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Vitamins C and E Attenuate Acetamiprid-induced Liver and Testicular Tissue Injury in Adult Male Rats

L
LOUKIL Bachir1,*
https://orcid.org/0009-0000-8332-3953
C
CHOUDER Wissam1
M
MHAMDIA Ismahan1
1Department of Biological Sciences, Faculty of Life and Natural Sciences and of Earth and Universe Sciences, Mohamed El Bachir El Ibrahimi University, 34000 Bordj Bou Arreridj, Algeria.

ABSTRACT

Background: Neonicotinoids, including acetamiprid (ACP), are widely used synthetic insecticides worldwide. However, their extensive environmental presence has raised significant concerns about their potential harmful effects on human health.

Methods: The goal of this study was to evaluate ACP-induced histological alterations in the liver and testes, as well as the role of vitamins C and E in mitigating these effects. Eighteen adult male rats were divided into three equal groups and orally administered distilled water (control), ACP alone (1/10 of LD50) and ACP (1/10 of LD50) plus vitamins C and E (250 mg/kg/body weight of vitamin C and 200 mg/kg/bw of vitamin E, administered every other day) for three weeks.

Result: The results indicated that ACP induced a non-significant reduction in body weight gain and a significant decrease in relative liver weight. In contrast, co-administration of vitamins C and E resulted in a highly significant increase in body weight gain compared with the control group. However, relative liver weight in the co-treated group remained significantly lower than that of the control group. No major change was observed in testicular weight. In addition, light microscopic examination revealed that ACP induced histological alterations in the liver and testes. Treatment of intoxicated rats with vitamins C and E reduced the severity of ACP-induced tissue damage. In conclusion, these findings demonstrate that ACP exposure induces significant histopathological alterations in the liver and testes. Furthermore, the alternating administration of Vitamins C and E significantly attenuates these damages, suggesting a protective effect likely mediated by their synergistic antioxidant properties.

INTRODUCTION

Neonicotinoids are currently the most widely used synthetic insecticides worldwide (Bass and Field, 2018). Their extensive use is primarily attributed to their systemic properties, allowing distribution throughout plant tissues and effective control of a broad range of piercing and sucking pests. In addition to direct insecticidal activity, they may also reduce aphid-mediated transmission of viral crop diseases (Simon-Delso et al., 2015; Jeschke et al., 2011). Beyond their insecticidal action, neonicotinoids enhance plant tolerance to biotic and abiotic stresses. Their use extends to agriculture, animal health and certain products intended for the general public (Jeschke et al., 2011; Jeschke and Nauen, 2008).
       
Their water solubility favors their dissemination beyond the application site and notable concentrations have been detected in soil, water and even foodstuffs (Bonmatin et al., 2015). This widespread dispersion raises concerns about their potentially harmful effects, not only on non-target insects but also on human health. Although intended to limit their toxicity in mammals while selectively targeting insect pests (Ensley, 2018), several studies have nevertheless reported detrimental effects in rodents. Exposure to neonicotinoids is associated with a significant reduction in liver and testicular weight as well as histopathological alterations in the seminiferous tubules and hepatic tissue (Hamed et al., 2023; Issa et al., 2025).
       
Acetamiprid, approved in over 120 countries (Jeschke and Nauen, 2008), possesses a 6-chloro-3-pyridyl group which confers a structural analogy with nicotine and epibatidine, two potent agonists of nicotinic acetylcholine receptors (nAChRs). This similarity explains its selective action on insect nAChRs (Matsuda and Sattelle, 2001). In practice, acetamiprid is commonly applied by foliar spray to protect the aerial parts of crops, particularly against piercing-sucking insects such as aphids on leafy vegetables and fruits (Pietrzak et al., 2019; Beránková et al., 2017; Jactel et al., 2019). Although acetamiprid was developed with the aim of minimizing toxicity in vertebrates, several experimental studies have highlighted its toxic effects on hepatic and testicular tissues. Thus, oral exposure for five weeks in rats led to a significant decrease in sperm count, viability and motility as well as severe hepatic alterations such as steatosis, leukocyte infiltration and hemorrhages (Toghan et al., 2022). Other work has shown a reduction in body and testicular weight combined with a series of  histopathological  changes and damage to the seminiferous tubules and Leydig cells in mice (Zhang et al., 2011). Similar hepatic damage, manifesting as necrosis, pyknosis, lymphocytic infiltration, blood congestion and vacuolization, was observed in pigeons (Noreen et al., 2023).
       
