- Research
- Open access
- Published:
Gallic acid counteracts tartrazine-induced testicular dysfunction in rats: biochemical, histopathological and ultrastructural evidences
The Journal of Basic and Applied Zoology volume 85, Article number: 24 (2024)
Abstract
Background
Tartrazine (Tz) is one of the most commonly used colorants incorporated in the food manufacturing. Its toxicity is derived from metabolic byproducts representing health hazards to consumers. Gallic acid (GA) is known for its redox stabilizing, anti-apoptotic, and cytoprotective characteristics. Therefore, the aim of this study is to explore the possible defensive effect of GA against Tz-induced testicular dysfunction. To achieve this objective, 18 male Wistar adult rats were randomly and equally categorized into three groups for 30 days. The control group received no treatment. Tz at a dose of 30 mg/kg BW was administered to the Tz group. The Tz + GA group received GA at a dose of 200 mg/kg BW in concurrent with the previously described Tz dosage. Both Tz and GA were supplemented orally once daily by a stomach tube.
Results
The marked decline in luteinizing hormone, follicle stimulating hormone, testosterone, and estradiol 17beta confirmed deviation in pituitary–gonadal axis of Tz-exposed rats. Imbalances in plasma redox equilibrium were evident, characterized by a notable increase in malondialdehyde and nitric oxide levels, along with a decrease in reduced glutathione and total antioxidant capacity. Deteriorations in histopathological features, fibrosis in testicular tissue, abnormalities in Sertoli cell, and up-regulation in caspase-3 were observed. Conversely, GA administration successfully reversed these issues.
Conclusion
The ability of GA to counteract toxicological molecular targets in Tz-exposed testes is believed to be achieved through the restoration of oxidant/antioxidant balance and the prevention of the apoptotic cascade.
Background
Synthetic colorants play a significant role in the food processing industry, serving consumer preferences and enhancing the appeal of food products. They provide color to food items, making them more visually appealing and easily recognizable (Dey & Nagababu, 2022). However, recent attention has focused on the potential side effects of food additives, particularly azo dyes, due to their widespread use driven by affordability and long-term stability (Kaya et al., 2021). Tartrazine (Tz), a commonly used member of this group, is found in various products such as beverages, fruit juices, chocolates, cookies, chewing gum, jams, candies, ice cream, sauces, and mustard (Zingue et al., 2021). A debate arises concerning safety window of Tz as some peer-reviewed articles confirmed lack of adverse effects (EEDAP et al., 2016; Pestana et al., 2010), while others presented an opposite viewpoint (Abd-Elhakim et al., 2019; Altinoz et al., 2021; Ismail & Rashed, 2022). Tz has been associated with various harmful consequences in humans, including attention deficit hyperactivity disorder (Miller et al., 2022), inflammatory responses (Leo et al., 2018), and allergic reactions (Ardern, 1996). Studies in rodents have also shown evidence of liver toxicity (Hashem et al., 2019), inflammatory effects (Meyer et al., 2017), and learning/memory defects (Gao et al., 2011) linked to Tz consumption.
Metabolic derivatives of Tz, such as sulphanilic acid and aminopyrazolone, generate excessive reactive oxidants that trigger lipid peroxidation, disrupt enzymatic antioxidative defenses, and damage subcellular structures, ultimately leading to cell death (Bhatt et al., 2018; Morales et al., 2004). The unique physiological characteristics of the testes, including a high rate of cell proliferation, oxygen consumption, and a rich content of unsaturated fats, make them particularly susceptible to peroxidative damage caused by Tz exposure (Asadi et al., 2017). According to the available literature, the not yet fully-researched testicular toxicity of Tz could be mediated by hindering spermatogenesis, testosterone output and testicular redox network and activating lipid peroxidation cascade (Ara et al., 2022; Boussada et al., 2017; El Rabey et al., 2019). An increase in the expression of testicular protein kinase 1, a gene involved in the meiotic phase of spermatogenesis, is implicated in testicular damage associated with Tz exposure. The disturbances in reproductive hormonal axis were mediated by alterations in fertility hormone receptor gene expressions (Wopara et al., 2021). Elevated levels of caspase-3 transcripts and reduced levels of Bcl-2 transcripts after Tz intervention may initiate cellular apoptosis in the testes Essawy et al., 2024). The down-regulation in expressions of the genes coding for catalase, glutathione peroxidase-1, glutathione-S-transferase, and nuclear factor erythroid 2-related factor 2 could be incriminated in the pro-oxidative effect of Tz on testicular microenvironment (Eteng et al., 2021).
Challenges such as low stability, weak coloring strength, interactions with food ingredients, and the inability to achieve desired hues hinder the substitution of synthetic colorants with natural alternatives (Sigurdson et al., 2017). Hence, incorporating natural protective agents into the diet to mitigate the harmful effects of synthetic food colorants offers a preferable option, with gallic acid (GA) standing out as a promising nutritional supplement. GA is a group of phenolic compounds, also identified as 3,4,5-trihydroxybenzoic acid, is a naturally produced secondary metabolite present in a range of plants, vegetables, nuts, and fruits (Govea‑Salas et al., 2016). GA, when utilized as a supplement, has the potential to inhibit the rancidity and deterioration of fats and oils in a variety of consumable products, including condiments, confectionery, beverages, and baked and fried foods (Kosuru et al., 2018). GA counteracts nephrotoxicity, hepatotoxicity, neurotoxicity, pulmonary fibrosis, myocardial injury, and metabolic disorders (Kahkeshani et al., 2019). It also known for its ability to enhance the pituitary–gonadal axis, maintain testicular redox balance, and preserve histo-architecture through its antioxidant, anti-apoptotic, and cytoprotective properties in various experimental models of testicular dysfunction (Hosseinzadeh et al., 2022; Olukole et al., 2020; Owumi et al., 2022). Nevertheless, there is a shortage in data regarding the plausible role of GA in fighting the Tz-induced testicular abnormalities. Thus, this study aims to address this gap in knowledge, considering the similarity in the toxicokinetic pathways of Tz in both human beings and laboratory animals (Elhkim et al., 2007), providing a hope to clinically apply the findings and increase the safety limit of artificial azo dyes.
Methods
Chemicals
Gallic acid (GA) and tartrazine (Tz) were purchased from the Indian companies Sd. Fine Chem. Ltd and Marine Chemicals Company, respectively. All other chemicals and reagents used were of the highest available commercial purity.
