Mechanisms of Cypermethrin-Induced Reproductive Toxicity

I. INTRODUCTION

Cypermethrin, a widely utilized synthetic pyrethroid insecticide, has garnered significant attention due to its effectiveness in pest control across various environments, including agricultural and residential settings. Its chemical formula, C22H19Cl2NO3 reveals a complex molecular structure characterized by the presence of a cyano group and a racemic mixture of isomers, each contributing to its insecticidal properties (Kumar Singh et al., 2012; Zhou et al., 2019). The IUPAC nomenclature-cyano (3-phenoxyphenyl) methyl3- (2, 2-dichloroethenyl)-2, 2-dimethylcyclopropane-1-carboxylate-underscores its sophisticated chemical makeup, advancing our understanding of how pyrethroids interact with pest populations (Zhou et al., 2019).

Cypermethrin's application spans a wide range of uses, from protecting crops (Dina, 1988) to controlling household pests like ants and cockroaches, making it a common component in popular insecticide brands like Raid and Ortho (Ali et al., 2022). However, its extensive use raises important questions regarding its safety and potential implications for human health and the environment.

Understanding the reproductive toxicity of cypermethrin is paramount, as research indicates alarming findings related to its impact on reproductive health in animal models. Studies have shown that exposure can result in reduced testosterone levels and structural alterations in sperm in male rats, alongside developmental delays in offspring and evidence of genetic damage through increased chromosomal abnormalities (Ikpeme et al., 2016; Alaa-Eldin et al., 2017; Abdel-Razik et al., 2021). These effects necessitate a deeper investigation into the safety profile of cypermethrin, especially given its classification as a potential human carcinogen due to its association with higher tumor frequencies in exposed animals (Ferre et al., 2018).

This review aims to meticulously analyze cypermethrin's chemical properties and classifications, evaluate its prevalence in various applications, and investigate the reproductive toxicity linked to its exposure. By synthesizing existing research, this review seeks to illuminate both the benefits and risks associated with cypermethrin, ultimately guiding safer practices in its application and informing regulatory considerations.

1.1 Search Strategy

A comprehensive search strategy was designed to explore the mechanisms underlying cypermethrin-induced reproductive toxicity, focusing on peer-reviewed studies published in scientific journals. This involved systematic searches in databases such as PubMed, Scopus, and Web of Science, using keywords like "cypermethrin," "reproductive toxicity," "mechanisms," and "endocrine disruption." By synthesizing findings from various research articles, we aimed to elucidate the pathways through which cypermethrin exerts its adverse effects on reproductive health.

II. MECHANISM OF ACTION OF CYPERMETHRIN

Cypermethrin exerts its effects primarily through interactions with ion channels and has significant implications for the endocrine system, influencing both neuronal activity and hormonal balance in various organisms.

2.1 Interaction with Ion Channels: Sodium Channel Modulation

Cypermethrin's primary mechanism of action involves its modulation of sodium channels located in neuronal cells (Kumar Singh et al., 2012; Ali, 2020). The compound binds to voltage-gated sodium channels, which are critical for the initiation and propagation of action potentials in neurons. This binding leads to prolonged activation of these channels, resulting in persistent depolarization. The consequences of this alteration include increased neuronal excitability and elevated neurotransmitter release, which can disrupt the normal signaling pathways within the nervous system. Such disruptions are problematic as they may culminate in neurotoxic effects, characterized by symptoms such as paralysis and death in target pest species (Ganguly et al., 2023). This modulation of sodium channels stands out as a core mechanism through which cypermethrin demonstrates its insecticidal properties, showcasing the compound's effectiveness against a wide range of insect pests.

2.1.1 Effects on Neuronal Signaling

The prolonged activation of sodium channels due to cypermethrin exposure can induce excessive neuronal firing. This hyperactivity not only disrupts typical neuronal signaling but may also lead to neurodegenerative effects over time. Research has indicated that cypermethrin can induce oxidative stress in neuronal cells, which contributes significantly to cellular damage and functional impairment (Ali et al., 2020; Abd El-Moneim Ibrahim et al., 2020; Zhao et al., 2021). Such oxidative stress pathways are integral to understanding the potential long-term impacts of cypermethrin, both in terms of ecological harm and implications for human health, given the closeness of some neurological mechanisms across species.

2.2 Involvement of the Endocrine System

2.2.1 Endocrine Disruption Potential

Cypermethrin is classified as an endocrine-disrupting chemical (EDC), meaning it has the potential to interfere with hormonal functions within biological systems. This is particularly evident in its capacity to alter levels of essential steroid hormones such as testosterone and estrogen. Research has highlighted that exposure to cypermethrin can lead to significant reductions in testosterone levels, as well as impairments in spermatogenesis in male mammals (Al-Hamdani et al., 2011). Cypermethrin has been recognized as a full endocrine disruptor due to its demonstrated effects on hormone levels and reproductive health, raising concerns about its long-term implications for wildlife and human populations alike (Saillenfait et al., 2017; Guo et al., 2017; Aziz et al., 2023).

2.2.2 Impact on Hormone Levels

Chronic exposure to cypermethrin has been associated with numerous reproductive issues, such as reduced fertility and alterations in hormone levels (Liu et al., 2006). For example, studies conducted on male mice found that even low doses of cypermethrin exposure resulted in significant histopathological changes within reproductive organs, along with a decrease in serum testosterone levels (Wang et al., 2021; Al-Hamdani et al., 2011). Furthermore, cypermethrin's influence extends beyond mammals; it has also been observed to affect the hypothalamic-pituitary-gonadal (HPG) axis in fish. This underscores the compound's pervasive disruptive effects across a variety of species, illustrating the far-reaching consequences of cypermethrin exposure on reproductive health and endocrine function (Ganguly et al., 2023).

III. EFFECTS OF CYPERMETHRIN ON THE MALE REPRODUCTIVE SYSTEM

Cypermethrin is a widely used synthetic pyrethroid insecticide that has garnered attention due to its potential adverse effects on male reproductive health. Numerous studies have documented significant impairments in spermatogenesis, hormonal balance, and overall fertility outcomes linked to cypermethrin exposure, highlighting the necessity for deeper investigation into this issue.