These observations suggest that this widely used neonicotinoid insecticide may induce notable histopathological alterations at the hepatic and testicular levels in different animal models. Vitamins C and E, known for their antioxidant properties, are likely to mitigate the oxidative and histopathological damage induced by xenobiotics. However, to date, no study has specifically explored the protective effect of alternate administration (every other day) of these vitamins against subacute exposure to acetamiprid. In this context, the present study was designed to evaluate the histopathological effects induced by acetamiprid on the liver and testes of rats after 21 days of exposure and to analyze the potential protective role of vitamins C and E administered alternately (every other day).

MATERIALS AND METHODS

Chemicals
 
The acetamiprid (20% active ingredient; commercial formulation Rustilan) was kindly supplied by SARL AGRO RAYANE (Algeria), the official distributor. Vitamin E was administered as a nutritional supplement (α-tocophérol, 400 mg/capsule, containing 60 mg of soybean oil) obtained from Biomax Algeria. Vitamin C was utilized in its pure form (C-Phytal), provided by Phytal laboratory (Algeria).
 
Animals
 
Eighteen adult male Wistar albino rats, weighing between 198 and 271 g, were procured from the Pasteur Institute of Algiers (Algeria). The animals were maintained in stainless steel cages under controlled laboratory conditions, with a temperature of  22±2°C, relative humidity of 70±10% and a 12 h light/12 h dark photoperiod. Standard laboratory diet and water were provided ad libitum. Prior to the initiation of the experimental procedures, all animals were acclimatized for a period of approximately 10 days.
 
Experimental design
 
Different concentrations of acetamiprid, vitamin C and vitamin E were prepared in distilled water and administered orally to the rats. Control animals received distilled water only. The dose of acetamiprid was determined based on its oral median lethal dose (LD50), reported to be 200 mg/kg body weight (Williams, 2013). Accordingly, the experimental dose used in this study was set at 20 mg/kg body weight (1/10 of the LD50). The doses of vitamin C and vitamin E were selected based on previously published studies demonstrating their efficacy in mitigating toxicity induced by various insecticides (Yu et al., 2008; Kalender et al., 2010).
       
After the acclimatization period, the animals were randomly divided into three groups (n = 6 per group) and treated orally once daily for 21 consecutive days as follows: (1) the control group received distilled water; (2) the acetamiprid group received 20 mg/kg body weight (bw) per day and (3) the treated group received acetamiprid (20 mg/kg bw per day) in combination with vitamins C and E. Vitamin C was administered at a dose of 250 mg/kg bw, while vitamin E was given at 200 mg/kg bw, with a 1 h interval between the two treatments. Both vitamins were administered on alternate days.
 
Sample preparation
 
At the end of the 21st day, 24 hours after the last administration of treatment with 12 hours of fasting, the animals were anaesthetized with chloroform for a very short time and sacrificed by decapitation. Immediately thereafter, the animals were incised from the abdominal to the thoracic region. After dissection, the liver and testes were carefully removed, rinsed with cold 0.9% NaCl and weighed.
 
Evaluation  of body weight gain and relative liver weight and testis weights
 
Body weights of all animals were recorded daily and at the end of the experimental period. Net body weight gain (g) was calculated as the difference between the final body weight (FBW) measured after 21 days of treatment and the initial body weight (IBW) recorded at the beginning of the experiment:
 
Net body weight gain (g) = Final body weight - Initial body weight
 
Body weight gain (%) was calculated using the following formula:


The liver and testes were excised and weighed for toxicological evaluation (U.S. Environmental Protection Agency, 1996). Relative liver weight was then calculated for each animal using the following equation:

 
Histopathological examination
 
For the histological examination, the liver and testes were fixed in 10% neutral formalin, then after dehydration in a series of graded alcohol, the tissue was embedded in paraffin and cut into 5 μm thickness using a rotary microtome and stained with Hematoxylin and eosin to evaluate cellular and tissue architecture (H&E). The slides were examined under an optical microscope (Optika) at ×10, ×40 and ×100 magnifications.

Statistical analysis
 
Data were expressed as mean ± standard error of the means (SEM). Statistical analysis of the data was performed using MINITAB Statistical Software, version 22.1. The comparison was made between control and treated groups by Student’s t-test. Values of P≤0.05, P≤0.01 and P≤0.001 were considered significant.

RESULTS AND DISCUSSION

Body and organ weights
 
No signs of mortality were observed in any group during the study period. At the end of the experimental period (21 days), acetamiprid-exposed rats showed a non-significant decrease in net body weight gain as compared to rats in the control and those administered acetamiprid combined with vitamins groups. The administration of vitamins C and E in combination with acetamiprid caused a highly significant (P≤0.01) increase in body weight gain as compared to the control group, reaching about 42.37% above the control values. Relative liver weight significantly (P≤0.001) decreased in rats treated with acetamiprid alone and significantly (P≤0.05) decreased in rats co-administered with vitamins and acetamiprid, while, testicular weights did not show significant changes as compared to the control group (Table 1). 