Experimental protocol
In this investigation, 18 adult male Wistar rats weighing 180 ± 30 g were employed. Animals were obtained from the Animal House of Faculty of Pharmacy, Cairo University, Egypt. Animals were housed in stainless steel cages at room temperature under the identical laboratory conditions of temperature (25 ± 2 °C) and 12 h light/12 h dark cycle. They were fed water and a regular commercial pellet meal during the research period. Rats were allocated randomly and equally into three groups (10 per group) for 30 days. Control group received no treatment. Tz group was daily administrated Tz at a dose of 30 mg/kg BW (Amin et al., 2010). Tz + GA group was administrated GA at a dose of 200 mg/kg BW (Karimi-Khouzani et al., 2017) in association with the above-mentioned dose of Tz. Both Tz and GA were supplemented orally once daily by a stomach tube. A single animal was used as an experimental unit. To maintain blinding throughout the experiment, the animal care technician was unaware of the group distribution. The primary outcome measure in this experiment was the changes in pituitary–gonadal hormones following the interventions.
Sample collection
At the end of the experiment, overnight fasted rats were anaesthetized by sodium thiopental, and blood was promptly drawn from each rat’s orbital sinus by heparinized microcapillary tubes. The blood samples were collected in EDTA tubes and centrifuged at 3000 rpm for 15 min to obtain plasma. To gather tissue samples, rats were killed through cervical dislocation. The testis was milked out of the incision site and promptly exposed by cutting the tunica vaginalis during the orchidectomy, which was done using an open castration approach through a midline incision. 0.5 g of testis was homogenate in 5 ml (0.1 M) phosphate buffer (pH 7.4) using a homogenizer (IKA Yellow line DI 18 Disperser, Germany). The homogenates were centrifuged for 1 h at 4 °C at 6000 rpm, and the supernatant cytosols were frozen at − 20 °C. Plasma and tissue hemolysates were kept at − 20 °C for the biochemical evaluations.
Biochemical analysis
Luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, and 17β-estradiol (E2) were measured by ELISA kits (Catalog No. LH231F, FS232F, TE373S, and ES380S, respectively) according to manufacturer’s instructions (Calbiotech Inc, El Cajon, USA). Malondialdehyde (MDA) was estimated according to the method of (Ohkawa et al., 1979) using tetramethoxypropane as an external standard. Nitric oxide (NO) was measured based on an earlier procedure (Ding et al., 1988) which based on conversion of phosphoric acid to a diazonium salt by reaction with nitrite in acid solution. The diazonium salt is then coupled to naphthylene diamine dihydrochloride forming an azo dye that can be spectrophotometrically quantitated. Total antioxidant capacity (TAC) was assessed according to the manufacturer’s instructions using commercial colorimetric kit (Catalog number: TA 2513) provided by Egyptian Company for Biotechnology, Cairo, Egypt. Glutathione (GSH) content was estimated using the method of (Beutler et al., 1963).
Histopathology
Testis tissue samples were fixed in 10% neutral buffered formalin, dehydrated with ascending alcohol grades, cleared with xylene, and embedded in paraffin. Tissue sections, 5 microns thick, were prepared and stained with hematoxylin and eosin (H&E) for general histological assessment and Sirius red staining to detect fibrosis (collagen I & III) (Banchroft et al., 1996).
Morphometric analysis
After histological testes tissue was processed, photographs were taken under an objective lens magnification of 40 × using a digital camera connected to a light microscope (Leitz Dialux 20 Microscope). This analysis was done with the computerized image analysis software system Image J. Spatial calibration by object micrometer was performed before each analysis. Five pictures were selected from each animal in each group. The following morphometric parameters were measured: mean value of the intensity of collagen I and III (red area) by Sirius red stain (%) and mean value of the intensity of caspase-3 immunostaining expression (%).
Transmission electron microscope
The samples were fixed in 5% cold glutaraldehyde for 24–48 h immediately after animal necropsy. Samples were then washed 3–4 times with cacodylate buffer (pH 7.2) for 20 min each, post-fixed with 1% O4S4 for 2 h, and then washed 4 times with the same buffer. Dehydration with ascending alcohol content (30, 50, 70, 90, and 100% for 2 h) was done (Bozzola & Russell, 1999), followed by embedding in epon mixture. Semi-thin sections (0.5–1 microns thick) were cut from embedded blocks using an LKB ultramicrotome. A Leica AG ultramicrotome was used to slice the tissue into ultra-thin sections (500–700 Å thick), and contrasted with uranyl acetate and lead citrate. The tissues were orientated and shot using a SC30 Olympus camera. CCD digital camera Model XR-41 and JEM 100 CXII electron microscope at 80 kV were used to inspect and take pictures. The program Photo Filter 6.3.2 we digitally colored the TEM pictures in order to identify various cell and structural types.
Immunohistochemistry of caspase-3
Paraffin sections of the testis were cleared in xylene, rehydrated in graded ethanol, immersed in water for 5–10 min, and incubated in 0.3% H2O2 and 70% methanol for 20 min to inhibit endogenous peroxidase activity. The specimens were then rinsed three times for five minutes in phosphate buffer saline (PBS), and epitopes were disguised by boiling in citrate buffer (pH 6.0) for 10–15 min. After rinsing in PBS, the specimens were blocked for 30–60 min in 3% bovine serum albumin in PBS, and were incubated with primary antibody against caspase-3 in 0.1% bovine serum albumin in PBS overnight at 4°C in a humidified chamber. The samples were then rinsed in PBS and incubated with 7.5 g/mL of biotinylated secondary antibody in 0.1% bovine serum albumin in PBS for 1 h at room temperature, followed by avidin–biotin amplification for 30 min, and were developed with 3,3- diaminobenzidine peroxidase substrate. Sections were counter-stained with Mayer hematoxylin for three minutes and mounted. Negative controls were obtained by substituting the primary antibody with PBS (Kazi et al., 2003).
Statistical analysis
The data were expressed as means ± standard error of the mean. Statistical variances between groups were assessed using one-way ANOVA, followed by the Duncan post-test. Prior to analysis, normality of the data was evaluated using the Shapiro–Wilk test, and homogeneity of variances was confirmed to ensure that the data met the assumptions of normal distribution and equal variances. Statistical analysis was performed using SPSS software version 16 (SPSS, Richmond, VA, USA). A difference was regarded as statistically significant when p < 0.05.
Results
Biochemical findings
The Tz group exhibited significant perturbations in the pituitary–gonadal axis, characterized by a significant decrease in LH, FSH, testosterone, and E2 levels compared to the control group. Although these reproductive outcomes were significantly increased in the Tz + GA group, they remained below the levels observed in the control group, except for E2, which showed no significant difference from the control group. Tz-induced testicular toxicity led to disturbances in plasma redox balance, evident by a significant increase in MDA and NO levels, along with a significant decrease in TAC and GSH levels. Co-administration of GA with Tz effectively restored the redox balance by normalizing these parameters (Table 1).