3.1 Spermatogenesis Impairment

3.1.1 Analysis of Sperm Quality and Quantity

Research into the effects of cypermethrin on sperm quality has consistently shown a considerable decline in critical parameters such as sperm count, motility, and viability. For instance, animals subjected to cypermethrin treatment exhibit a remarkable reduction in daily sperm counts and epididymal sperm counts when compared to control groups, revealing the detrimental impact on reproductive potential (Katragadda et al., 2021; Sharma et al., 2018). Furthermore, histopathological examinations of the testes have unveiled significant damage, characterized by reduced weights of reproductive organs and altered cellular architectures within the seminiferous tubules. These alterations are indicative of impaired spermatogenesis and suggest a direct correlation between cypermethrin exposure and male reproductive dysfunction (Abd El-Hameed, A. M., & Mahmoud, 2020; Katragadda et al., 2021).

3.1.2 Histopathological Findings in Testes

Detailed histological analyses highlight pronounced degeneration of germ cells and severe impairment of spermatogenesis, attributed to cypermethrin toxicity. This degradation is often associated with oxidative stress, which leads to significant cellular damage, particularly affecting Leydig cells responsible for testosterone production. Consequently, the toxicity of cypermethrin has a cascading effect on the entire male reproductive system, interrupting the delicate balance required for normal spermatogenesis (Solati et al., 2010; Sharma et al., 2018).

3.2 Hormonal Changes

3.2.1 Alterations in Testosterone Levels

Exposure to cypermethrin has been shown to lead to significant decreases in serum testosterone levels. This reduction can be traced back to the insecticide's antiandrogenic properties and its ability to disrupt the activity of steroidogenic enzymes, such as 3β-HSD and 17β-HSD, which are crucial for testosterone biosynthesis (Katragadda et al., 2021; Sharma et al., 2018). Additionally, lower testosterone levels correlate with decreased expression of steroidogenic acute regulatory protein (StAR), a key player in the transport of cholesterol essential for testosterone production (Katragadda et al., 2021; Sharma et al., 2018).

3.2.2 Effects on Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH)

Cypermethrin treatment has been associated with alterations in gonadotropin levels, particularly through the observation of increased LH and FSH concentrations. These changes are likely a result of negative feedback mechanisms triggered by the observed reductions in testosterone levels. Interestingly, some studies also suggest that prolonged exposure to cypermethrin may ultimately lead to decreased levels of LH and FSH as well, indicating a complex and potentially detrimental endocrine disruption (Solati et al., 2010; Sharma et al., 2018; Abd El-Hameed, A.M., & Mahmoud, 2020).

3.3 Fertility Outcomes

3.3.1 Impact on Mating Behavior

Male rats that have been exposed to cypermethrin demonstrate altered mating behaviors, which may act as a contributing factor to reduced fertility rates. The observed impairments in sexual behavior are likely intertwined with the hormonal disruptions induced by cypermethrin exposure, further compromising reproductive outcomes (Solati et al., 2010; Abd El-Hameed, A. M., & Mahmoud, 2020).

3.3.2 Consequences on Pregnancy Rates

The fertility outcomes following cypermethrin exposure are further diminished by increased rates of pre- and post-implantation losses observed in mating studies involving treated males (Katragadda et al., 2021). This finding suggests that cypermethrin impacts male reproductive health not only directly but also significantly influences the overall reproductive success rates of mating pairs, indicating a broad spectrum of reproductive challenges linked to this insecticide.

IV. EFFECTS OF CYPERMETHRIN ON THE FEMALE REPRODUCTIVE SYSTEM

Cypermethrin has garnered increasing attention due to its significant adverse effects on the female reproductive system, as evidenced by a growing body of research. The detrimental impacts of cypermethrin can be categorized into three principal areas: ovarian function and hormone production, effects on implantation and fetal development, and implications for reproductive longevity.

4.1 Ovarian Function and Hormone Production

4.1.1 Disruption of the Menstrual Cycle

Research has demonstrated that exposure to cypermethrin is associated with alterations in the estrous cycle of female rats, serving as a model for understanding potential implications in humans (Zhou et al., 2018; Wang et al., 2019). Specifically, studies have identified a dose-dependent decrease in luteinizing hormone (LH) levels, a critical hormone in regulating ovulation (Al-Hamdani & Yajurvedi, 2017; Obinna & Agu, 2019). Such hormonal disruptions can lead to abnormalities in the menstrual cycle, specifically prolonged diestrus phases, which may ultimately result in infertility issues for affected females. The intricate balance of hormones necessary for a regular menstrual cycle and successful ovulation can be significantly disturbed by exposure to this pesticide (Zhou et al., 2018; Obinna & Agu, 2019).

4.2 Altered Ovarian Morphology and Function

Histological assessments of ovarian tissues from cypermethrin-exposed females have revealed notable morphological alterations (Singh et al., 2008; 2020). These changes include luteinization of ovarian follicles, a reduction in primordial follicular reserves, and the presence of multi-oocyte follicles, all of which suggest compromised ovarian functionality. Furthermore, cypermethrin exposure has been linked to oxidative stress in uterine tissues, contributing to a broader spectrum of reproductive and developmental problems, with profound implications for overall reproductive health (Obinna & Agu, 2016; Singh et al., 2020). This points to the pesticide's potential to instigate long-term changes in the ovarian environment.

4.3 Impacts on Implantation and Fetal Development

4.3.1 Maternal Health Effects

Maternal exposure to cypermethrin has been shown to induce adverse effects such as embryonic resorption and stillbirths in pregnant rats (Al-Hamdani, & Yajurvedi, 2017; Singh et al., 2020). These findings highlight the pesticide's detrimental impact on maternal health, particularly its ability to cause histological damage to maternal liver tissue, which may compromise essential physiological functions during pregnancy. The integrity of maternal health is vital for the development of the fetus, and disruption in this area can lead to a cascade of negative outcomes, including compromised gestational success and the health of the offspring (Al-Hamdani, & Yajurvedi, 2017; Singh et al., 2020).

4.3.2 Consequences for Fetal Outcomes

The negative ramifications of cypermethrin exposure extend beyond maternal health to affect fetal development directly (Obinna & Agu, 2019; Singh et al., 2020). Research findings indicate a concerning increase in pre-implantation loss and a significant reduction in litter sizes among the offspring of cypermethrin-exposed mothers (Singh et al., 2020). This suggests a disturbing trend where the health and viability of newborns are adversely compromised. Furthermore, instances of perinatal exposure have been connected to long-term reproductive dysfunction in female offspring of the first filial generation (F1), indicating potential transgenerational effects that could unfurl across multiple generations, thereby exacerbating the impact of this environmental toxin on reproductive health (Obinna & Agu, 2019; Singh et al., 2020).