Table 1: Effects of acetamiprid and its co-administration with vitamins C and E on the body and organ weights in male rats after daily oral treatment for 21 days.



Rats exposed to ACP exhibited lower body weight gain as compared to the control group, indicating systemic toxicity associated with ACP exposure (Phogat et al., 2022). Similar findings were reported by Arıcan et al. (2020), who observed a non-significant reduction in body weight following oral administration of 25 mg/kg ACP for 90 days and by El-Gendy et al. (2022), who noted a marked decrease in weight gain in ACP-treated mice. This reduction may result from the toxic impact of ACP on physiological functions, including disruption of metabolic processes and organ function, ultimately leading to impaired growth and general health. Altered feeding behavior could also contribute to the observed loss of body weight (Aioub et al., 2024). Interestingly, alternate-day co-administration of vitamins C and E mitigated the adverse effects of ACP on body weight gain in intoxicated rats. These findings align with previous reports showing that vitamins C and E exert protective effects against neonicotinoid-induced toxicity in rodents (Hamed et al., 2023; Zhang et al., 2011).
       
A highly significant decrease in relative liver weight was observed in acetamiprid-treated rats as compared to the control. Previous studies have also reported a reduction in liver weight in rats exposed to neonicotinoid insecticides (Toor et al., 2013; Askri et al., 2022). This decrease in liver weight may be due to ACP-induced hepatic toxicity, leading to degeneration and cellular loss, which translates into a reduction in liver mass. The administration of vitamins with ACP resulted in an increased liver weight, but this remained significant compared to the control group.
       
In the current study, post-experimental evaluation of testicular weights in rats revealed no statistically significant differences between the control group and the two treated groups. These observations are consistent with the work of Sevim et al., (2023), who reported similar results.
 
Histopathological examination
 
In the control group, no histopathological changes were observed in the liver and testes. However, the acetamiprid-only treated group showed histological lesions in several areas of the liver, including hepatocytes lysis due to necrosis, severe congestion, moderate infiltration of lymphocytic cells and dilation of the hepatic artery, bile duct, sinusoids and central vein. Co-administration of vitamins C and E every other day with 1/10 of the LD50 of acetamiprid markedly improved the histopathological alterations as compared to acetamiprid group and represented by reducing the degree of congestion, lymphocytic infiltration, necrosis in hepatocytes and dilation of hepatic artery, bile duct, sinusoids and central vein (Fig 1). Acetamiprid caused many histopathological variations in the testes, including, an irregular basement membrane, immature cells in the lumen of some seminiferous tubules, congested capsular blood vessels, vacuole formation in the germinal epithelium and desquamated germinal epithelium as well as enlarged lumina and Interstitial spaces with Leydig cell degeneration, were also observed. However, supplementation with vitamins C and E in rats exposed to acetamiprid protected testes tissue damage and approached normal tissue architecture (Fig 2).

Fig 1: Photomicrograph of liver sections of male rats treated with acetamiprid and with the combination of acetamiprid and vitamins C/E for 21 days (H&E, 4×, 10× and 40×).



Fig 2: Photomicrograph of testis sections of male rats treated with acetamiprid and with the combination of acetamiprid and vitamins C/E for 21 days (H&E, 10× et 40×).


       
This study demonstrates clear evidence of the toxicological impact of acetamiprid (ACP) on multiple histopathological endpoints in rats. As a commonly used neonicotinoid insecticide, ACP has been shown to disrupt normal organ function and compromise tissue architecture. These findings further emphasize its potential hazard to non-target organisms, particularly mammals (Toghan et al., 2022). The observations from this work confirm that ACP exposure induces deleterious effects on hepatic and testicular tissues, consistent with the findings of prior research (El-Hak et al., 2022).
       
ACP exposure induced severe hepatic histopathological alterations, notably characterized by necrosis, lymphocytic infiltration, congestion, as well as dilation of the hepatic artery, bile duct, sinusoids and central vein. These observations are consistent with those found by Awadalla et al., (2025) and Chakroun et al., (2016), as well as previous studies evaluating the effects of other neonicotinoids (Issa et al., 2025; Soujanya et al., 2013).
       
