F. carica ): The fig ( F. carica ) fruits were dried in the shade and crushed. Methanol (80%) was used to make a hydroalcoholic solution for socking in a glass beaker. Two hundred grams of grounded F. carica fruit were placed in a beaker containing 80% methanol and covered with aluminum foil for three days. Shake the beaker for 10 min every day. For rough ultrafiltration, several muslin fabric layers were used to filter the wet substance. Then, Whatman # 01 filter paper was used to filter the rough solution. The concentrate was reduced to one-third of its original volume by employing a rotary vacuum evaporator at 40 E C under low pressure. The extract was placed in dark brown color bottles with some residues. To remove the impurities, Whatman paper # 01 filter paper was used to purify the extracted material. Finally, a dark extract was produced and kept in a freezer for future use 18,19 Animals: Forty grown-up male BALB/c mice with a weight of 27±4 g/each, obtained from the Theodor Bilharz Institute (Cairo, Egypt), were used in this experiment. All mice were accustomed to a well-ventilated 5 cages (8/cage), at the animal house, (Faculty of Medicine, Assiut University) one week before the onset of the experiment. The animals were housed under standard laboratory circumstances (23 E C temperature, 60-70% relative humidity and a light/dark period of 12 hrs) and were nourished a diet of typical commercialized pellet diet (containing 20% rough protein and 11% rough fiber). After 7 days of acclimatization, mice were randomly categorized into five groups (8 mice each); the powder of fig and the dough of olive were blended with distilled water as doses of the two extracts Ethical consideration: Under the rules of the Institutional Animal Care and Use Committee, the experimental procedures concerning the animals were carried out. This research was approved by the (Institutional Review Board) of the Faculty of Medicine at Assiut University, Assiut, Egypt, with IRB approval number: 17300721 Animal treatments: C Group 1: Negative control group was intraperitoneally injected with normal saline (0.9% NaCl) C Group 2: Positive control group (p. con.) was injected with 2-NP (100 mg/kg b.wt.) intraperitoneally 20 C Group 3: The 2-NP+ F. carica was intraperitoneally injected with 2-NP (100 mg/kg b.wt.) and was gavaged with figs as an oral supplement (300 mg/kg b.wt.) 21 C Group 4: The 2-NP+OFE was intraperitoneally injected with 2-NP (100 mg/kg b.wt.) and was supplemented orally with olive by gavage (100 mg/kg b.wt.) 22 C Group 5: The 2-NP+ F. carica +OFE was intraperitoneally injected with 2-NP (100 mg/kg b.wt.) and was orally gavaged supplemented with the mixture of fig and olive at a ratio of 1:1, respectively The duration of the experiment was three times weekly for eight weeks. Testicle harmfulness was initiated in mice in the last four groups (n = 32) Chemicals and reagent kits: The 2-NP, thiobarbituric acid, Glutathione (GSH), superoxide dismutase (SOD), epinephrine and 5,5ʼ-Dithiobis- (2-Nitrobenzoic Acid (DTNB) were bought from Sigma-Aldrich Company (St. Louis, Missouri, USA). By using commercially available kits, activities of Glutathione Peroxidase (GSH-Px), Glutathione S Transferase (GSH-ST), Glucose-6-Phosphate Dehydrogenase (G 6 PD) and Catalase (CAT) were determined. The other different chemicals were obtained from regional sources with excellent purity Sample collection: After 2-NP injection, animals were slaughtered at day 57, heart blood was drawn for biochemical measurements. The plasma was stored at -80 E C till use. For paraffin processing and sectioning, the first section was soaked in 10% neutral buffered formalin to be studied with a light microscope. The second part was prepared for immunohistochemical assessment for the expression of Proliferating Cell Nuclear Antigen (PCNA) and caspase-3 (Cas-3). The third part was homogenized with IKA Yellow line DI homogenizer (18 Disperser, Germany) in 0.1 M cold phosphate-buffered (pH 7.4) at 6000 rpm for one hour at 4 E C For biochemical studies, the supernatant has been frozen at -20 E C Oxidant/antioxidant measurement: Colorimetric method, serum and tissue total proteins were determined according to Lowry et al 23 . Thiobarbituric Acid Reactive Substances (TBARS) of testes were assessed according to the method described by Uchiyama and Mihara 24 . Glutathione (GSH) levels were calculated 25 . The superoxide dismutase (SOD) activity was evaluated using method of Misra and Fridovich 26 . The 219