4.3.3 Impact on Reproductive Longevity

Cypermethrin's adverse effects on reproductive longevity are particularly alarming, as studies have indicated its capacity to induce irreversible changes in ovarian activity at specific dosage levels (Al-Hamdani, & Yajurvedi, 2017; Marettova et al., 2017). Research has shown that even exposure to low doses of cypermethrin can culminate in infertility over time, signaling a concerning trend whereby long-term reproductive consequences may follow exposure to this pesticide (Al-Hamdani, & Yajurvedi, 2017; Marettova et al., 2017). The cumulative nature of hormonal disruption, coupled with morphological changes in the ovaries, poses a significant risk for the reproductive lifespan of females. This decline in reproductive potential underlines the need for careful consideration of cypermethrin usage and exposure, especially in contexts related to female reproductive health and fertility (Al-Hamdani, & Yajurvedi, 2017; Marettova et al., 2017). The evidence presented emphasizes the urgent need for further investigation into the mechanisms underlying cypermethrin's harmful effects and the potential establishment of more stringent regulations regarding its use to safeguard female reproductive health.

V. EXPERIMENTAL EVIDENCE OF CYPERMETHRIN'S INDUCED REPRODUCTIVE TOXICITY

Given its widespread application, there has been a growing concern regarding its potential impact on human health, particularly in relation to reproductive toxicity. Numerous studies across various biological models have sought to elucidate the effects of cypermethrin on reproductive health. This review aims to provide a detailed overview of existing experimental evidence derived from animal studies, in vitro experiments, and human exposure assessments.

5.1 Animal Studies

5.1.1 Rodent Models

In many reproductive toxicity studies, rodent models, particularly rats and mice, are employed due to their genetic, biological, and behavioral similarities to humans. For example, a pivotal study that investigated perinatal exposure to cypermethrin in female F1 generation rats revealed noteworthy findings. While the exposure did not significantly alter the estrous cycle or most serum sex hormone levels—except for a marked decrease in luteinizing hormone (LH)—it led to persistent phases of diestrus in these animals. Such prolonged periods of diestrus can disrupt the normal reproductive cycle, potentially culminating in infertility (Obinna & Agu, 2019). This highlights the need for further investigation into the long-term effects of cypermethrin exposure on reproductive capabilities.

Another critical study assessed the impact of cypermethrin on pregnant female albino rats. Results indicated a significant reduction in neonatal birth weights, suggesting suboptimal development in utero. Furthermore, increased rates of embryonic resorption—a condition where embryos fail to implant or are reabsorbed by the body—and stillbirths were noted among the treated groups (Obinna & Agu, 2016). These alarming indicators of reproductive toxicity raise concerns regarding the implications of cypermethrin exposure during sensitive developmental windows.

5.1.2 Effects on Fertility and Reproductive Parameters

Investigations into the fertility effects of cypermethrin highlight its role as an endocrine disruptor. In male rabbits subjected to cypermethrin exposure, significant toxicopathological changes were documented, which negatively impacted semen quality and overall testicular health (Ahmad et al., 2012). Such findings underscore the potential for cypermethrin to disrupt male reproductive function, which could have far-reaching implications for fertility.

In contrast, female rats demonstrated severe toxicity manifestations following exposure to varying doses of cypermethrin. Observable symptoms included substantial reductions in body weight along with compromised reproductive health parameters, indicating a clear negative impact on female fertility and reproductive potential (Shuklan et al., 2023). Collectively, these findings emphasize the potential risks associated with cypermethrin exposure for both genders.

5.2 In Vitro Studies

5.2.1 Impact on Gamete Viability and Function

In vitro research has revealed that cypermethrin has a detrimental impact on gamete viability and function. Specifically, studies indicate that exposure to this insecticide can lead to impaired sperm motility and alterations in motility patterns. Such impairments suggest that cypermethrin exposure may have significant implications for reproductive outcomes, potentially reducing the likelihood of successful fertilization (Shuklan et al., 2023).

5.2.2 Effects on Reproductive Cell Lines

Investigations involving reproductive cell lines have highlighted the cellular mechanisms through which cypermethrin may exert its toxic effects. Notably, exposure to cypermethrin has been shown to induce oxidative stress within these cells, leading to cellular damage and impairments in reproductive function (Shuklan et al., 2023). Moreover, the antiandrogenic effects of pyrethroids have been observed in various assays, implicating disrupted hormonal signaling pathways that are essential for normal reproductive processes (Shuklan et al., 2023). These findings underscore the need for continuous monitoring of cypermethrin's effects at the cellular level.

5.3 Human Exposure Studies

5.3.1 Epidemiological Data

Epidemiological studies have been pivotal in linking chronic exposure to pyrethroids, including cypermethrin, with adverse reproductive outcomes in humans (Koureas et al., 2012; Burns & Pastoor, 2018; Wang et al., 2020). Although establishing direct causal relationships is challenging due to the presence of confounding factors, a discernible association has been noted between pyrethroid exposure and altered hormone levels in adult males. Such hormonal changes could serve as indicators of potential fertility issues, warranting further investigation into the long-term effects of cypermethrin exposure on reproductive health in humans (Shuklan et al., 2023).

5.3.2 Case Studies and Reported Outcomes

Numerous case studies have documented significant reproductive health concerns among individuals exposed to cypermethrin through occupational or environmental routes (Obinna & Agu, 2016; Ullah et al., 2018). Reported issues include decreased fertility rates and increased instances of pregnancy complications, although comprehensive data remains limited. The variability in exposure levels and individual susceptibility complicates the establishment of a clear causative link, underscoring the need for additional research to elucidate the full scope of cypermethrin's impact on human reproductive health (Obinna & Agu, 2016).

VI. MECHANISMS OF CYPERMETHRIN-INDUCED CELLULAR AND MOLECULAR TOXICITY

6.1 Oxidative Stress and Its Implications

6.1.1 Generation of Reactive Oxygen Species (ROS)

Cypermethrin exposure is characterized by an elevation in the production of Reactive Oxygen Species (ROS), which play a pivotal role in triggering oxidative stress across various cell types, including but not limited to macrophages and hepatocytes. The excessive generation of ROS initiates a cascade of oxidative damage that is closely linked to significant cellular injury through mechanisms such as lipid peroxidation and protein oxidation. These events can severely disrupt cellular functions and compromise cellular integrity, resulting in a range of detrimental effects on cell viability and health (Huang et al., 2016; Elblehi et al., 2023; Hussain et al., 2023).