Prior investigations have identified the liver as one of the main target organs for ACP exposure, due to its central role in the metabolism of this compound (Khovarnagh and Seyedalipour, 2021; Karaca et al., 2019). The observed histological lesions could be attributed to excessive production of reactive oxygen species (ROS) induced by ACP. These free radicals interact with cellular proteins and DNA, leading to lipid peroxidation and damage to hepatocyte membranes. This oxidative process explains the hepatic toxicity of ACP, which is responsible for the severe tissue damage observed in the liver (Khovarnagh and Seyedalipour, 2021). Furthermore, ACP-induced vascular congestion and decreased hepatic blood flow can lead to local anoxia, thus promoting the degeneration of hepatic tissues (Mondal et al., 2014). The histological observations obtained in the present study confirm these findings.
       
In the ACP-treated group, histological observations revealed marked alterations in the testicular structure. The seminiferous tubules appeared distorted and disorganized, separated by widened interstitial spaces. Numerous spermatogenic cells exhibited signs of degeneration accompanied by vacuolization, while desquamation of the germinal epithelium was observed. Moreover, the capsular blood vessels were dilated and congested. These observations are consistent with those reported in previous studies (Zhang et al., 2011; Kong et al., 2017; Zayman et al., 2022; Arıcan et al., 2020).
       
These lesions can be attributed to oxidative stress induced by ACP, which manifests as increased lipid peroxidation and nitric oxide (NO) production, as well as decreased activity of antioxidant enzymes (Mosbah et al., 2016; Kong et al., 2017; Zhang et al., 2011; Arıcan et al., 2020). This oxidative imbalance leads to damage to sperm DNA, proteins and lipids, thereby disrupting steroidogenesis and spermatogenesis (Walczak-Jedrzejowska et al., 2013; Chainy et al., 1997). Furthermore, oxidative stress alters proliferation and apoptosis processes within the testis, particularly in spermatogonia and primary spermatocytes, through the activation of the p38 MAPK pathway, known to inhibit cell growth and promote apoptosis (Kong et al., 2017; Zhang et al., 2011; Arıcan et al., 2020). Additionally, ACP metabolites generated in the liver could also contribute to these deleterious effects on the testes (Zhang et al., 2011). The histological results obtained in the present study confirm these observations. Conversely, the co-administration of vitamins exerted a protective effect against ACP-induced tissue alterations, consistent with observations reported in rats exposed to ACP and supplemented with vitamins (Zhang et al., 2011; Zayman et al., 2022).
       
The histopathological alterations induced by ACP were significantly attenuated in rats receiving co-administration of vitamins C and E. The observed improvement in hepatic and testicular tissues could be attributed to the synergistic antioxidant properties of these vitamins. Indeed, several previous studies have demonstrated that vitamins C and E exert a protective role against neonicotinoid-induced oxidative stress by limiting the increase in markers of lipid peroxidation (MDA) and nitric oxide (NO), while stimulating the activity of endogenous antioxidant enzymes (Zhang et al., 2011; El-Gendy et al., 2010; Soujanya et al., 2013). Moreover, Yi-Wang et al. (2012) reported that vitamin E significantly contributes to the reduction of acetamiprid residues in mouse hepatic tissues, underscoring its key role in hepatic detoxification and the preservation of cellular integrity.

CONCLUSION

In conclusion, subacute exposure to acetamiprid induced significant histopathological alterations in the liver and testes of adult male rats, including hepatocellular necrosis, vascular congestion, inflammatory infiltration and marked disruption of the seminiferous tubule architecture. In addition, alternate-day co-administration of vitamins C and E markedly reduced these hepatic and testicular lesions, leading to partial restoration of normal tissue architecture. This protective antioxidant effect may be of particular relevance for occupationally exposed populations, such as agricultural workers, who are frequently in contact with neonicotinoid pesticides. However, vitamin supplementation should be regarded as a supportive and temporary protective strategy, while the priority remains the reduction of acetamiprid use and the development of safer alternatives.

ACKNOWLEDGEMENT

The authors sincerely thank the staff of the ANAPAT Laboratory, Bouzidi Lakhder Hospital, Bordj Bou Arreridj, Algeria, for their technical support and valuable collaboration.
 
Disclaimers
 
The views and conclusions presented in this article are those of the authors and do not necessarily reflect the positions of their affiliated institutions. The authors assume responsibility for the accuracy and completeness of the information provided; however, they disclaim any liability for direct or indirect damages arising from the use of this content.
 
Informed consent
 
All experimental procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee and were conducted in accordance with established guidelines for the care and handling of laboratory animals.

CONFLICT OF INTEREST

The authors declare no competing interests. This research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Furthermore, no external funding or sponsorship had any role in the study design, data acquisition, analysis, decision to publish, or manuscript preparation.