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Int. J. Pharmacol., 20 (2): 217-228, 2024 methods defined by Aebi 27 , Bonab et al 28 , Habig et al 29 and Kornberg et al 30 were used to evaluate CAT, GSH-Px, GSH-ST and G 6 PD, respectively Histopathological analysis: The specimens of testicular tissues were fixed in 10% neutral buffer formalin. Fixed tissues have been processed for paraffin-embedded technique. At 3 µm, the embedded tissues were sectioned and stained with Hematoxylin and Eosin (H&E) 31 . By the light microscope (Olympus CX 31, Japan), the stained slices were examined and photographed using a digital camera (Olympus, Camedia C-5060, Japan) PCNA and Cas-3 immunohistochemistry: To assess the expression of PCNA and Cas-3, immunohistochemistry was done according to the previously published protocols 32 Briefly, fixed mice testes were dehydrated using ascending series of ethanol and cleared in xylene. The embedded tissues in paraffin were sliced at a thickness of 5 µm, deparaffinized and rehydrated. By incubating 1% hydrogen peroxide in methanol for 30 min, endogenous peroxidase activity was blocked and the parts were then rinsed and overnight incubated with phosphate-buffered saline (PBS) with mouse monoclonal antibody against PCNA (Dako, Milan, Italy) at a concentration of 1:250 in 10% BSA and rabbit polyclonal antibody for Cas-3 (Cell Signaling Technology, Inc.; Beverly, MA), after that the tissues were incubated with goat anti-mouse IgG (1:500) and goat anti-rabbit IgG, respectively, in 10% BSA. The conventional avidin-biotin complex (ABC) according to Hsu et al 33 by using a filtered solution of 5 mg of 3-3'-diaminobenzidine tetrahydrochloride (DAB; Sigma) dissolved in 15 mL of Tris buffer 0.05 M, pH 7.6 and 0.03% H 2 O 2 , the peroxidase activity was developed. Finally, parts were positioned in a synthetic medium and examined with imaging software through an Olympus light microscope Estimation of testosterone: Testosterone levels were measured using testosterone enzyme immunoassay test kit Enzyme Immunoassay Method (ELISA) using specific kits (My BioSource, California, USA) as directed by the manufacturer. About 0.02 ng/mL was the lowest measurable testosterone concentration Statistical analysis: Using One-way Variance Analysis (ANOVA), the results were statistically investigated, then by a post-test multiple comparison test from Newman-keuls. These assessments were carried out using GraphPad software version 0.7, Inc., San Diego California USA. The significance level among groups was agreed at p<0.05, 0.01, 0.001 The results were presented as Mean±Standard error of the mean (SEM) RESULTS Fig and olive extracts or its combination succeeded in restoration of oxidant/antioxidant balance in 2-NP challenged mice: It was observed that LPO level significantly increased in 2-NP intoxicated mice as compared to the control group (Fig. 1). However, activities of CAT, G 6 PD, GSH, GSH-Px, GSH-ST and SOD were significantly decreased (Fig. 2-7) levels of LPO were decreased in the intoxicated groups treated with fig and/or olive, while CAT, G 6 PD, GSH, GSH-Px, GSH-ST and SOD activities increased as compared to 2-NP challenged group Fig and olive extracts or their combination alleviated the reduction in androgenic secretory capacity of the testis in 2-NP challenged mice: Serum testosterone concentrations were significantly (p<0.05) lower in the 2-NP exposed mice than in the control rats (Fig. 8). On the other hand, its concentrations in the F. carica and OFE or the combination of the extracts along with 2-NP increased significantly (p<0.05) and returned nearly to the normal values Fig and olive