Histopathological findings
The lesion score of the histopathological results of the testes in all studied groups were summarized in Table 2. Histological examination of the testes in the Tz group revealed interstitial edema containing a foamy, proteinaceous fluid and congested blood vessels. Some sections showed dilated seminiferous tubules (ST) and arrested spermatogenesis. Irregularity in shape of some ST and large area of proliferated Leydig cells was also prominent (Fig. 1). In contrast, the Tz + GA group showed relatively normal seminiferous tubules with complete spermatogenesis and interstitial edema in some sections (Fig. 2A–C). The control group displayed normal appearance of seminiferous tubules with different stages of spermatogenesis and normal interstitial tissues (Fig. 2D, E).
Photomicrographs of rat testis sections of Tz group (A–H) stained by H&E showing; interstitial edema (stars), congestion of the blood vessels (black arrow), proliferation of Leydig cells (yellow arrows), seminiferous tubules are dilated with arrest of spermatogenesis (ST), and Irregularity in shape of some seminiferous tubules (head arrows). H&E
Photomicrographs of rat testis sections stained by H&E showing; A–C Tz + GA group: slightly normal seminiferous tubules with complete spermatogenesis (ST) and interstitial edema (star). D, E Control group: normal appearance of seminiferous tubules with complete stages of spermatogenesis (ST). H&E
Sirius red staining for fibrosis confirmed the presence of a large amount of fibrous tissues in the interstitial tissues, around blood vessels, and around seminiferous tubules in the Tz group (Fig. 3A), while fibrosis was reduced in the Tz + GA group (Fig. 3B). The control group showed a mild amount of fibrous tissues around blood vessels and seminiferous tubules (Fig. 3C). Statistically, there were significant differences between the groups as shown in Fig. 3D.
Photomicrographs of rat testis sections stained by Sirius red showing; A Tz group: increase amount of red fibrous tissue. B Tz + GA group: moderate amount of fibrous tissue. C Control group: mild amount of red fibrous tissue. Around blood vessels (head arrow), around seminiferous tubules (arrows), and in the interstitial tissues (stars). D The mean value of the intensity of Sirius red stain for collagen I & III in control and different treated groups. a−c different letters indicate significant differences at p < 0.05 between the groups
Ultrastructural findings
Examination of seminiferous tubules in the Tz group revealed the presence of Sertoli cells with necrosis in their nuclei and multiple large vacuoles. Hemorrhages were observed in the interstitial spaces (Fig. 4A, B). The Tz and Tz + GA groups showed normal appearance of spermatocytes (Fig. 4C). The control group exhibited typical features of spermatocytes and spermatids (Fig. 4D).
Transmission electron micrograph: A, B Tz group showing seminiferous tubules with Sertoli cells only (S), vacuolation (V) and interstitial hemorrhages (red arrows). C Tz + GA group showing normal appearance of spermatocytes. D Control group showing normal appearance of spermatocytes (SC) and spermatids (SP)
Immunohistochemistry of caspase-3
The Tz group showed severe expression of caspase-3 in intracytoplasmic testicular cells and in the interstitial tissue cells compared to the control (Fig. 5A). The positive reaction of caspase-3 in the interstitial tissue cells was obvious in the Tz + GA group (Fig. 5B). The control group revealed a slight positive caspase-3 expression in very few interstitial tissue cells (Fig. 5C). Statistical analysis showed a significant difference in caspase-3 expression between the groups (Fig. 5D).
Immunohistochemical staining of caspase-3 expression in rat testis: A Tz group showing strong positive caspase-3 immunostaining (deep brown) appeared in intracytoplasmic of seminiferous tubules (arrow), and in the interstitial tissue cells (star). B Tz + GA group showing positive expression in the interstitial tissues only and negative expression in seminiferous tubules. C Control group showing slightly positive caspase-3 immunostaining in the interstitial tissues only. D The mean value of caspase-3 immunostaining expression in control and different treated groups. a−cDifferent letters indicate significant differences at p < 0.05 between the groups
Discussion
The dysregulation in the pituitary–gonadal axis following the exposure to Tz is consistent with previous reports (Elewa et al., 2019). Decreased expression levels of testicular steroidogenic enzymes and androgen and gonadotropic receptors, and disruption of the reproductive axis by azo dye colorants (Abbas & Al-Hamadawi, 2019; Alsudani & Alhamadawi, 2020; Montaser et al., 2018) are suggested to be explanatory factors. Low LH output impairs the ability of Leydig cells to synthesize testosterone, as it is needed to translocate cholesterol into mitochondria (Zirkin & Papadopoulos, 2018). The drop in testosterone could happen due to the detrimental influence of extra release of reactive oxygen species and depletion of antioxidant stock on Leydig cells (Mohamed et al., 2017). The improvement in reproductive hormones following GA supplementation in concurrent UA exposure agrees with that found in zearalenone-mediated testicular defects in rats (Owumi et al., 2022). This outcome is attributed to increased mRNA levels of steroidogenic acute regulatory protein (Dai et al., 2021).
The disturbance in redox equilibrium in Tz-exposed rats is consistent with that observed in serum, kidney, and liver homogenate in previous reports (El Rabey et al., 2019). The aromatic amines, which are released following the biotransformation of Tz by intestinal microbiota, produce reactive oxidants when interacting with dietary nitrogenous compounds (Moutinho et al., 2007). In response to the surplus formation of free radicals, the antioxidant defense capacity of the body started to be consumed to stop their adverse impacts, while MDA accumulated as a result of lipid peroxidation caused by their action on cellular membrane lipids (Amin et al., 2010). The reduction in plasma GSH content could be attributed to the increased activity of glutathione peroxidase which consumes GSH reserve during reduction of hydrogen peroxide and lipid peroxides (Bhatt et al., 2018). Down-regulation of nuclear factor erythroid 2-related factor 2, a main regulator to a variety of antioxidant response element–dependent genes, can participate in the depletion of plasma TAC and GSH levels (Akintoye et al., 2022). Overgeneration of reactive oxygen species is responsible for lipid peroxidation, and genomic fragmentation in the reproductive system, and germ cell death (Agarwal et al., 2020). Thus, interrupting the propagation of free radicals can limit autoxidation and subsequently block the lipid peroxidation cascade. Accordingly, we used GA to counteract the Tz-linked redox imbalance owing to its free radicals-scavenging properties and its ability to up-regulate antioxidant gene expression (Gao et al., 2019; Ojeaburu & Oriakhi, 2021). Several scholarly articles confirmed the testicular protective effect of GA against chemotoxicants secondary to its redox-stabilizing action (Abarikwu et al., 2022; Owumi et al., 2020).
Similar to a previous finding (Khayyat et al., 2017), the plasma NO of the Tz group elevated due to increased transcript abundance of endothelial NO synthase (Abd-Elhakim et al., 2018). The raised NO level in the Tz group inhibits testicular steroidogenesis and gonadotropin-releasing hormone-induced LH secretion (Chatterjee et al., 1997; Kostic et al., 2000). Dysfunction in sperm characteristics and a drop in gonadotropin output are the consequences of NO when presents in excess (Dutta & Sengupta, 2022). Also, it up-regulates the expression levels of caspase-3 and Bax and down-regulates the expression level of Bcl-2 (Zhou et al., 2019). The reduction in the protein expression level of inducible NO synthase (Mard et al., 2015) could explain the normalization of NO level in the Tz + GA group.