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    Full Research Article

    Vitamins C and E Attenuate Acetamiprid-induced Liver and Testicular Tissue Injury in Adult Male Rats

    L
    LOUKIL Bachir1,*
    https://orcid.org/0009-0000-8332-3953
    C
    CHOUDER Wissam1
    M
    MHAMDIA Ismahan1
    1Department of Biological Sciences, Faculty of Life and Natural Sciences and of Earth and Universe Sciences, Mohamed El Bachir El Ibrahimi University, 34000 Bordj Bou Arreridj, Algeria.

    ABSTRACT

    Background: Neonicotinoids, including acetamiprid (ACP), are widely used synthetic insecticides worldwide. However, their extensive environmental presence has raised significant concerns about their potential harmful effects on human health.

    Methods: The goal of this study was to evaluate ACP-induced histological alterations in the liver and testes, as well as the role of vitamins C and E in mitigating these effects. Eighteen adult male rats were divided into three equal groups and orally administered distilled water (control), ACP alone (1/10 of LD50) and ACP (1/10 of LD50) plus vitamins C and E (250 mg/kg/body weight of vitamin C and 200 mg/kg/bw of vitamin E, administered every other day) for three weeks.

    Result: The results indicated that ACP induced a non-significant reduction in body weight gain and a significant decrease in relative liver weight. In contrast, co-administration of vitamins C and E resulted in a highly significant increase in body weight gain compared with the control group. However, relative liver weight in the co-treated group remained significantly lower than that of the control group. No major change was observed in testicular weight. In addition, light microscopic examination revealed that ACP induced histological alterations in the liver and testes. Treatment of intoxicated rats with vitamins C and E reduced the severity of ACP-induced tissue damage. In conclusion, these findings demonstrate that ACP exposure induces significant histopathological alterations in the liver and testes. Furthermore, the alternating administration of Vitamins C and E significantly attenuates these damages, suggesting a protective effect likely mediated by their synergistic antioxidant properties.

    INTRODUCTION

    Neonicotinoids are currently the most widely used synthetic insecticides worldwide (Bass and Field, 2018). Their extensive use is primarily attributed to their systemic properties, allowing distribution throughout plant tissues and effective control of a broad range of piercing and sucking pests. In addition to direct insecticidal activity, they may also reduce aphid-mediated transmission of viral crop diseases (Simon-Delso et al., 2015; Jeschke et al., 2011). Beyond their insecticidal action, neonicotinoids enhance plant tolerance to biotic and abiotic stresses. Their use extends to agriculture, animal health and certain products intended for the general public (Jeschke et al., 2011; Jeschke and Nauen, 2008).
           
    Their water solubility favors their dissemination beyond the application site and notable concentrations have been detected in soil, water and even foodstuffs (Bonmatin et al., 2015). This widespread dispersion raises concerns about their potentially harmful effects, not only on non-target insects but also on human health. Although intended to limit their toxicity in mammals while selectively targeting insect pests (Ensley, 2018), several studies have nevertheless reported detrimental effects in rodents. Exposure to neonicotinoids is associated with a significant reduction in liver and testicular weight as well as histopathological alterations in the seminiferous tubules and hepatic tissue (Hamed et al., 2023; Issa et al., 2025).
           
    Acetamiprid, approved in over 120 countries (Jeschke and Nauen, 2008), possesses a 6-chloro-3-pyridyl group which confers a structural analogy with nicotine and epibatidine, two potent agonists of nicotinic acetylcholine receptors (nAChRs). This similarity explains its selective action on insect nAChRs (Matsuda and Sattelle, 2001). In practice, acetamiprid is commonly applied by foliar spray to protect the aerial parts of crops, particularly against piercing-sucking insects such as aphids on leafy vegetables and fruits (Pietrzak et al., 2019; Beránková et al., 2017; Jactel et al., 2019). Although acetamiprid was developed with the aim of minimizing toxicity in vertebrates, several experimental studies have highlighted its toxic effects on hepatic and testicular tissues. Thus, oral exposure for five weeks in rats led to a significant decrease in sperm count, viability and motility as well as severe hepatic alterations such as steatosis, leukocyte infiltration and hemorrhages (Toghan et al., 2022). Other work has shown a reduction in body and testicular weight combined with a series of  histopathological  changes and damage to the seminiferous tubules and Leydig cells in mice (Zhang et al., 2011). Similar hepatic damage, manifesting as necrosis, pyknosis, lymphocytic infiltration, blood congestion and vacuolization, was observed in pigeons (Noreen et al., 2023).
           