extracts or their combination improved the histological features of testis in 2-NP exposed mice: Control mice's testes were histopathologically examined and found to have a normal histoarchitecture. (Fig. 9(a-c) con.). Following eight weeks of exposure to 2-NP, the histological examination of the testes showed pathological changes when compared with the control counterpart. The testes showed damaged seminiferous tubules, the degree of damage varied from distinctly usual looking to abnormal, disorganized and disrupted tubules that dissociated from each other. The degenerated seminiferous epithelium is lined with single layers of cells composed of sertoli cells and a few spermatogonia. The degenerative changes included most stages of spermatogenesis and the spermatogenic cells were pyknotic with extreme pyknosis in their nuclei. There was congestion in the interstitial blood vessels associated with an increase in its wall thickness. The leydig cells showed nuclear distortion such as karyolysis and karyorrhexis and in some cases reached necrosis and nuclear pyknosis (Fig. 9(a-c) 2-NP) After co-treatment of mice with F. carica , OFE, or its mixture, the seminiferous tubule structure was almost preserved. The tubulesʼ basement membrane was partially 220

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Int. J. Pharmacol., 20 (2): 217-228, 2024 Fig. 1: Effect of 2-NP and co-treatment of fig, olive or their combination on LPO level in testes of BALB/c mice LPO: Lipid peroxides, data were expressed as Mean±SEM, n = 8, a: Significance difference between control group and 2-NP group, b: Significance difference between 2-NP group and the other co-treated groups (one-way analysis of variance followed by Newman-Keuls multiple comparison test) and 3: Level of significance (p<0.001) Fig. 2: Effect of 2-NP and co-treatment of fig, olive or their combination on CAT activity in testes of BALB/c mice CAT: Catalase, data were reported as Mean±SE, where, n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups and 3: Level of significance (p<0.001) Fig. 3: Effect of 2-NP and co-treatment of fig, olive or their combination on G 6 PD activity in testes of BALB/c mice G 6 PD: Glucose-6-Phosphate Dehydrogenase, data were reported as Mean±SE, where, n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups and 3: Level of significance (p<0.001) 221 60 40 20 0 60 40 20 0 Con p. con Fig Olive Mix a 3 b 3 b 3 b 3 LPO mol/mg protein 15 12 9 6 3 0 Con p. con Fig Olive Mix a 3 b 3 b 3 b 3 CAT U/min/mg protein 15 12 9 6 3 0 Con p. con Fig Olive Mix a 3 b 3 b 3 b 3 G 6 PD mol/min/mg protein 8 7 6 5 4 3 2 1 0 8 7 6 5 4 3 2 1 0

[Find the meaning and references behind the names: Gst]

Int. J. Pharmacol., 20 (2): 217-228, 2024 Fig. 4: Effect of 2-NP and co-treatment of fig, olive or their combination on GSH activity in testes of BALB/c mice GSH: Reduced Glutathione, data were reported as Mean±SE, where n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups, 2: Level of significance (p<0.01) and 3: Level of significance (p<0.001) Fig. 5: Effect of 2-NP and co-treatment of fig, olive or their combination on G 6 PD activity in testes of BALB/c mice GSH-Px: Glutathione Peroxidase, data were reported as Mean±SE, where n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups, 1: Level of significance (p<0.05) and 3: Level of significance (p<0.001) Fig. 6: Effect of 2-NP and co-treatment of fig, olive, or their combination on GST activity in testes of BALB/c mice GST: Glutathione S-Transferase, data were reported as Mean±SE, where n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups, 2: Level of significance (p<0.01) and 3: Level of significance (p<0.001) 222 Con p. con Fig Olive Mix a 3 b 2 b 3 b 3 GSH mmol/mg protein 80 70 60 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 Con p. con Fig Olive Mix a 3 b 3 b 1 b 3 GSH-Px U/mg protein 50 40 30 20 10 0 50 40 30 20 10 0 Con p. con Fig Olive Mix a 3 b 2 b 3 b 3 GST µg/mg protein 30 25 20 15 10 5 0 30 25 20 15 10 5 0

