Female infertility caused by organophosphates: an insight into the latest biochemical and histomorphological findings

Abstract The etiology of female infertility includes a variety of causes, all of which could be induced by environmental pollutants. Organophosphates (OPs) are major constituents of pollutants that cause infertility in aquatic and terrestrial organisms. However, no study has comprehensively reviewed the female fertility-related consequences of exposure to OPs. In this study, the reviewed studies revealed that OPs exposure could elicit detrimental alterations in organ histomorphology, sex hormone levels, and related signaling pathways. Furthermore, preconceptional exposure was associated with poor pregnancy outcomes, where prenatal exposure negatively impacted newborn health. Therefore, it is necessary to restrict the current widespread application of OPs or to alter their chemical structure so not to negatively impact female fertility.


Introduction
Fertility is defined as the capability of an individual to procreate, while infertility refers to an inability of a couple to successfully incept a pregnancy following twelve months of unprotected sexual intercourse. A woman's fecundity is considered the biological ability to reproduce according to the monthly probability of conception. The incidence of infertility continues to rise, and given the failure of genetic factors to suitably explain it, much attention has been given to environmental causes (Bala et al. 2021, Giudice 2021. The etiology of female infertility is diverse, and includes multiple factors, such as anatomical mullerian abnormalities and pelvic factors, genetic mutations, chromosome abnormalities, disrupted steroids balance, and ovulatory disorders, all of which could be induced by environmental and pharmaceutical chemicals. Indeed, the occurrence of environmental pollutants, for example organophosphates (OPs), is considered as one of the main causes of reproductive development alterations in both wildlife and humans (Mitra andMaitra 2018, Liu et al. 2021).

A concise introduction to organophosphates
OPs are one of the main constituents of pesticides, insecticides, fungicides, and herbicides. Also, OPs are used in the production of flame retardants (FRs), warfare agents, as well as domestic purposes. The application of OPs continues to rise all over the world as these chemicals are attractive alternatives to persistent organochlorine pesticides by representing the capability of rapid degradation under natural conditions (Sidhu et al. 2019). Most OPs are water-soluble and thereby disseminate effortlessly into the environment through dissolution, abrasion, and volatilization (Wang et al. 2014). It is well known that OPs inhibit acetyl-variety of OPs in terms of application, we will first make a brief introduction to OPs' two main groups, including pesticides and FRs, and then discuss their adverse effects on female fecundity concerning biochemical and histopathological aspects.

Organophosphate pesticides
Pesticides refer to chemical substances used to interrupt, destroy, repel or mitigate any pest ranging from insects, rodents, and herbs to microorganisms (Mart ın Reina et al. 2017). Since the 1980s, the second-generation broad-spectrum pesticides consist of OPs and Carbamates, and have gradually replaced the persistent organochlorines due to fast degradation in soil and biota, the low potential of bioaccumulation in the environment, lower probability of movement in the ecosystem via food webs, and relative selectivity in causing toxicity (Mitra and Maitra 2018). Chemically, organophosphate pesticides (OPPs) are organic ester derivatives of phosphorous, commonly thiol or amide derivatives of thiophosphoric, phosphonic, phosphinic, phosphoric acids with additional side chains of cyanide, phenoxy, and thiocyanate group (O'Brien 2016). Azinophosmethyl, parathion, chlorpyrifos, diazinon, fonofos, and disulfoton are well-known OPPs representing extensive applications in agriculture, horticulture, plastic making, pest control, FRs, and other household applications ( Figure 1). Furthermore, Ops are widely used chemicals in agriculture to protect crops against insects (Fryer et al. 2004). OP insecticides, such as chlorpyrifos, malathion, and diazinon, (Figure 1) are a class of insecticides described by their ability to inhibit acetylcholinesterase activity. As the application of OPPs is widespread, humans may be exposed via multiple routes, such as inhalation during the spraying process, ingestion of residues on foods, soil, and dust, as well as dermal absorption from skin contiguity (Lewis et al. 2015). Along with anticholinesterase activity, OPPs and OP insecticides represent endocrine disrupting properties that could cause reproductive and neurological consequences.