    These observations suggest that this widely used neonicotinoid insecticide may induce notable histopathological alterations at the hepatic and testicular levels in different animal models. Vitamins C and E, known for their antioxidant properties, are likely to mitigate the oxidative and histopathological damage induced by xenobiotics. However, to date, no study has specifically explored the protective effect of alternate administration (every other day) of these vitamins against subacute exposure to acetamiprid. In this context, the present study was designed to evaluate the histopathological effects induced by acetamiprid on the liver and testes of rats after 21 days of exposure and to analyze the potential protective role of vitamins C and E administered alternately (every other day).

    MATERIALS AND METHODS

    Chemicals
     
    The acetamiprid (20% active ingredient; commercial formulation Rustilan) was kindly supplied by SARL AGRO RAYANE (Algeria), the official distributor. Vitamin E was administered as a nutritional supplement (α-tocophérol, 400 mg/capsule, containing 60 mg of soybean oil) obtained from Biomax Algeria. Vitamin C was utilized in its pure form (C-Phytal), provided by Phytal laboratory (Algeria).
     
    Animals
     
    Eighteen adult male Wistar albino rats, weighing between 198 and 271 g, were procured from the Pasteur Institute of Algiers (Algeria). The animals were maintained in stainless steel cages under controlled laboratory conditions, with a temperature of  22±2°C, relative humidity of 70±10% and a 12 h light/12 h dark photoperiod. Standard laboratory diet and water were provided ad libitum. Prior to the initiation of the experimental procedures, all animals were acclimatized for a period of approximately 10 days.
     
    Experimental design
     
    Different concentrations of acetamiprid, vitamin C and vitamin E were prepared in distilled water and administered orally to the rats. Control animals received distilled water only. The dose of acetamiprid was determined based on its oral median lethal dose (LD50), reported to be 200 mg/kg body weight (Williams, 2013). Accordingly, the experimental dose used in this study was set at 20 mg/kg body weight (1/10 of the LD50). The doses of vitamin C and vitamin E were selected based on previously published studies demonstrating their efficacy in mitigating toxicity induced by various insecticides (Yu et al., 2008; Kalender et al., 2010).
           
    After the acclimatization period, the animals were randomly divided into three groups (n = 6 per group) and treated orally once daily for 21 consecutive days as follows: (1) the control group received distilled water; (2) the acetamiprid group received 20 mg/kg body weight (bw) per day and (3) the treated group received acetamiprid (20 mg/kg bw per day) in combination with vitamins C and E. Vitamin C was administered at a dose of 250 mg/kg bw, while vitamin E was given at 200 mg/kg bw, with a 1 h interval between the two treatments. Both vitamins were administered on alternate days.
     
    Sample preparation
     
    At the end of the 21st day, 24 hours after the last administration of treatment with 12 hours of fasting, the animals were anaesthetized with chloroform for a very short time and sacrificed by decapitation. Immediately thereafter, the animals were incised from the abdominal to the thoracic region. After dissection, the liver and testes were carefully removed, rinsed with cold 0.9% NaCl and weighed.
     
    Evaluation  of body weight gain and relative liver weight and testis weights
     
    Body weights of all animals were recorded daily and at the end of the experimental period. Net body weight gain (g) was calculated as the difference between the final body weight (FBW) measured after 21 days of treatment and the initial body weight (IBW) recorded at the beginning of the experiment:
     
    Net body weight gain (g) = Final body weight - Initial body weight
     
    Body weight gain (%) was calculated using the following formula:


    The liver and testes were excised and weighed for toxicological evaluation (U.S. Environmental Protection Agency, 1996). Relative liver weight was then calculated for each animal using the following equation:

     
    Histopathological examination
     
    For the histological examination, the liver and testes were fixed in 10% neutral formalin, then after dehydration in a series of graded alcohol, the tissue was embedded in paraffin and cut into 5 μm thickness using a rotary microtome and stained with Hematoxylin and eosin to evaluate cellular and tissue architecture (H&E). The slides were examined under an optical microscope (Optika) at ×10, ×40 and ×100 magnifications.

    Statistical analysis
     
    Data were expressed as mean ± standard error of the means (SEM). Statistical analysis of the data was performed using MINITAB Statistical Software, version 22.1. The comparison was made between control and treated groups by Student’s t-test. Values of P≤0.05, P≤0.01 and P≤0.001 were considered significant.

    RESULTS AND DISCUSSION

    Body and organ weights
     
    No signs of mortality were observed in any group during the study period. At the end of the experimental period (21 days), acetamiprid-exposed rats showed a non-significant decrease in net body weight gain as compared to rats in the control and those administered acetamiprid combined with vitamins groups. The administration of vitamins C and E in combination with acetamiprid caused a highly significant (P≤0.01) increase in body weight gain as compared to the control group, reaching about 42.37% above the control values. Relative liver weight significantly (P≤0.001) decreased in rats treated with acetamiprid alone and significantly (P≤0.05) decreased in rats co-administered with vitamins and acetamiprid, while, testicular weights did not show significant changes as compared to the control group (Table 1). 