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Int. J. Pharmacol., 20 (2): 217-228, 2024 Fig. 7: Effect of 2-NP and co-treatment of fig, olive or their combination on SOD activity in testes of BALB/c mice SOD: Superoxide dismutase, data were reported as Mean±SE, where n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups, 1: Level of significance (p<0.05), 2: Level of significance (p<0.01) and 3: Level of significance (p<0.001) Fig. 8: Effect of 2-NP and co-treatment of fig, olive or their combination on serum testosterone level Data represent the Mean±SE, where n = 8, a: Significance difference between control group and 2-NP (positive control) group, b: Significance difference between 2-NP (positive control) group and the other co-treated groups and 1,3: Level of significance (p<0.05) corrugated. Standard spermatocytes and sertoli cells were present in many tubules (which appear ordinary with a vesicular nucleus) along with a few attached mature sperms. The interstitial connective tissue was normal with typical blood vessels and the leydig cells had a vesicular nucleus with prominent nucleolus (Fig. 9) Immunohistochemical results: Immunohistochemical analysis of the testis using Cas-3 markers demonstrated that the expression of Cas-3 gene was observed in the group of mice exposed to 2-NP toxicity. This reaction varied from moderate to a strong reaction, in comparison with the testis of control mice which showed a weak reaction with normal apoptosis. On the other hand, the mice treated with F. carica , OFE or its mixture showed moderate to weak reactions antigen revealed that all experimental groups showed weak reactions (Fig. 9) DISCUSSION Due to their broad use, the human body is repeatedly exposed to nitro compounds. Nitroalkanes are known as carcinogens, genotoxicants and are suspected as cardiovascular toxins and neurotoxins 34 . The purpose of this work was to evaluate the influence effect of 2-NP (one of the nitro alkane groups) on the reproductive system, as most of these substances are testicular toxicants. However, a few experiments studied the potentially toxic effects of 2-NP on the genital system of mammals. The 2-NP was used in experimental work to induce oxidative damage and LPO in 223 Con p. con Fig Olive Mix a 3 b 1 b 3 b 2 SOD U/min/mg protein 30 25 20 15 10 5 0 30 25 20 15 10 5 0 Con p. con Fig Olive Mix a 3 b 1 b 3 b 3 b 3 6 5 4 3 2 1 0 6 5 4 3 2 1 0 Serum testoster one level (pg/mL)

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Int. J. Pharmacol., 20 (2): 217-228, 2024 Fig. 9: Photomicrograph of a section from the testis of mice from control group showed (a) circular ST with regular contour X 100, (b) the ST lined with series of spermatogenic cells (arrow) and sertoli cells (arrowhead) ×250, (c) The interstitium contains normal blood vessel and Leydig cells (crossed arrow) ×400 H&E immuno-expression of Cas-3 (D) and PCNA (E) showed weak reaction (arrow) ×250. The 2-NP treated mice showed (a) Normal looking ST (N) and irregular disorganized ST (D) ×100, (b) Sertoli cell showing degeneration and vacuolation (arrowhead) and pyknotic spermatogenic cell (arrow) ×400 (c) Interstitial cells of leydig showed deeply stained pyknotic nucleus (crossed arrow ×250) H&E. Immunexpression of Cas-3 showed strong reaction (arrow) ×250 and Immuno-expression of PCNA showed weak reaction (arrow) ×250. Olive-treated mice showed (a) ST appear normal in shape and distribution ×100, (b) ST with normal sertorli cell (arrowhead) and spermatogenic cell (arrow) ×400, (c) Interstitial tissue containing normal leydig cell (crossed arrow) ×250 H&E. Immuno-expression of Cas-3 showed moderate reaction (arrow) ×250 and immuno-expression of PCNA showed weak reaction (arrow) ×250. Fig treated mice showed (a) ST with normal shape ×100, (b) Cells lined the ST with normal sertoli cell (arrowhead) and spermatogenic cell (arrow) ×250, (c) Interstitial tissue with normal appearance of leydig cell (crossed arrow) ×400 H&E. Immuno-expression of Cas-3 and PCNA showed weak reaction (arrow) ×250. Olive and fig (mix) treated group showed (a) ST with normal structure ×250, (b) ST with nearly normal sertoli cell (arrow