The histoarchitectural deteriorations in the testis of TZ-exposed rats are in harmony with the findings of (Elewa et al., 2019). These cytological responses could emerge from lipid peroxidation as metabolic byproducts of Tz elicit oxidative overloading (Bhatt et al., 2018). ST dilatation might be due to a reduction in E2 failing the efferent ducts to resorb ST fluid with possible compression and atrophy of germinal epithelium (Heuser et al., 2013). The arrest in spermatogenesis in the histological sections is similar to (Al-Seeni et al., 2018). By generating regulatory signals and nutritive supplies for preserving the growing germ cells, FSH both alone and in conjunction with either LH or testosterone influences the multiplication, development, and viability of the sustentacular Sertoli cells (Oduwole et al., 2018, 2021). Thus, the depletion of reproductive hormones creates an unfavorable biological environment in maintenance and driving the spermatogenic potential. Sertoli cells in rats were harmed by TZ, reducing their ability to support spermatogenesis (Mahfouz & Moussa, 2015). It also suppresses the proliferation of spermatogonia and differentiation of Sertoli cells (Elewa et al., 2019). As a zinc-chelating compound, Tz deprives the testis of the indispensable role of zinc in cell proliferation and growth, resulting in the suppression of spermatogenesis (Visweswaran & Krishnamoorthy, 2012). Fibrosis in the interstitial and perivascular spaces is corresponding to what occurred in colon mucosa (Altinoz et al., 2021) and hepatic tissue (Balta et al., 2019) of TZ-supplemented rats; owing to up-regulation of fibrotic markers collagen 1-α, tumor growth factor β-1, and fibronectin (Abd-Elhakim et al., 2019). Sertoli cell vacuolation in the testis of Tz-intoxicated rats is in line with previous findings by (Montaser et al., 2018). These vacuoles could be regarded as locations of germ cell loss after elimination by Sertoli cells (Eid et al., 2002). These vacuoles mostly include damaged mitochondria that have been trapped within autophagic vacuoles (Eid et al., 2013). The cell vacuolation can be explained by promoting cell death or disrupting the autophagosome maturation (Cayli et al., 2020). The presence of vacuoles in Sertoli cells could impair their functions and be associated with infertility (Cayli et al., 2020).
GA intervention restored the testicular histological features in Tz-intoxicated rats in line with its improving effect on busulfan- and phthalate-induced testicular abnormalities (Abarikwu et al., 2022; Hosseinzadeh et al., 2022). The androgenic, cytoprotective, and antioxidant potentials of GA are positively reflected on the histo-architectural profile. From another mechanistic viewpoint, GA motivates the electron transport chain and oxidative phosphorylation to energize the germ cells (Gungor et al., 2019).
Intense immuno-expression of caspase-3 in the testis of TZ-challenged rats is in corresponding to what observed by (Mahfouz & Moussa, 2015). The increase in apoptotic/survival ratio under Tz burden is due to a decrease in mRNA levels of BCl-2 and proliferating cell nuclear antigen, increase in mRNA levels of Bax, and failure in repairing DNA damage (Elewa et al., 2019; Essawy et al., 2023; Haridevamuthu et al., 2023). Inadequate testosterone production by Leydig cells is associated with mitochondrial abnormalities by blocking respiratory electron flux and subsequently exhausting energy stores, causing eventually apoptosis (Wang et al., 2015). By activation of the mitochondrial, death receptor, and endoplasmic reticulum apoptotic pathways, excessive production of free radicals is incriminated in the induction of programmed cell death (Redza-Dutordoir & Averill-Bates, 2016). Increased NO declines the probability of cell survival by favoring apoptosis at the expense of autophagy (Zhang et al., 2019). GSH depletion disrupts the mitochondrial membrane permeability leading to the induction of intrinsic apoptotic pathway (Malla et al., 2020). As gonadotrophic hormones act as anti-apoptotic effectors (Li et al., 2020; Wang et al., 2018a), thus the decrease in their output could be causatively linked to the shift in the cell programming toward death decisions.
According to our findings and consistent with the gastric ulcer rat model, GA exhibited anti-apoptotic potential by decreasing the protein expression of caspase-3 and Bax and increasing the protein expression of Bcl-2 (Zhou et al., 2020). By lowering the Bax/Bcl-2 ratio and mitochondrial depolarization, increasing ATP generation, and blocking mitogen-activated protein kinase and Fas death receptor-mediated apoptosis, the drop in NO exerts an anti-apoptotic impact (Wang et al., 2018b). Thus, the reduction in the elevated NO level by GA supplementation hindered the process of cell death. The transcript abundance of proliferating cell nuclear antigen, a nuclear protein that encodes crucial DNA replication proteins, is enhanced by GA (dos Santos Silva et al., 2023), resulting in a reaction that encourages cellular survival over suicidal signals. Similar to the glyoxal-induced renal fibrotic rat model (Yousuf & Vellaichamy, 2015), concurrent administration of GA ameliorated fibrosis by reducing the protein expression of collagen type I, fibronectin, connective tissue growth factor and matrix metalloproteinase (Jin et al., 2018; Yousuf & Vellaichamy, 2015).
Conclusions
Our findings confirmed the sensitivity of testis to Tz exposure on both biochemical and cytological levels. Thus, it is mandatory to increase public knowledge of the health risks associated with this dye. GA was an effective phytochemical strategy in fighting Tz-related testicular disorders by restoring reproductive hormonal balance and oxidant/antioxidant responses and dampening cellular death signals and histological lesions. Therefore, GA provides a relatively safe and cost-effective approach to antagonizing gonadotoxic agents. However, it’s important to acknowledge the limitations of our study, including the lack of assessment of lipid peroxidation biomarker levels, antioxidant activities in testicular tissue, and semen quality parameters. Further studies are strongly recommended to highlight the potential protective effects of GA against other health problems induced by Tz.
Availability of data and materials
All data are available from the corresponding author on reasonable request.
Abbreviations
- ANOVA:
-
One-way analysis of variance
- E2:
-
17β-estradiol
- FSH:
-
Follicle stimulating hormone
- GA:
-
Gallic acid
- GSH:
-
Glutathione
- LH:
-
Luteinizing hormone
- MDA:
-
Malondialdehyde
- NO:
-
Nitric oxide
- TAC:
-
Total antioxidant capacity
- Tz:
-
Tartrazine
References
Abarikwu, S. O., Mgbudom-Okah, C. J., Njoku, R. C., Okonkwo, C. J., Onuoha, C. C., & Wokoma, A. F. S. (2022). Gallic acid ameliorates busulfan-induced testicular toxicity and damage in mature rats. Drug and Chemical Toxicology, 45, 1881–1890. https://doi.org/10.1080/01480545.2021.1892949
Abbas, J. R., & Al-Hamadawi, H. A. (2019). Effect of chocolate brown HT E155 on some hormones in male albino rats. EurAsian Journal of BioSciences, 13, 485–489.