6.1.2 Cellular Damage and Apoptosis

The accumulation of ROS not only leads to oxidative stress but also results in substantial DNA damage and the initiation of apoptosis. Research has established that cypermethrin can induce apoptotic pathways through signaling mechanisms involving Jun N-terminal Kinase (JNK) and Extracellular signal-Regulated Kinase (ERK). Notably, the inhibition of these pathways has shown potential in partially reversing the apoptotic effects induced by cypermethrin. The morphological features of apoptosis are evident in affected cells, displaying characteristics such as nuclear fragmentation and chromatin condensation, indicative of the cell undergoing programmed cell death (Huang et al., 2016; Ashafaq et al., 2023).

6.2 Inflammatory Responses

6.2.2 Cytokine Release and Its Effects on Reproduction

Cypermethrin exposure is strongly associated with an increase in the levels of pro-inflammatory cytokines, including Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α) (Elblehi et al., 2023; Hussain et al., 2023). Elevated levels of these cytokines have been shown to disrupt reproductive health by altering hormonal balances and impairing various reproductive processes. The implications of the inflammatory response are not confined to local tissues but may extend systemically, contributing to broader reproductive health concerns and issues (Elblehi et al., 2023; Hussain et al., 2023).

6.3 Genetic and Epigenetic Effects

6.3.1 DNA Damage and Repair Mechanisms

Cypermethrin has been documented to inflict significant DNA damage across a variety of organisms, including zebrafish and mammalian models (Jin et al., 2011; Paravani et al., 2018, 2019). Such damage can overwhelm cellular repair mechanisms, consequently leading to mutations and potential carcinogenic outcomes. The inability of cells to effectively repair DNA lesions instigated by cypermethrin exposure raises concerns regarding long-term genetic stability and the risks of oncogenesis (Jin et al., 2011).

6.3.2 Epigenetic Changes Influencing Reproductive Health

The exposure to cypermethrin may induce epigenetic modifications that significantly influence gene expression patterns related to reproductive health (Irani et al., 2022; Song et al., 2022; Hussain et al., 2023). These modifications can alter the development and functionality of germ cells, giving rise to substantial long-term reproductive complications (Hussain et al., 2023). The ramifications of these epigenetic changes underscore the necessity for further investigation into how environmental toxins like cypermethrin can alter genetic expression and consequently affect reproductive outcomes over successive generations (Hussain et al., 2023).

6.4 Signaling Pathways Affected by Cypermethrin

6.4.1 Role of Apoptosis in Reproductive Toxicity

The activation of apoptotic pathways, primarily driven by oxidative stress through ROS generation, is critical in understanding cypermethrin's reproductive toxicity. The dysregulation of these apoptotic pathways can lead to compromised germ cell viability and functionality, raising vital questions about the long-term implications of such toxicity on reproductive health (Huang et al., 2016; Ashafaq et al., 2023).

6.4.2 Alterations in Gene Expression Related to Reproduction

Cypermethrin exposure is implicated in the alteration of gene expression associated with critical reproductive processes (Elblehi et al., 2023; Hussain et al., 2023). These alterations may disrupt normal processes such as spermatogenesis (the development of sperm) and oocyte maturation (the maturation of eggs), significantly affecting overall fertility and reproductive success (Elblehi et al., 2023; Hussain et al., 2023).

6.5 Impact on Germ Cell Development and Function

6.5.1 Effects on Spermatogenesis

Research has indicated that cypermethrin adversely influences spermatogenesis, primarily through the induction of oxidative stress and subsequent apoptosis in Sertoli cells, which are essential for the proper development of sperm (Ashafaq et al., 2023). The implications of such effects extend to the fertility potential of males exposed to this insecticide, highlighting critical concerns regarding reproductive health in male populations (Ashafaq et al., 2023).

6.5.2 Effects on Oocyte Maturation

Similarly, cypermethrin exposure has been shown to substantially impair oocyte maturation, predominantly via mechanisms associated with oxidative stress. These impairments can directly affect fertility outcomes, suggesting that exposure to cypermethrin poses a profound risk to female reproductive health and the quality of eggs produced (Jin et al., 2011).

VII. SEX DIFFERENCES IN CYPERMETHRIN TOXICITY

Research indicates that there are significant sex differences in the toxicity of cypermethrin, a widely used pyrethroid insecticide. Studies have demonstrated that male and female subjects exhibit different responses to cypermethrin exposure, particularly concerning physiological and biochemical parameters. This variation is crucial for understanding the safety and environmental implications of cypermethrin use.

7.1 Physiological Effects

In various animal studies, cypermethrin exposure has shown to result in differing impacts on body and organ weights between the sexes. For example, male rats have demonstrated markedly more pronounced reproductive toxicity, which includes lower testosterone levels and impaired spermatogenesis following exposure to cypermethrin. This response is notably more severe in males compared to females, highlighting potential susceptibility differences associated with sex (Grewal et al., 2010). It has been observed that male animals often suffer from additional physiological stressors that further exacerbate the toxic effects of cypermethrin, leading to a heightened risk of reproductive issues.

7.2 Biochemical Responses

Significant differences in biochemical markers have been identified based on sex. For instance, levels of liver enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are indicative of liver function and damage, tend to fluctuate in response to cypermethrin exposure. Alongside these markers, indicators of oxidative stress, including malondialdehyde levels, as well as metrics for DNA damage, such as micronuclei formation, also vary. Males typically exhibit a greater tendency towards higher susceptibility to oxidative stress and genotoxic effects. This greater vulnerability suggests a heightened risk of organ damage and reproductive impairment as a consequence of cypermethrin exposure (Seven et al., 2022; Grewal et al., 2010). These biochemical alterations not only reflect the immediate toxicological impact but also provide insight into long-term health risks.

7.3 Genotoxicity

The genotoxic effects of cypermethrin have been extensively documented, revealing that it can induce chromosomal abnormalities in both male and female mice; however, the frequency and severity of these chromosomal aberrations can diverge based on sex. Research indicates that male mice are more prone to exhibit higher rates of chromosomal aberrations in bone marrow cells in comparison to their female counterparts, thereby suggesting an increased risk of genetic damage arising from exposure to cypermethrin in males (Seven et al., 2022; Grewal et al., 2010). This distinction underscores the need for sex-specific evaluations in toxicological studies involving cypermethrin.