    Table 1: Effects of acetamiprid and its co-administration with vitamins C and E on the body and organ weights in male rats after daily oral treatment for 21 days.



    Rats exposed to ACP exhibited lower body weight gain as compared to the control group, indicating systemic toxicity associated with ACP exposure (Phogat et al., 2022). Similar findings were reported by Arıcan et al. (2020), who observed a non-significant reduction in body weight following oral administration of 25 mg/kg ACP for 90 days and by El-Gendy et al. (2022), who noted a marked decrease in weight gain in ACP-treated mice. This reduction may result from the toxic impact of ACP on physiological functions, including disruption of metabolic processes and organ function, ultimately leading to impaired growth and general health. Altered feeding behavior could also contribute to the observed loss of body weight (Aioub et al., 2024). Interestingly, alternate-day co-administration of vitamins C and E mitigated the adverse effects of ACP on body weight gain in intoxicated rats. These findings align with previous reports showing that vitamins C and E exert protective effects against neonicotinoid-induced toxicity in rodents (Hamed et al., 2023; Zhang et al., 2011).
           
    A highly significant decrease in relative liver weight was observed in acetamiprid-treated rats as compared to the control. Previous studies have also reported a reduction in liver weight in rats exposed to neonicotinoid insecticides (Toor et al., 2013; Askri et al., 2022). This decrease in liver weight may be due to ACP-induced hepatic toxicity, leading to degeneration and cellular loss, which translates into a reduction in liver mass. The administration of vitamins with ACP resulted in an increased liver weight, but this remained significant compared to the control group.
           
    In the current study, post-experimental evaluation of testicular weights in rats revealed no statistically significant differences between the control group and the two treated groups. These observations are consistent with the work of Sevim et al., (2023), who reported similar results.
     
    Histopathological examination
     
    In the control group, no histopathological changes were observed in the liver and testes. However, the acetamiprid-only treated group showed histological lesions in several areas of the liver, including hepatocytes lysis due to necrosis, severe congestion, moderate infiltration of lymphocytic cells and dilation of the hepatic artery, bile duct, sinusoids and central vein. Co-administration of vitamins C and E every other day with 1/10 of the LD50 of acetamiprid markedly improved the histopathological alterations as compared to acetamiprid group and represented by reducing the degree of congestion, lymphocytic infiltration, necrosis in hepatocytes and dilation of hepatic artery, bile duct, sinusoids and central vein (Fig 1). Acetamiprid caused many histopathological variations in the testes, including, an irregular basement membrane, immature cells in the lumen of some seminiferous tubules, congested capsular blood vessels, vacuole formation in the germinal epithelium and desquamated germinal epithelium as well as enlarged lumina and Interstitial spaces with Leydig cell degeneration, were also observed. However, supplementation with vitamins C and E in rats exposed to acetamiprid protected testes tissue damage and approached normal tissue architecture (Fig 2).

    Fig 1: Photomicrograph of liver sections of male rats treated with acetamiprid and with the combination of acetamiprid and vitamins C/E for 21 days (H&E, 4×, 10× and 40×).



    Fig 2: Photomicrograph of testis sections of male rats treated with acetamiprid and with the combination of acetamiprid and vitamins C/E for 21 days (H&E, 10× et 40×).


           
    This study demonstrates clear evidence of the toxicological impact of acetamiprid (ACP) on multiple histopathological endpoints in rats. As a commonly used neonicotinoid insecticide, ACP has been shown to disrupt normal organ function and compromise tissue architecture. These findings further emphasize its potential hazard to non-target organisms, particularly mammals (Toghan et al., 2022). The observations from this work confirm that ACP exposure induces deleterious effects on hepatic and testicular tissues, consistent with the findings of prior research (El-Hak et al., 2022).
           
    ACP exposure induced severe hepatic histopathological alterations, notably characterized by necrosis, lymphocytic infiltration, congestion, as well as dilation of the hepatic artery, bile duct, sinusoids and central vein. These observations are consistent with those found by Awadalla et al., (2025) and Chakroun et al., (2016), as well as previous studies evaluating the effects of other neonicotinoids (Issa et al., 2025; Soujanya et al., 2013).
           