Abd-Elhakim, Y. M., Hashem, M. M., El-Metwally, A. E., Anwar, A., Abo-EL-Sooud, K., Moustafa, G. G., & Ali, H. A. (2018). Comparative haemato-immunotoxic impacts of long-term exposure to tartrazine and chlorophyll in rats. International Immunopharmacology, 63, 145–154. https://doi.org/10.1016/j.intimp.2018.08.002
Abd-Elhakim, Y. M., Moustafa, G. G., Hashem, M. M., Ali, H. A., Abo-EL-Sooud, K., & El-Metwally, A. E. (2019). Influence of the long-term exposure to tartrazine and chlorophyll on the fibrogenic signalling pathway in liver and kidney of rats: The expression patterns of collagen 1-α, TGFβ-1, fibronectin, and caspase-3 genes. Environmental Science and Pollution Research, 26, 12368–12378. https://doi.org/10.1007/s11356-019-04734-w
Agarwal, A., Leisegang, K., & Sengupta, P. (2020). Oxidative stress in pathologies of male reproductive disorders. In V. R. Preedy (Ed.), Pathology. USA: Elsevier.
Akintoye, O. O., Ajibare, A. J., Folawiyo, M. A., Asuku, A. O., Jimoh-Abdulghaffar, H. O., Akintoye, A. O., Babalola, K. T., Idowu, O. O., & Oyiza, Y. G. (2022). Virgin coconut oil-supplemented diet reverses behavioural phenotypes of sodium benzoate-model of acetylcholinesterase dysfunction and cognitive impairment: Role of Nrf2/NfKb signaling pathway. Nigerian Journal of Physiological Sciences, 37, 225–233.
Al-Seeni, M. N., El Rabey, H. A., Al-Hamed, A. M., & Zamazami, M. A. (2018). Nigella sativa oil protects against tartrazine toxicity in male rats. Toxicology Report, 5, 146–155. https://doi.org/10.1016/j.fct.2010.07.039
Alsudani, A. A., & Alhamadawi, H. A. (2020). The role of Moringa leaf extract to reduce the negative effect of some food additives on gene expression of CYP11A1 gene in male albino rats. EurAsian Journal of BioSciences, 14, 4397–4403. https://doi.org/10.1088/1742-6596/1664/1/012122
Altinoz, E., Erdemli, M. E., Gül, M., Erdemli, Z., Gül, S., & Turkoz, Y. (2021). Prevention of toxic effects of orally administered tartrazine by crocin in Wistar rats. Toxicological & Environmental Chemistry, 103, 184–198. https://doi.org/10.1080/02772248.2021.1942472
Amin, K. A., Hameid, H. A., II., & Abd Elsttar, A. H. (2010). Effect of food azo dyes tartrazine and carmoisine on biochemical parameters related to renal, hepatic function and oxidative stress biomarkers in young male rats. Food and Chemical Toxicology, 48, 2994–2999. https://doi.org/10.5897/AJB2017.16300
Ara, C., Arshad, A., Faheem, M., Khan, M., & Shakir, H. A. (2022). Protective potential of aqueous extract of Allium cepa against tartrazine induced reproductive toxicity. Pakistan Veterinary Journal, 42, 358–363. https://doi.org/10.29261/pakvetj/2022.029
Ardern, K., Cochrane Airways Group. (1996). Tartrazine exclusion for allergic asthma. Cochrane Database of Systematic Reviews, 2017, CD000460. https://doi.org/10.1002/14651858.CD000460
Asadi, N., Bahmani, M., Kheradmand, A., & Rafieian-Kopaei, M. (2017). The impact of oxidative stress on testicular function and the role of antioxidants in improving it: A review. Journal of Clinical and Diagnostic Research, 11, IE01. https://doi.org/10.7860/JCDR/2017/23927.9886
Balta, I., Sevastre, B., Mireşan, V., Taulescu, M., Raducu, C., Longodor, A. L., Marchiş, Z., Mariş, C. S., & Coroian, A. (2019). Protective effect of blackthorn fruits (Prunus spinosa) against tartrazine toxicity development in albino Wistar rats. BMC Chemistry, 13, 1–11. https://doi.org/10.1186/s13065-019-0610-y
Banchroft, J. D., Stevens, A., & Turner, D. R. (1996). Theory and practice of histological techniques (4th ed.). Churchil Livingstone.
Beutler, E., Duron, O., & Kelly, M. (1963). Colorimetric method for determination of glutathione reduced. Journal of Laboratory and Clinical Medicine, 61, 3.
Bhatt, D., Vyas, K., Singh, S., John, P. J., & Soni, I. (2018). Tartrazine induced neurobiochemical alterations in rat brain sub-regions. Food and Chemical Toxicology, 113, 322–327. https://doi.org/10.1016/j.fct.2018.02.011
Boussada, M., Lamine, J. A., Bini, I., Abidi, N., Lasrem, M., El-Fazaa, S., & El-Golli, N. (2017). Assessment of a sub-chronic consumption of tartrazine (E102) on sperm and oxidative stress features in Wistar rat. International Food Research Journal, 24, 1473–1481.
Bozzola, J. J., & Russell, L. D. (1999). Electron microscopy: Principles and techniques for biologists. Jones & Bartlett Learning.