VIII. ROLE OF GENETIC AND HORMONAL FACTORS

The differences in sensitivity to cypermethrin toxicity between males and females can be attributed to several genetic and hormonal factors that significantly shape the response to toxic exposures.

8.1 Hormonal Influence

Hormonal levels significantly affect how each sex metabolizes toxins like cypermethrin. For instance, testosterone has been shown to influence the metabolism of various xenobiotics, leading to increased susceptibility in males (Abd El-Hameed & Mahmoud, 2020). This increased vulnerability may result from relatively lower detoxification capabilities compared to females, who typically have higher levels of estrogen. Estrogen has been suggested to provide protective effects against certain toxins, potentially contributing to the observed differences in sensitivity to cypermethrin (Elser et al., 2020; Ganguly et al., 2023). Therefore, hormonal context plays a pivotal role in defining the toxic thresholds and responses in males versus females.

8.2 Genetic Factors

Beyond hormonal influences, genetic predispositions also play a crucial role in determining individual sensitivity to toxic substances. Variations in genes responsible for the metabolism of pyrethroids can result in differing toxicity levels observed in males versus females. For example, genetic polymorphisms in cytochrome P450 enzymes, which are essential for detoxification processes, may exhibit sex-specific expression patterns. These variations in enzyme activity can influence overall susceptibility to cypermethrin, with implications for health outcomes following exposure (Ganguly et al., 2023; Han et al., 2024). This aspect emphasizes the importance of considering genetic background when assessing risk and vulnerability to toxic substances on a sex-specific basis.

8.3 Intergenerational Effects

Moreover, exposure to cypermethrin during critical developmental periods can yield lasting impacts on offspring, with maternal exposure affecting fetal development in ways that differ based on the sex of the offspring. Studies have indicated that prenatal exposure can disrupt neurodevelopmental pathways, with significant differences noted between male and female offspring. This observation suggests that the hormonal environments present during gestation could influence these developmental outcomes, potentially leading to sex-specific vulnerabilities that persist beyond prenatal stages (Elser et al., 2020; Han et al., 2024).

IX. ENVIRONMENTAL AND ECOLOGICAL IMPLICATIONS OF CYPERMETHRIN TOXICITY

Cypermethrin presents significant environmental and ecological challenges, particularly with respect to wildlife reproduction and the regulatory framework governing its use. As its prevalence in agricultural practices continues to rise, understanding the extensive implications of cypermethrin toxicity becomes increasingly vital.

9.1 Impact on Wildlife Reproduction

9.1.1 Reproductive Toxicity

Research reveals that exposure to cypermethrin can lead to substantial reproductive toxicity across various animal models. For instance, studies conducted on pregnant rats have demonstrated that cypermethrin significantly reduces litter weight and adversely affects fetal development. This occurs likely due to disruptions in placental function and nutrient uptake, which are critical during gestation (Obinna & Agu, 2016;

Sharma et al., 2018). Furthermore, the administration of cypermethrin has resulted in decreased weights of vital reproductive organs, including the testes and epididymis, alongside diminished sperm counts and motility (Sharma et al., 2014; 2018). These detrimental effects imply that chronic exposure to cypermethrin could severely compromise reproductive success in wildlife populations, potentially leading to declines in species numbers and disruptions in local ecosystems.

9.1.2 Effects on Hormonal Profiles

Cypermethrin has also been linked to significant alterations in hormone levels that are essential for reproduction. In studies involving male rats, exposure to cypermethrin led to decreased levels of testosterone and other critical reproductive hormones, which are necessary for normal spermatogenesis (Sharma et al., 2014). The resulting hormonal disruptions may have cascading effects on population dynamics, leading to reduced fertility rates among affected species. The implications of these alterations extend beyond individual organisms, threatening the stability and resilience of entire populations.

9.1.3 Broader Ecological Consequences

The impact of cypermethrin toxicity is not confined to direct reproductive effects; it can also disrupt behavioral patterns within wildlife populations. For instance, altered reproductive behaviors stemming from neurological impacts may lead to decreased mating success, further jeopardizing population stability (Grewal et al., 2010). The cumulative ramifications of these disruptions could result in long-term ecological imbalances, particularly within ecosystems that heavily depend on vulnerable species. As key players in food webs, the decline of specific wildlife can trigger ripple effects throughout the ecosystem, affecting plant diversity, predation dynamics, and overall habitat health.

9.2 Considerations for Pesticide Regulation and Usage

9.2.1 Regulatory Challenges

Given the alarming evidence of cypermethrin's toxicity to wildlife, there is an urgent need to address regulatory challenges surrounding its use. While cypermethrin has received approval for agricultural applications, the ongoing potential for chronic exposure via food chains necessitates a critical reevaluation of current pesticide regulations (Sharma et al., 2014; Sharma et al., 2018). Regulatory agencies must take into account not only the immediate effects stemming from pesticide application but also the extensive long-term ecological impacts on non-target species. Failure to adequately assess these risks could precipitate further declines in sensitive wildlife populations and disrupt the ecological balance.

9.2.2 Usage Guidelines

In an effort to mitigate the risks associated with cypermethrin usage, it is crucial to establish comprehensive guidelines that emphasize integrated pest management (IPM) strategies. These strategies should minimize reliance on chemical pesticides by promoting a diverse range of pest control methods, including biological control agents, crop rotation, and organic farming practices (Shuklan et al., 2023). Additionally, public awareness campaigns can play a significant role in educating farmers and agricultural stakeholders about the potential ecological consequences of pesticide usage. By fostering a culture of sustainability and responsible pesticide application, the agricultural sector can shift toward practices that preserve biodiversity and maintain ecological integrity.

9.2.3 Research and Monitoring

Ongoing research into the ecological impacts of cypermethrin is paramount for safeguarding wildlife and the environments they inhabit. Longitudinal studies that monitor wildlife populations in regions with high pesticide utilization can provide critical data regarding the long-term effects of exposure. Furthermore, establishing stricter monitoring protocols for pesticide residues in agricultural products can help protect both human health and environmental integrity (Grewal et al., 2010; Shuklan et al., 2023). By generating robust data and maintaining vigilance regarding pesticide application, stakeholders can better inform regulatory frameworks and promote agricultural practices that are more attuned to ecological health.