head) and spermatogenic cell (arrow) ×400, (c) Normal leydig cells in the interstitial tissue (crossed arrow) ×400 H&E. Immuno-expression of Cas-3 and PCNA showed weak reaction (arrow) ×250 hepatic tissue 35 . Oxidative stress, DNA damage and hepatocyte apoptosis are the main factors behind hepatic damage induced by 2-NP 36 . The present result revealed that intraperitoneally injection of 2-NP increased LPO as expressed by a raise in MDA level in testes, indicating testicular injury. As well, a drop in the activities of the CAT, SOD, G 6 PD, GSH, GST and GSH-Px was detected. In this aspect, so far, the effects of 2-NP on mice or rat testes haven't been studied in this way, therefore, we were unable to compare our findings to those obtained previously, which led to hinder wider discussion of our results. Otherwise, few researchers have investigated the effect of aliphatic or aromatic nitro compounds on rats, 224 Control 2-NP Olive Fig Mix H&E H&E H&E Cas-3 PCNA (a) (b) (c) (d) (e) (a) (b) (c) (d) (e) (a) (b) (c) (d) (e) (a) (b) (c) (d) (e) (a) (b) (c) (d) (e)

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Int. J. Pharmacol., 20 (2): 217-228, 2024 mice and even their progeny 37 demonstrated that after administration of nitrotoluenes (a chemical intermediate in the manufacture of pharmaceutical products) in the feed to males for 13 weeks, there were testicular degeneration as well as the density, motility and the number of sperm cells have been decreased. According to the latest epidemiological investigations, there is a reverse connection between the consumption of antioxidants and the occurrence pace of different diseases, it is assumed that the most effective components in the prevention of oxidative stress-related diseases are the antioxidants 38 . In this regard, the significance of natural antioxidant compounds that may delay disease progress has increased markedly in recent decades. According to that, in the present study, the co-treatment of fig, olive extracts and its combination decreased the level of LPO in comparison with 2-NP intoxicated mice. It is widely acknowledged, that after consumption of some xenobiotics, LPO is elevated followed by superoxide excess output, which generates disintegrating singlet oxygen and H 2 O 2 , which can be quickly transformed into reactive OH, in this respect, the increased activities of GST are considered to function as defensive reactions to remove the exotic bodies 39 It was reported that the increase in hepatic methanolinduced LPO was reduced in animals pretreated by extract of F. carica stem, which demonstrates that F. carica stem extraction contains large quantities of flavonoid and polyphenolic compounds 40 . The GSH and CAT are the key peroxide detoxifying methods, CAT is an H 2 O 2 destructive antioxidant enzyme that can synthesize a highly reactive OH 41 In the present work, a major decline in the level of MDA, which is an LPO by-product and marked rises in serum GSH, CAT and GSH-Px activities in rats receiving OFE and F. carica were observed, such results indicate that they have powerful antioxidative effects. It was found that fig fruits contain various polyphenols involving avonoids 42 . The obtained data showed also an increase in the activities of CAT, SOD, G 6 PD, GSH, GST and GSH-Px and the level of testosterone in mice cotreated with F. carica fruit extract together with a marked reduction in the level of MDA. After administration of F. carica to 2-NP treated mice, the amount of LPO decreased. This could be because some of the phytochemicals in the plant, such as phenol, flavonoids, tannins and coumarins, function as antioxidants by reducing the generation of reactive oxygen species 43 . These findings were in agreement with Recknagel et al 44 , who discovered that F. carica protected the livers of CCl 4 -intoxicated rats. The extract's suppressive action, which inhibits cytochrome P 450 s and hinders CCl 4 's bioactivation into its equivalent reactive species, may be the cause of the drop in LPO. A previous publication was carried out with 2-NP and the