Cayli, S., Sahin, C., Sanci, T. O., & Nakkas, H. (2020). Inhibition of p97/VCP function leads to defective autophagosome maturation, cell cycle arrest and apoptosis in mouse Sertoli cells. Theriogenology, 158, 196–206. https://doi.org/10.1016/j.theriogenology.2020.09.017
Chatterjee, S., Collins, T. J., & Yallampalli, C. (1997). Inhibition of nitric oxide facilitates LH release from rat pituitaries. Life Sciences, 61, 45–50. https://doi.org/10.1016/S0024-3205(97)00356-1
Dai, X., Sun, X. F., Wang, A. Q., Wei, W. H., & Yang, S. M. (2021). Effect of gallic acid on the reproduction of adolescent male Brandt’s voles (Lasiopodomys brandtii). Canadian Journal of Zoology, 99, 783–791. https://doi.org/10.1139/cjz-2020-029
Dey, S., & Nagababu, B. H. (2022). Applications of food color and bio-preservatives in the food and its effect on the human health. Food Chemistry Advances, 1, 100019. https://doi.org/10.1016/j.focha.2022.100019
Ding, A. H., Nathan, C. F., & Stuehr, D. J. (1988). Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. The Journal of Immunology, 141, 2407–2412. https://doi.org/10.4049/jimmunol.141.7.2407
dos Santos Silva, R. L., Lins, T. L. B. G., do Monte, A. P. O., de Andrade, K. O., de Sousa Barberino, R., da Silva, G. A. L., Campinho, D., Junior, R. C. P., & de Matos, M. H. (2023). Protective effect of gallic acid on doxorubicin-induced ovarian toxicity in mouse. Reproductive Toxicology, 115, 147–156. https://doi.org/10.1016/j.reprotox.2022.12.008
Dutta, S., & Sengupta, P. (2022). The role of nitric oxide on male and female reproduction. Malaysian Journal of Medical Sciences, 29, 18–30. https://doi.org/10.21315/mjms2022.29.2.3
EEDAP, Rychen, G., Azimonti, G., Bampidis, V., de Lourdes Bastos, M., Bories, G., Chesson, A., Cocconcelli, P. S., Flachowsky, G., & Gropp, J. (2016). Safety and efficacy of tartrazine (E 102) for cats and dogs, ornamental fish, grain-eating ornamental birds and small rodents. EFSA Journal, 14, e04613. https://doi.org/10.2903/j.efsa.2016.4613
Eid, N., Ito, Y., & Otsuki, Y. (2013). The autophagic response to alcohol toxicity: The missing layer. Journal of Hepatology, 59, 396–401. https://doi.org/10.1016/j.jhep.2013.03.038
Eid, N. A. S., Shibata, M. A., Ito, Y., Kusakabe, K., Hammad, H., & Otsuki, Y. (2002). Involvement of Fas system and active caspases in apoptotic signalling in testicular germ cells of ethanol-treated rats. International Journal of Andrology, 25, 159–167. https://doi.org/10.1046/j.1365-2605.2002.00341.x
El Rabey, H. A., Al-Seeni, M. N., Al-Sieni, A. I., Al-Hamed, A. M., Zamzami, M. A., & Almutairi, F. M. (2019). Honey attenuates the toxic effects of the low dose of tartrazine in male rats. Journal of Food Biochemistry, 43, e12780. https://doi.org/10.1111/jfbc.12780
Elewa, Y. H. A., Mohamed, A. A., Galal, A. A. A., El-Naseery, N. I., Ichii, O., & Kon, Y. (2019). Food Yellow4 reprotoxicity in relation to localization of DMC1 and apoptosis in rat testes: Roles of royal jelly and cod liver oil. Ecotoxicology and Environmental Safety, 169, 696–706. https://doi.org/10.1016/j.ecoenv.2018.11.082
Elhkim, M. O., Héraud, F., Bemrah, N., Gauchard, F., Lorino, T., Lambré, C., Frémy, J. M., & Poul, J. M. (2007). New considerations regarding the risk assessment on Tartrazine: An update toxicological assessment, intolerance reactions and maximum theoretical daily intake in France. Regulatory Toxicology and Pharmacology, 47, 308–316. https://doi.org/10.1016/j.yrtph.2006.11.004
Essawy, A., Matar, S., Mohamed, N., Abdel-Wahab, W., & Abdou, H. (2024). Ginkgo biloba extract protects against tartrazine-induced testicular toxicity in rats: Involvement of antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. Environmental Science and Pollution Research, 31, 15065–15077. https://doi.org/10.1007/s11356-024-32047-0
Essawy, A., Mohamed, A. I., Ali, R. G., Ali, A. M., & Abdou, H. M. (2023). Analysis of melatonin-modulating effects against tartrazine-induced neurotoxicity in male rats: Biochemical, pathological and immunohistochemical markers. Neurochemical Research, 48, 131–141. https://doi.org/10.1007/s11064-022-03723-9
Eteng, O. E., Moses, C. A., Ugwor, E. I., Enobong, J. E., Akamo, A. J., Akinloye, D. I., Sadiku, I. O., Iwara, A., & Ubana, E. (2021). Sub-acute exposure to Sudan IV-adulterated palm oil induces oxidative stress and represses the expression of Nrf2 and antioxidant genes in male albino rats. Journal of Environmental Science and Health, Part C, 39, 400–412. https://doi.org/10.1080/26896583.2021.1965851
Gao, J., Hu, J., Hu, D., & Yang, X. (2019). A role of gallic acid in oxidative damage diseases: A comprehensive review. Natural Product Communications, 14, 1934578X19874174. https://doi.org/10.1177/1934578X198741
Gao, Y., Li, C., Shen, J., Yin, H., An, X., & Jin, H. (2011). Effect of food azo dye tartrazine on learning and memory functions in mice and rats, and the possible mechanisms involved. Journal of Food Science, 76, T125–T129. https://doi.org/10.1111/j.1750-3841.2011.02267.x
Govea-Salas, M., Rivas-Estilla, A. M., RodrÃguez-Herrera, R., Lozano-Sepúlveda, S. A., Aguilar-Gonzalez, C. N., Zugasti-Cruz, A., Salas-Villalobos, T. B., & Morlett-Chávez, J. A. (2016). Gallic acid decreases hepatitis C virus expression through its antioxidant capacity. Experimental and Therapeutic Medicine, 11, 619–624. https://doi.org/10.3892/etm.2015.2923
Gungor, S., Inanc, M. E., Ozturk, C., Korkmaz, F., Bastan, I., Cil, B., & Kastelic, J. P. (2019). Gallic and carnosic acids improve quality of frozen-thawed ram spermatozoa. Andrologia, 51, e13393. https://doi.org/10.1111/and.13393