    Prior investigations have identified the liver as one of the main target organs for ACP exposure, due to its central role in the metabolism of this compound (Khovarnagh and Seyedalipour, 2021; Karaca et al., 2019). The observed histological lesions could be attributed to excessive production of reactive oxygen species (ROS) induced by ACP. These free radicals interact with cellular proteins and DNA, leading to lipid peroxidation and damage to hepatocyte membranes. This oxidative process explains the hepatic toxicity of ACP, which is responsible for the severe tissue damage observed in the liver (Khovarnagh and Seyedalipour, 2021). Furthermore, ACP-induced vascular congestion and decreased hepatic blood flow can lead to local anoxia, thus promoting the degeneration of hepatic tissues (Mondal et al., 2014). The histological observations obtained in the present study confirm these findings.
           
    In the ACP-treated group, histological observations revealed marked alterations in the testicular structure. The seminiferous tubules appeared distorted and disorganized, separated by widened interstitial spaces. Numerous spermatogenic cells exhibited signs of degeneration accompanied by vacuolization, while desquamation of the germinal epithelium was observed. Moreover, the capsular blood vessels were dilated and congested. These observations are consistent with those reported in previous studies (Zhang et al., 2011; Kong et al., 2017; Zayman et al., 2022; Arıcan et al., 2020).
           
    These lesions can be attributed to oxidative stress induced by ACP, which manifests as increased lipid peroxidation and nitric oxide (NO) production, as well as decreased activity of antioxidant enzymes (Mosbah et al., 2016; Kong et al., 2017; Zhang et al., 2011; Arıcan et al., 2020). This oxidative imbalance leads to damage to sperm DNA, proteins and lipids, thereby disrupting steroidogenesis and spermatogenesis (Walczak-Jedrzejowska et al., 2013; Chainy et al., 1997). Furthermore, oxidative stress alters proliferation and apoptosis processes within the testis, particularly in spermatogonia and primary spermatocytes, through the activation of the p38 MAPK pathway, known to inhibit cell growth and promote apoptosis (Kong et al., 2017; Zhang et al., 2011; Arıcan et al., 2020). Additionally, ACP metabolites generated in the liver could also contribute to these deleterious effects on the testes (Zhang et al., 2011). The histological results obtained in the present study confirm these observations. Conversely, the co-administration of vitamins exerted a protective effect against ACP-induced tissue alterations, consistent with observations reported in rats exposed to ACP and supplemented with vitamins (Zhang et al., 2011; Zayman et al., 2022).
           
    The histopathological alterations induced by ACP were significantly attenuated in rats receiving co-administration of vitamins C and E. The observed improvement in hepatic and testicular tissues could be attributed to the synergistic antioxidant properties of these vitamins. Indeed, several previous studies have demonstrated that vitamins C and E exert a protective role against neonicotinoid-induced oxidative stress by limiting the increase in markers of lipid peroxidation (MDA) and nitric oxide (NO), while stimulating the activity of endogenous antioxidant enzymes (Zhang et al., 2011; El-Gendy et al., 2010; Soujanya et al., 2013). Moreover, Yi-Wang et al. (2012) reported that vitamin E significantly contributes to the reduction of acetamiprid residues in mouse hepatic tissues, underscoring its key role in hepatic detoxification and the preservation of cellular integrity.

    CONCLUSION

    In conclusion, subacute exposure to acetamiprid induced significant histopathological alterations in the liver and testes of adult male rats, including hepatocellular necrosis, vascular congestion, inflammatory infiltration and marked disruption of the seminiferous tubule architecture. In addition, alternate-day co-administration of vitamins C and E markedly reduced these hepatic and testicular lesions, leading to partial restoration of normal tissue architecture. This protective antioxidant effect may be of particular relevance for occupationally exposed populations, such as agricultural workers, who are frequently in contact with neonicotinoid pesticides. However, vitamin supplementation should be regarded as a supportive and temporary protective strategy, while the priority remains the reduction of acetamiprid use and the development of safer alternatives.

    ACKNOWLEDGEMENT

    The authors sincerely thank the staff of the ANAPAT Laboratory, Bouzidi Lakhder Hospital, Bordj Bou Arreridj, Algeria, for their technical support and valuable collaboration.
     
    Disclaimers
     
    The views and conclusions presented in this article are those of the authors and do not necessarily reflect the positions of their affiliated institutions. The authors assume responsibility for the accuracy and completeness of the information provided; however, they disclaim any liability for direct or indirect damages arising from the use of this content.
     
    Informed consent
     
    All experimental procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee and were conducted in accordance with established guidelines for the care and handling of laboratory animals.

    CONFLICT OF INTEREST

    The authors declare no competing interests. This research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Furthermore, no external funding or sponsorship had any role in the study design, data acquisition, analysis, decision to publish, or manuscript preparation.

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