same extracts, the study revealed a significant role of ROS in pathogenesis of the 2-NP-induced liver, kidney and spleen toxicity. It also showed the extracts from olive and fig fruits contain a considerable number and amount of healthy compounds namely polyphenols and flavonoids, which act as antioxidant defenses, that can react as free radical scavengers which delayed the oxidation and damage of tissues 45 . The suppression of endogenous antioxidant enzymes activities (CAT and SOD) was ameliorated by F. carica treatment in 2-NP exposed mice which may be due to the role of flavonoids, one of its active components, as powerful antioxidant, by reducing the accumulation of 2-NP through the action of tannins which act as a chelating agent 46 The findings of this research have shown that F. carica ameliorated the reduction in serum testosterone levels in 2-NP intoxicated mice. The primary component, saponin, which functions as testosterone, may be the cause of this improvement in the F. carica group. These results are consistent with those of Njoku-Oji et al 47 , who discovered that F. carica improved spermatogenesis and folliclestimulating hormone levels, hence increasing semen quality and testosterone levels in normal rats According to the findings of this study, OFE treatment in the olive co-treated group reduced the amount of MDA relative to the 2-NP group. The OFE has been found to substantially improve or repair sperm and testicular defects. Alirezaei et al 48 similarly, disclosed that administration of olive leaf extract significantly reduced testicular MDA levels and improved sperm parameters and testicular oxidative stress after rotenone exposure. The previous research displayed that oleuropein minimized LPO in rat testis in oxidative stress induced by ethanol. On the contrary, it was revealed that the administration of OFE had harmful consequences on sperm indications and reproductive organs in rats. That controversy may be due to differences in the duration of treatment and the dose of OFE 49 Through normal spermatogenesis and under normal conditions to balance the ratio of the number of germ cells and sertoli cells in the testicular tissue, apoptosis must take place 50 . However, in case of exposure to cytotoxic agents, an irregular rate of apoptosis in spermatocyte, spermatid and spermatogenic cells, could be seen and leads to pathological condition 51 . According to this study, testosterone levels in the plasma of mice exposed to 2-NP significantly decreased and co-treatment with F. carica and OFE, separately or in combination improved this outcome. The significant reduction in testosterone levels may be a result of the direct damaging effect of 2-NP on the leydig cells 52 . The previous opinion was confirmed histopathologically in the present 225

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Int. J. Pharmacol., 20 (2): 217-228, 2024 study by the presence of disorganized, disrupted and damaged seminiferous tubules, the degenerative changes in spermatogenic cells in our study are matched with that found in nitrotriazolone intoxicated rats as a result of reduced testosterone level including degeneration of spermatocytes and reduction of spermatids length 53 . It is well known that sertoli cells supply germ cells with nutrition and are very important for spermatogenesis. Therefore, the toxic substances which induce dysfunction in sertoli cells could lead to testicular germ cell apoptosis 54 . Vacuolation of sertoli cells is a typical response to toxicity observed after exposure to 2,5-hexanedione and 1,3-dinitrobenzene 55 . Mainly, sertoli cell vacuolation comes first followed by germ cell deterioration, in the current work, sertoli cell vacuolation and germ cell degeneration co-occurred. Treatment with F. carica and OFE, separately or in combination with 2-NP resulted in moderate attenuation of the histopathological changes induced by 2-NP in the testes. The severe pathological change caused by 2-NP could be attributed to overproduction of free radicals. On the other hand, F. carica and OFE and its combination