Haridevamuthu, B., Murugan, R., Seenivasan, B., Meenatchi, R., Pachaiyappan, R., Almutairi, B. O., Arokiyaraj, S., & Arockiaraj, J. (2023). Synthetic azo-dye, tartrazine induces neurodevelopmental toxicity via mitochondria-mediated apoptosis in zebrafish embryos. Journal of Hazardous Materials, 461, 132524. https://doi.org/10.1016/j.jhazmat.2023.132524
Hashem, M. M., Abd-Elhakim, Y. M., Abo-EL-Sooud, K., & Eleiwa, M. M. (2019). Embryotoxic and teratogenic effects of tartrazine in rats. Toxicological Research, 35, 75–81. https://doi.org/10.5487/TR.2019.35.1.075
Heuser, A., Mecklenburg, L., Ockert, D., Kohler, M., & Kemkowski, J. (2013). Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas. Toxicologic Pathology, 41, 615–627. https://doi.org/10.1177/0192623312463783
Hosseinzadeh, A., Mehrzadi, S., Siahpoosh, A., Basir, Z., Bahrami, N., & Goudarzi, M. (2022). Gallic acid ameliorates di-(2-ethylhexyl) phthalate-induced testicular injury in adult mice. Human & Experimental Toxicology, 41, 09603271221078867. https://doi.org/10.1177/096032712210788
Ismail, O. I., & Rashed, N. A. (2022). Riboflavin attenuates tartrazine toxicity in the cerebellar cortex of adult albino rat. Scientific Reports, 12, 19346. https://doi.org/10.1038/s41598-022-23894-3
Jin, L., Sun, S., Ryu, Y., Piao, Z. H., Liu, B., Choi, S. Y., Kim, G. R., Kim, H. S., Knee, H. J., & Jeong, M. H. (2018). Gallic acid improves cardiac dysfunction and fibrosis in pressure overload-induced heart failure. Scientific Reports, 8, 9302. https://doi.org/10.1038/s41598-018-27599-4
Kahkeshani, N., Farzaei, F., Fotouhi, M., Alavi, S. S., Bahramsoltani, R., Naseri, R., Momtaz, S., Abbasabadi, Z., Rahimi, R., Farzaei, M. H., & Bishayee, A. (2019). Pharmacological effects of gallic acid in health and diseases: A mechanistic review. Iranian Journal of Basic Medical Sciences, 22, 225. https://doi.org/10.22038/ijbms.2019.32806.7897
Karimi-Khouzani, O., Heidarian, E., & Amini, S. A. (2017). Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats. Pharmacological Reports, 69, 830–835. https://doi.org/10.1016/j.pharep.2017.03.011
Kaya, S. I., Cetinkaya, A., & Ozkan, S. A. (2021). Latest advances on the nanomaterials-based electrochemical analysis of azo toxic dyes sunset yellow and tartrazine in food samples. Food and Chemical Toxicology, 156, 112524. https://doi.org/10.1016/j.fct.2021.112524
Kazi, M., Thyberg, J., Religa, P., Roy, J., Eriksson, P., Hedin, U., & Swedenborg, J. (2003). Influence of intraluminal thrombus on structural and cellular composition of abdominal aortic aneurysm wall. Journal of Vascular Surgery, 38, 1283–1292. https://doi.org/10.1016/S0741-5214(03)00791-2
Khayyat, L., Essawy, A., Sorour, J., & Soffar, A. (2017). Tartrazine induces structural and functional aberrations and genotoxic effects in vivo. PeerJ, 5, e3041. https://doi.org/10.7717/peerj.3041
Kostic, T. S., Andric, S. A., Maric, D., & Kovacevic, R. Z. (2000). Inhibitory effects of stress-activated nitric oxide on antioxidant enzymes and testicular steroidogenesis. Journal of Steroid Biochemistry and Molecular Biology, 75, 299–306. https://doi.org/10.1016/S0960-0760(00)00185-0
Kosuru, R. Y., Roy, A., Das, S. K., & Bera, S. (2018). Gallic acid and gallates in human health and disease: Do mitochondria hold the key to success? Molecular Nutrition & Food Research, 62, 1700699. https://doi.org/10.1002/mnfr.201700699
Leo, L., Loong, C., Ho, X. L., Raman, M. F. B., Suan, M. Y. T., & Loke, W. M. (2018). Occurrence of azo food dyes and their effects on cellular inflammatory responses. Nutrition, 46, 36–40. https://doi.org/10.1016/j.nut.2017.08.010
Li, C., Zhou, J., Liu, Z., Zhou, J., Yao, W., Tao, J., Shen, M., & Liu, H. (2020). FSH prevents porcine granulosa cells from hypoxia-induced apoptosis via activating mitophagy through the HIF-1α-PINK1-Parkin pathway. FASEB Journal, 34, 3631–3645. https://doi.org/10.1096/fj.201901808RRR
Mahfouz, M. E., & Moussa, E. A. (2015). The impact of curcumin administration on the food colouring sunset yellow-induced damage in testes and liver of male rat: Gene expression and ultrastructural studies. Egyptian Academic Journal of Biological Sciences, 11, 43–60.
Malla, J. A., Umesh, R. M., Yousf, S., Mane, S., Sharma, S., Lahiri, M., & Talukdar, P. (2020). A glutathione activatable ion channel induces apoptosis in cancer cells by depleting intracellular glutathione levels. Angewandte Chemie International Edition, 59, 7944–7952. https://doi.org/10.1002/anie.202000961
Mard, S. A., Mojadami, S., Farbood, Y., & Naseri, M. K. G. (2015). The anti-inflammatory and anti-apoptotic effects of gallic acid against mucosal inflammation-and erosions-induced by gastric ischemia-reperfusion in rats. Veterinary Research Forum, 6, 305–311.
Meyer, S. K., Probert, P. M., Lakey, A. F., Axon, A. R., Leitch, A. C., Williams, F. M., Jowsey, P. A., Blain, P. G., Kass, G. E. N., & Wright, M. C. (2017). Hepatic effects of tartrazine (E 102) after systemic exposure are independent of oestrogen receptor interactions in the mouse. Toxicology Letters, 273, 55–68. https://doi.org/10.1016/j.toxlet.2017.03.024
Miller, M. D., Steinmaus, C., Golub, M. S., Castorina, R., Thilakartne, R., Bradman, A., & Marty, M. A. (2022). Potential impacts of synthetic food dyes on activity and attention in children: A review of the human and animal evidence. Environmental Health, 21, 45. https://doi.org/10.1186/s12940-022-00849-9
Mohamed, A. A., Mohamed, W. A. M., & Khater, S. I. (2017). Imidacloprid induces various toxicological effects related to the expression of 3β-HSD, NR5A1, and OGG1 genes in mature and immature rats. Environmental Pollution, 221, 15–25. https://doi.org/10.1016/j.envpol.2016.08.082
Montaser, M., Abiya, R. A. E., Afifi, M., Saddick, S., Allogmani, A. S., & Almaghrabi, O. A. (2018). Effect of natural and synthetic food colorants on spermatogenesis and the expression of its controlling genes. Slovenian Veterinary Research, 55, 187–199.