X. MITIGATION STRATEGIES OF CYPERMETHRIN-INDUCED REPRODUCTIVE TOXICITY

10.1 Antioxidants

10.1.1 Vitamin C, E & Curcumin

Numerous scientific studies have demonstrated that Vitamin C and Curcumin has a significant mitigating effect on the reproductive toxicity that can be induced by cypermethrin (Obinna & Agu, 2016; Ziada et al., 2020), particularly in pregnant rat models. The administration of Vitamin C resulted in a notable decrease in the rates of embryonic resorption and stillbirths, with concurrent improvements observed in neonatal birth weights when compared to untreated control groups (Obinna & Agu, 2016). These findings suggest that antioxidants such as Vitamin C may be effective in counteracting the oxidative stress that arises from exposure to cypermethrin, thereby offering potential therapeutic benefits during pregnancy. Studies have shown that Cypermethrin exposure leads to a marked increase in oxidative stress levels, as evidenced by elevated concentrations of malondialdehyde (MDA) in both serum and tissue samples of affected rats. MDA serves as a biomarker for lipid peroxidation, indicating that cellular membranes are being compromised due to oxidative damage (Ziada et al., 2020). Concurrently, the activities of key antioxidant enzymes, crucial for mitigating oxidative damage, such as superoxide dismutase (SOD) and catalase, were notably diminished, further emphasizing the detrimental effects of Cypermethrin on oxidative balance. In light of these findings, the protective roles of Vitamins C and Curcumin have gained attention as potential countermeasures against oxidative stress induced by pesticide exposure (Ziada et al., 2020). When administered in combination, these antioxidants significantly reduced MDA levels, signifying a decrease in lipid peroxidation and an overall improvement in oxidative status. The enhancement of antioxidant enzyme activity observed with the combination treatment, particularly in SOD and catalase, suggests a reinvigoration of the body's natural defense mechanisms against oxidative stress. The biochemical improvements following the combined administration of Vitamins C and Curcumin underscore their protective effects against Cypermethrin-induced toxicity. Parameters disrupted by the toxic effects of the pesticide showed normalization, indicating a restoration of physiological balance (Ziada et al., 2020). This reveals a promising avenue for therapeutic interventions aimed at ameliorating the oxidative damage and biochemical disruptions caused by pesticide exposure, emphasizing the importance of antioxidants in safeguarding health against environmental toxins.

In addition to their antioxidant properties, vitamins C and E has also demonstrated a remarkable ability to prevent apoptosis, a form of programmed cell death that can be detrimental to cellular health (Bhardwaj et al., 2018). The administration of these vitamins significantly reduces caspase-3 activity, an essential executor of apoptosis, thereby suggesting that they play a protective role in cellular survival. Histological analyses indicate that supplementation with vitamins C and E helps maintain the structural integrity of testicular tissues, effectively preventing the degeneration of spermatogonial cells (Bhardwaj et al., 2018). This preservation of testicular architecture is pivotal for the overall health and functionality of the male reproductive system. Ultimately, the protective effects of vitamins C and E against oxidative stress, particularly in the context of cypermethrin (CYP)-induced toxicity, can have profound implications for male fertility (Bhardwaj et al., 2018). By safeguarding spermatogonial cells from oxidative damage and subsequent loss, these vitamins contribute to the maintenance of reproductive health. Thus, their supplementation may serve as a valuable strategy for enhancing male fertility and providing a countermeasure against oxidative stress-induced reproductive disorders.

Molavi et al.'s 2016 study revealed that cypermethrin significantly affects ovarian health in rats, particularly follicular atresia. The study found an increase in atretic follicles in rats exposed to cypermethrin, with the early antral and antral stages being the most affected. This raises concerns about the reproductive implications of pesticide exposure, particularly disrupting normal ovarian function. The study also revealed significant biochemical alterations, with reduced serum estradiol levels, indicating impaired ovarian function. However, the introduction of vitamin E in conjunction with cypermethrin showed a protective role, reducing the incidence of follicular atresia and improving serum estradiol levels, suggesting restoration of normal ovarian function. The protective effects of vitamin E may be attributed to its role in energy metabolism, counteracting oxidative stress induced by cypermethrin. Future research could explore interventions targeting oxidative damage and energy homeostasis to mitigate reproductive toxicity associated with pesticide exposure.

10.1.2 Curcumin and Quercetin

Sharma et al.'s 2018 study found that curcumin and quercetin can protect against reproductive system impairment caused by synthetic pyrethroid insecticides, specifically cypermethrin and deltamethrin, in male Wistar rats. The antioxidants reduced reproductive toxicity and oxidative damage, leading to increased sex organ weights, improved sperm count, and elevated levels of sex hormones. The study also revealed that curcumin and quercetin upregulated essential steroidogenic enzymes, particularly 3β-HSD and 17β-HSD, which play a crucial role in testosterone synthesis. The antioxidants also restored disrupted testicular architecture, indicating a direct cytoprotective effect on tissues. While curcumin showed marginally greater protective effects compared to quercetin when administered alone, the combination of both antioxidants provided superior protection. This suggests the potential for synergistic effects when used together, suggesting new therapeutic interventions for combating reproductive toxicity induced by environmental pollutants.

10.1.3 Resveratrol

Resveratrol, a naturally occurring polyphenolic compound found in various plants, has been investigated for its protective properties against testicular damage associated with cypermethrin exposure. Research indicates that resveratrol can enhance sex hormone levels while concurrently reducing markers of oxidative stress. Notably, treatment with resveratrol led to improvements in sperm quality parameters as well as bolstered antioxidant defense mechanisms in male rats exposed to cypermethrin (Sharma et al., 2014). This suggests that incorporating resveratrol into dietary interventions may provide significant protective effects against reproductive impairment resulting from toxic exposures.

10.1.4 L-carnitine-Loaded Nanoparticles

A study by Alyasari and Selman (2023) found that L-carnitine-loaded nanoparticles can protect against cypermethrin, a common pesticide, in adult male rats. Cypermethrin exposure led to reduced testosterone levels and adverse effects on sperm parameters, highlighting the potential risks. Treatment with L-carnitine-loaded nanoparticles restored testosterone levels, improved sperm count and motility, and reduced morphological abnormalities in sperm cells. The enhanced bioavailability of L-carnitine facilitated by the nanoparticles promotes improved cellular energy metabolism and reduces oxidative stress in testicular tissues. This suggests that L-carnitine-loaded nanoparticles may safeguard reproductive functions and represent a promising therapeutic approach for countering pesticide-related reproductive toxicity.