attenuated the generation of free radicals and improved the antioxidant defensive mechanisms which may ameliorate the testicular toxicity induced by 2-NP. In a former study, F. carica succeeded in preventing some deleterious effects of formaldehyde on testis most probably due to presence of several antioxidants in F. carica leaf extracts 56 . Ayoub et al 57 after qualitative phytochemical analysis of Ficus carica L and Olea europaea L. leaves extracts revealed the presence of seven known compounds as polyphenols, alkaloids, flavonoids, coumarins, anthocyanins, terpenoids and saponins in Ficus carica L. leaves extract. While Olea europaea L leaves extract has shown the presence of all previously tested compounds except the saponins, which have been replaced by tannins. All these compounds have powerful antioxidant activities To date, almost no information exists on the effect of 2-NP on Cas-3 expression as well as the effect of F. carica and OFE in the correction of 2-NP toxicity. In the present study, Cas-3 expression increased in the testicular tissues indicating that 2-NP evokes apoptosis in the testis of mice. After inducing varicocele in testicular germ cells, Lee et al 58 discovered increased expression of activated Cas-3 in the testicles 58 Interestingly, the addition of F. carica and OFE improved the condition by lowering the Cas-3 expressions. The intranuclear polypeptide PCNA is a DNA polymerase delta cofactor that is critical for replication, excision and repair 59 . The PCNA was used in this study as a tool to evaluate spermatogenesis, as it is a complicated cell cycle finished with sperm formation. In the present study, in early spermatocyte stages of control mice, PCNA-positive cells were highly indicated. In contrast, in 2-NP intoxicated mice, the density of PCNA-positive germ cells was markedly decreased, which meant a disturbance in proliferation and spermatogenesis. Concerning testicular tissue, it has been proven that elevation in PCNA expression is considered a mark of increasing proliferative activity and inducement of spermatogenesis 54 . This study showed that the passive result of decreased expression of PCNA in 2-NP challenged mice is recovered by treatment with F. carica or OFE. Thereby, an increase in the expression of PCNA has contributed to promoting cell cycle advancement and apoptosis lowering. F. carica and OFE extracts are involved in ameliorating many cellular activities concerning testicular cells 60 CONCLUSION In conclusion, administration of 2-NP induced testicular damage mediated by oxidative stress and apoptosis. Dietary supplementation of F. carica and/or OFE offered protection against 2-NP testicular toxicity by lowering LPO improving antioxidant and detoxifying enzyme function. Researchers might explore the potential synergistic effects of combining F. carica and OFE to enhance their efficacy. This should include evaluating potential side effects, interactions with medications and determining the optimal dosage for therapeutic benefits without adverse effects SIGNIFICANCE STATEMENT The purpose of this work is to evaluate to what extent fig and olive extracts could ameliorate the toxicity of testis caused by 2-nitropropane. The principal results concluded that dietary supplementation of fig and/or olive extracts may offer such protection. The 2-NP has been widely used in industry as a solvent, particularly for paints, inks and varnishes. It has also been found in substantial amounts of cigarette smoke, so it was necessary to minimize its bad effects on humans through natural products. Hope to conduct further studies to find more natural compounds to use to fix the toxicity of these industrial compounds REFERENCES 1 Oyeyipo, I.P., Y. Raji and A.F. Bolarinwa, 2014. Antioxidant profile changes in reproductive tissues of rats treated with nicotine. J. Hum. Reprod. Sci., 7: 41-46 2 Iammarrone, E., R. Balet, A.M. Lower, C. Gillott and J.G. Grudzinskas, 2003. Male infertility. Best Pract. Res. Clin. Obstet. Gynaecol., 17: 211-229 226

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