Morales, A. E., Pérez-Jiménez, A., Hidalgo, M. C., Abellán, E., & Cardenete, G. (2004). Oxidative stress and antioxidant defenses after prolonged starvation in Dentex dentex liver. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology, 139, 153–161. https://doi.org/10.1016/j.cca.2004.10.008
Moutinho, I. L. D., Bertges, L. C., & Assis, R. V. C. (2007). Prolonged use of the food dye tartrazine (FD&C yellow n° 5) and its effects on the gastric mucosa of Wistar rats. Brazilian Journal of Biology, 67, 141–145. https://doi.org/10.1590/s1519-69842007000100019
Oduwole, O. O., Huhtaniemi, I. T., & Misrahi, M. (2021). The roles of luteinizing hormone, follicle-stimulating hormone and testosterone in spermatogenesis and folliculogenesis revisited. International Journal of Molecular Sciences, 22, 12735. https://doi.org/10.3390/ijms222312735
Oduwole, O. O., Peltoketo, H., & Huhtaniemi, I. T. (2018). Role of follicle-stimulating hormone in spermatogenesis. Frontiers in Endocrinology, 9, 763. https://doi.org/10.3389/fendo.2018.00763
Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Ojeaburu, S. I., & Oriakhi, K. (2021). Hepatoprotective, antioxidant and anti-inflammatory potentials of gallic acid in carbon tetrachloride-induced hepatic damage in Wistar rats. Toxicology Reports, 8, 177–185. https://doi.org/10.1016/j.toxrep.2021.01.001
Olukole, S. G., Ola-Davies, E. O., Lanipekun, D. O., & Oke, B. O. (2020). Chronic exposure of adult male Wistar rats to bisphenol A causes testicular oxidative stress: Role of gallic acid. Endocrine Regulations, 54, 14–21. https://doi.org/10.2478/enr-2020-0003
Owumi, S. E., Adedara, I. A., Akomolafe, A. P., Farombi, E. O., & Oyelere, A. K. (2020). Gallic acid enhances reproductive function by modulating oxido-inflammatory and apoptosis mediators in rats exposed to aflatoxin-B1. Experimental Biology and Medicine, 245, 1016–1028. https://doi.org/10.1177/1535370220936206
Owumi, S. E., Bello, S. A., Najophe, S. E., Nwozo, S. O., & Esan, I. O. (2022). Coadministration of gallic acid abates zearalenone-mediated defects in male rat’s reproductive function. Journal of Biochemical and Molecular Toxicology, 36, e22940. https://doi.org/10.1002/jbt.22940
Pestana, S., Moreira, M., & Olej, B. (2010). Safety of ingestion of yellow tartrazine by double-blind placebo controlled challenge in 26 atopic adults. Allergologia Et Immunopathologia, 38, 142–146. https://doi.org/10.1016/j.aller.2009.09.009
Redza-Dutordoir, M., & Averill-Bates, D. A. (2016). Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1863, 2977–2992. https://doi.org/10.1016/j.bbamcr.2016.09.012
Sigurdson, G. T., Tang, P., & Giusti, M. M. (2017). Natural colorants: Food colorants from natural sources. Annual Review of Food Science and Technology, 8, 261–280. https://doi.org/10.1146/annurev-food-030216-025923
Visweswaran, B., & Krishnamoorthy, G. (2012). Oxidative stress by tartrazine in the testis of Wistar rats. Journal of Pharmaceutical and Biological Sciences, 2, 44–49. https://doi.org/10.9790/3008-0234447
Wang, F., Yang, J., Sun, J., Dong, Y., Zhao, H., Shi, H., & Fu, L. (2015). Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction. Journal of Endocrinology, 225, 101–111. https://doi.org/10.1530/JOE-14-0638
Wang, X., Zou, P., He, Y., Meng, K., Quan, F., & Zhang, Y. (2018a). Effect of luteinizing hormone on goat theca cell apoptosis and steroidogenesis through activation of the PI3K/AKT pathway. Animal Reproduction Science, 190, 108–118. https://doi.org/10.1016/j.anireprosci.2018.01.014
Wang, Y. Y., Chen, M. T., Hong, H. M., Wang, Y., Li, Q., Liu, H., Yang, M. W., Hong, F. F., & Yang, S. L. (2018b). Role of reduced nitric oxide in liver cell apoptosis inhibition during liver damage. Archives of Medical Research, 49, 219–225. https://doi.org/10.1016/j.arcmed.2018.09.001
Wopara, I., Modo, E. U., Mobisson, S. K., Olusegun, G. A., Umoren, E. B., Orji, B. O., Mounmbegna, P. E., & Ujunwa, S. O. (2021). Synthetic Food dyes cause testicular damage via up-regulation of pro-inflammatory cytokines and down-regulation of FSH-R and TESK-1 gene expression. JBRA Assisted Reproduction, 25, 341. https://doi.org/10.5935/1518-0557.20200097
Yousuf, M. J., & Vellaichamy, E. (2015). Protective activity of gallic acid against glyoxal-induced renal fibrosis in experimental rats. Toxicology Reports, 2, 1246–1254. https://doi.org/10.1016/j.toxrep.2015.07.007
Zhang, X., Jin, L., Tian, Z., Wang, J., Yang, Y., Liu, J., Chen, Y., Hu, C., Chen, T., Zhao, Y., & He, Y. (2019). Nitric oxide inhibits autophagy and promotes apoptosis in hepatocellular carcinoma. Cancer Science, 110, 1054–1063. https://doi.org/10.1111/cas.13945
Zhou, D., Yang, Q., Tian, T., Chang, Y., Li, Y., Duan, L. R., Li, H., & Wang, S. W. (2020). Gastroprotective effect of gallic acid against ethanol-induced gastric ulcer in rats: Involvement of the Nrf2/HO-1 signaling and anti-apoptosis role. Biomedicine & Pharmacotherapy, 126, 110075. https://doi.org/10.1016/j.biopha.2020.110075
Zhou, Y., Ming, J., Li, Y., Deng, M., Chen, Q., Ma, Y., Chen, Z., Zhang, Y., & Liu, S. (2019). Ligustilide attenuates nitric oxide-induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways. Journal of Cellular and Molecular Medicine, 23, 3357–3368. https://doi.org/10.1111/jcmm.14226
Zingue, S., Mindang, E. L. N., Awounfack, F. C., Kalgonbe, A. Y., Kada, M. M., Njamen, D., & Ndinteh, D. T. (2021). Oral administration of tartrazine (E102) accelerates the incidence and the development of 7, 12-dimethylbenz (a) anthracene (DMBA)-induced breast cancer in rats. BMC Complementary Medicine and Therapies, 21, 1–11. https://doi.org/10.1186/s12906-021-03490-0
Zirkin, B. R., & Papadopoulos, V. (2018). Leydig cells: Formation, function, and regulation. Biology of Reproduction, 99, 101–111. https://doi.org/10.1093/biolre/ioy059
Acknowledgements
Not applicable.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
HW, MMBA, and SMMS designed the experiment. KMAH and SMMS carried out the histological techniques. HW and RFEE performed the biochemical analysis. NSA carried out the statistical analysis and was the main contributor in writing the manuscript. All authors read and approved the final manuscript for submission.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The procedures in the current study were conducted in accordance with the University’s guidelines for the care of experimental animals. Ethical approval (06/2023/0132) was obtained from the Committee of the Faculty of Veterinary Medicine at Assiut University, Egypt. The study adheres to the reporting standards outlined in the ARRIVE guidelines.
Competing interests
The authors declare that there are no competing interests.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Waly, H., Ezz El-Arab, R.F., Abou Khalil, N.S. et al. Gallic acid counteracts tartrazine-induced testicular dysfunction in rats: biochemical, histopathological and ultrastructural evidences. JoBAZ 85, 24 (2024). https://doi.org/10.1186/s41936-024-00370-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s41936-024-00370-0