10.1.5 Astaxanthin

Astaxanthin, a potent xanthophyll carotenoid, is known for its unique red pigmentation and antioxidant properties. Although it does not exhibit pro-Vitamin A activity in humans, it may surpass other carotenoids in biological activity, particularly in protecting against cellular damage and enhancing immune function. A study by Sun et al. (2023) revealed that exposure to cypermethrin (CYP), a widely used pyrethroid insecticide, significantly diminishes porcine oocyte maturation rates due to increased reactive oxygen species (ROS) and a decrease in glutathione, leading to oxidative stress. DNA damage was observed in oocytes subjected to CYP, and disruptions in endoplasmic reticulum function were observed. However, when treated with astaxanthin, porcine oocytes exposed to CYP showed a marked improvement in maturation rates and embryo development compared to those exposed only to CYP. Astaxanthin's antioxidant properties play a crucial role in alleviating oxidative stress and repairing DNA damage caused by the insecticide.

10.1.6 L-DOPA

Baghel and Prasad's 2021 study explores the protective effects of L-DOPA against the reproductive toxicity caused by cypermethrin in Japanese quail. Cypermethrin negatively impacts reproductive function in non-target organisms, particularly avian species. The research highlights the need for effective mitigative strategies to address these toxicological concerns. L-DOPA, a precursor to dopamine, was found to alleviate reproductive toxicity associated with cypermethrin exposure. The study found significant improvements in reproductive performance among quails treated with L-DOPA compared to those treated with cypermethrin (Baghel and Prasad, 2021). L-DOPA also restored disrupted hormonal levels, suggesting its role in maintaining endocrine balance. Histopathological assessments confirmed the protective effects, with L-DOPA treatment causing less severe damage to reproductive organs. These results suggest the potential use of L-DOPA as a therapeutic agent in mitigating reproductive toxicity in avian species.

10.1.7 Glutathione

The study by He et al. (2023) investigates the harmful effects of beta-cypermethrin ( -CYP) on porcine oocytes, highlighting its potential to induce meiotic defects. The research emphasizes the importance of understanding the impact of pesticides on animal husbandry and ecological integrity. The study also found that glutathione (GSH) can counteract the adverse effects of -CYP exposure by reducing the incidence of meiotic defects (He et al., 2023). GSH regulates reactive oxygen species (ROS) levels, which can lead to oxidative stress and disrupt meiotic processes (He et al., 2023). This suggests that antioxidants can protect oocyte quality in toxic environments. The research emphasizes the need for therapeutic interventions that use natural compounds like glutathione to combat environmental pollutants' negative effects on reproductive functions.

10.1.8 Date Fruit (Phoenix Dactylifera)

Ubah et al.'s study investigates the impact of date fruit (Phoenix dactylifera) on sperm cell morphology and reproductive hormonal profiles in Wistar rats with cypermethrin-induced male infertility (Ubah et al., 2021). Cypermethrin, a pesticide, has been linked to detrimental reproductive effects, with significant decreases in sperm motility, viability, and mass activity in the cypermethrin-only group. However, date fruit extracts alone showed promising results, improving sperm motility and viability. The combined treatment of date fruit extracts with cypermethrin resulted in better outcomes, indicating the potential of date fruit as a supportive treatment. The study also found lower testosterone and follicle-stimulating hormone levels in the cypermethrin-only group, raising concerns about hormonal balance. The study's statistical analysis revealed significant differences between treatment groups, highlighting the potential of date fruit in mitigating reproductive health challenges posed by environmental toxins.

10.2 Other Nutritional Supplements

10.2.1 Selenium-Enriched Spirulina

In addition to the aforementioned antioxidants, the incorporation of selenium-enriched spirulina has emerged as a promising avenue for research concerning its protective effects against reproductive toxicity (Lu et al., 2021). A study focusing on zebrafish exposed to betacypermethrin revealed that spirulina supplementation could mitigate the adverse effects on reproduction. These findings indicate that nutritional interventions utilizing specific supplements might have broad applicability across different species, potentially enhancing reproductive health and resilience against pesticide-related toxicity (Lu et al., 2021).

10.2.2 Selenium Nanoparticles (SeNPs)

The study by Hozyen et al. (2020) found that selenium nanoparticles (SeNPs) can mitigate reproductive toxicity caused by environmental contaminants like deltamethrin in male rats. The SeNPs-treated group showed significant improvements in reproductive parameters, including increased sperm quality and overall reproductive performance compared to the DLM-only group. Hormonal balance was restored, as elevated testosterone levels were restored. SeNPs also reduced malondialdehyde levels, indicating oxidative damage, and increased antioxidant markers, demonstrating their protective role against DLM-induced oxidative stress. Histological examination revealed that SeNPs preserved the normal architecture and function of testicular tissue, whereas the DLM-only group showed disruptions in testicular morphology, potentially leading to long-term reproductive issues. The study suggests SeNPs could be a potential therapeutic approach to combat reproductive toxicity.

10.3 Regulatory Recommendations and Safety Guidelines

10.3.1 Exposure Limits

It is imperative for regulatory agencies to establish strict guidelines regarding allowable limits of cypermethrin exposure, especially for particularly vulnerable populations, which include pregnant women and children (Roberts et al., 21012). This call for stringent regulations is grounded in the growing body of evidence that underscores the reproductive toxicity associated with cypermethrin exposure. By enacting and enforcing lower exposure limits, we can better protect these at-risk groups from potential harm.

10.3.2 Safety Guidelines

Risk Assessment

It is essential to conduct regular assessments of both environmental and occupational exposure levels of cypermethrin, particularly in agricultural environments where this pesticide is frequently utilized (Ullah et al., 2018; Behnami et al., 2021; Taheri et al., 2023). These risk assessments can provide critical data that can inform safety practices and regulatory decisions, aiming to minimize exposure risks among workers and the surrounding community.

Public Awareness Campaigns

The implementation of public awareness campaigns is vital in educating communities about the potential health risks associated with cypermethrin exposure (Thammachai et al., 2022; Ullah et al., 2018). Such educational efforts can highlight safer alternative pest management strategies and empower individuals to make informed choices regarding exposure, thereby serving to mitigate health risks associated with this pesticide.

10.3.3 Research and Monitoring:

Continued research into the long-term effects of cypermethrin on reproductive health is crucial for understanding the broader implications of its use in agriculture and pest control (Farag et al., 2021). In parallel, robust monitoring programs should be established to track the impacts of cypermethrin exposure on both wildlife and human populations. By fostering ongoing research and effective monitoring, we can better assess the cumulative effects of cypermethrin, ensuring that necessary adjustments to guidelines and practices are made promptly to safeguard reproductive health.

XI. FUTURE RESEARCH DIRECTIONS OF CYPERMETHRIN-INDUCED REPRODUCTIVE TOXICITY

11.1 Gaps in Current Knowledge

11.1.1 Mechanisms of Action

While numerous studies have demonstrated that cypermethrin is capable of inducing reproductive toxicity, the precise molecular mechanisms underlying this phenomenon remain inadequately explored. Notably, the pathways through which cypermethrin disrupts hormonal balance and reproductive functions have not been sufficiently elucidated. Current findings suggest that cypermethrin may interfere with the hypothalamic-pituitary-gonadal (HPG) axis, a crucial network involved in reproductive hormone regulation (Ye et al., 2017; Gan et al., 2023). However, the intricate details of these mechanisms, including specific cellular pathways and molecular interactions, continue to elude researchers, highlighting a critical area for further investigation.

11.1.2 Long-Term Effects

The majority of existing research tends to concentrate on the acute or short-term impacts of cypermethrin exposure. However, there exists a substantial knowledge gap regarding the long-term reproductive effects and potential cumulative toxicity that may arise from chronic exposure to low doses of this pesticide. This is particularly important for at-risk populations, such as pregnant women and developing fetuses, who may be more susceptible to the adverse effects of cypermethrin. Comprehensive studies aimed at elucidating the long-term reproductive consequences of cypermethrin exposure are essential for a more complete understanding of its safety profile (Obinna & Agu, 2016).

11.1.3 Species Variability

A significant portion of the current literature is grounded in research conducted on specific animal models, such as rats and zebrafish. Despite the insights gained from these studies, there is an urgent need for investigations across a broader array of species, particularly human populations, to evaluate the translational relevance of findings related to cypermethrin's reproductive toxicity. Understanding species-specific differences in response to cypermethrin exposure can provide valuable information for risk assessments and regulatory decisions (Sharma et al., 2014).

11.1.4 Protective Agents

Although some preliminary studies have investigated the potential protective effects of antioxidants such as resveratrol and vitamin C against cypermethrin-induced toxicity, the exploration of various protective agents remains limited. A comprehensive evaluation of different antioxidants, as well as hormonal therapies that may mitigate the toxicity associated with cypermethrin exposure, is essential. Such investigations could lead to the identification of effective strategies for minimizing reproductive risks in exposed populations (Sharma et al., 2014).

11.2 Suggestions for Mechanistic Studies and Long-Term Exposures

11.2.1 In Vitro Studies

In vitro research utilizing human-derived cell lines represents a promising avenue for dissecting the cellular mechanisms affected by cypermethrin. Such studies can facilitate the identification of specific gene expressions and signaling pathways involved in the manifestation of reproductive toxicity, providing foundational knowledge that could enhance our understanding of the pesticide's impact on human health.

11.2.2 Longitudinal Animal Studies

The implementation of long-term animal studies designed to simulate chronic exposure to cypermethrin could yield critical insights into its cumulative effects on reproductive health over time. These studies should encompass assessments of reproductive outcomes across multiple generations, allowing researchers to evaluate potential transgenerational effects that may arise from parental exposure to cypermethrin (Obinna & Agu et al., 2016; Lu et al., 2021).

11.2.3 Focus on Endocrine Disruption

Delving into the interactions between cypermethrin and endocrine systems can yield important insights into its role as an endocrine disruptor. Researchers should pay particular attention to cypermethrin's effects on estrogen and testosterone signaling pathways, as well as its impact on fertility-related hormones such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Lu et al., 2021; Aziz et al., 2023). This focus could illuminate the broader implications of cypermethrin exposure on reproductive health.

11.2.4 Environmental Impact Studies

Research that explores the effects of environmental concentrations of cypermethrin on wildlife and ecosystems is also crucial. Specifically, studies should focus on aquatic species, which may serve as sensitive indicators of broader ecological impacts resulting from pesticide exposure (Abd El-Hameed & Mahmoud, 2020). Understanding these dynamics can inform regulatory practices and promote sustainable agricultural practices.

11.2.5 Development of Biomarkers

There is a need to establish biomarkers for the early detection of reproductive toxicity associated with cypermethrin exposure. Identifying such biomarkers could greatly facilitate monitoring and intervention strategies in both animal models and human populations that are exposed to this pesticide. Early detection of reproductive effects could lead to timely interventions and potentially improve health outcomes for vulnerable populations impacted by cypermethrin exposure.

XII. CONCLUSION

Cypermethrin, a pyrethroid insecticide, has been linked to reproductive toxicity due to hormonal disruption, oxidative stress, and genetic damage. Hormonal disruption can lead to developmental abnormalities, changes in reproductive organ function, and impaired fertility. Oxidative stress can cause cellular damage and inflammation, further affecting reproductive tissues. Cypermethrin's genetic effects may induce DNA damage, leading to mutations and potential long-term consequences for reproductive success and viability. Understanding these pathways is crucial for assessing environmental risks associated with cypermethrin exposure. To mitigate these risks, more comprehensive research is needed to investigate the full extent of its reproductive effects across various species, life stages, and exposure scenarios. This will help clarify dose-response relationships and the mechanisms at play, ultimately informing regulatory policies and risk management strategies.

Ethical clearance statement

This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all authors included in the study.

Funding

This research was not funded

CRediT authorship contribution statement

Oyovwi Mega Obukohwo' Udi Onoriode Andrew, Adedeji David Atere, Uchechukwu Gregory Joseph, Ogbutor Udoji Godsday participated in sorting and conceptualizing the manuscript and wrote the manuscript. Oyovwi Mega Obukohwo' Udi Onoriode Andrew, Adedeji David Atere, and Uchechukwu Gregory Joseph organized the literature and presented ideas. Oyovwi Mega Obukohwo and Udi Onoriode Andrew read and approved the submitted version. Oyovwi Mega Obukohwo' Udi Onoriode Andrew, Adedeji David Atere, Uchechukwu Gregory Joseph, Ogbutor Udoji Godsday is responsible for the contribution. Oyovwi Mega Obukohwo and Udi Onoriode Andrew contributed to the revision of the manuscript, read and approved the submitted version.

Declaration of Competing Interest

The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Consent for publication

Not Applicable

ACKNOWLEDGMENTS

We thank the reviewers for their helpful comments.

Data availability

No data was used for the research described in the article.