Organophosphate flame retardants
FRs, substances used in industrial applications and consumer products, are one of the most well-known endocrine-disrupting chemicals (EDCs) that are special additives applied to thwart the spread of fire from combustible materials, thereby, FRs are found throughout the home and workplace. Since the constituents of FRs are not attached to the basic material, they could leach off to accumulate in household dust that is subsequently ingested or inhaled by humans (Greaves andLetcher 2017, Hoffman et al. 2017). For decades, polybrominated diethyl ethers were applied as FRs. However, the abundant presence of these chemicals in the environment and the subsequent Figure 1. Examples of the chemical structure of organophosphate pesticides. Chemically, OPPs are organic ester derivatives of phosphorous, commonly thiol or amide derivatives of thiophosphoric, phosphonic, phosphinic, and phosphoric acids with some additional side chains. The chemical structures were designed via ChemDraw Professional software 17.1 windows version. detrimental endocrine and neurological consequences led to a phase-out of manufacturing in the United States between 2004 and 2013 amid growing concerns regarding their reproductive and neurological toxicity (Zota et al. 2013, Doherty et al. 2019). Subsequently, organophosphate flame retardants (OPFRs) were considered as chemical replacements for polybrominated diethyl ethers, which became ubiquitous in home and work environments (Liu et al. 2019). Chemically, OPFRs belong to organophosphate esters (OPEs), which are characterized by the presence of a phosphate group attached to alkyl or aryl groups. The OPEs are described as a diverse group of chemicals due to differences in the degree of halogenation, arylation, and the length and branching of side chains. The application of OPFRs, which are usually a mixture of several compounds, led to the resolution of persisting and bioaccumulation of polybrominated diethyl ethers. However, OPFRs, similar to polybrominated diethyl ethers, are additives not chemically bound to materials; thereby are capable of transferring to the environment (Van der Veen and de Boer 2012). In addition to the environment, human biomonitoring studies from different countries have found OPFRs or metabolites in urine, placenta, and breast milk (Ding et al. 2016, Jayatilaka et al. 2017, Ospina et al. 2018. As a result, exposure to OPFRs is widespread and, more importantly, the fetus and neonate could be exposed through placental transfer or breast feeding. Tris(1,3-dichloro-2 propyl)phosphate (TDCPP), tricresyl phosphate (TCP), triphenyl phosphate (TPHP), tris(2-chloroethyl) phosphate (TCEP), and tributyl phosphate (TNBP) are examples of the most important OPFRs ( Figure 2). As briefly mentioned above, different types of OPs, despite their abundance functions and benefits in the industry, agriculture, and housing, effortlessly leak into the environment and cause toxicity to living organisms. Therefore, many studies have been conducted to investigate the effects of OPs on the physiological function of various organs of living organisms. The aim of this review was to investigate the OPs-induced biochemical and histopathological alterations associated with female fertility in aquatic inhabitants, mammals, and, ultimately, humans. For this purpose, related keywords including; organophosphates, pesticides, herbicides, insecticides, rodenticides, fungicides, and flame retardants, alongside terms such as fertility, infertility, fecundity, reproduction, implantation, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrus cycle, female, women, and pregnancy, were searched on Web of Science, Google Scholar, PubMed, and Scopus databases. Published articles, from database inception until April 2022, were included. After reviewing the abstract, irrelevant articles were excluded by considering exclusion Figure 2. The chemical structure of some important organophosphate flame retardants. OPFRs are special additives applied to thwart the spread of fire from combustible materials which belong to OPEs, characterized by the presence of a phosphate group attached to alkyl or aryl groups. The chemical structures were designed via ChemDraw Professional software 17.1 windows version. criteria, such as irrelevant subjects, non-English or non-original, and unavailability of data.

Organophosphates cause female infertility in aquatic ecosystems
Despite the undeniable importance of reproduction for all living beings in order to preserve survival and continuity of race, the inexorably increasing environmental pollution acts as an inhibitor of the reproductive system in aquatic habitats. Liberal application of OPs, at almost all crop production stages, starting from seed processing and ending with agricultural product storage, leads to pollution of aquatic ecosystems as OPs could be carried into aquatic environment through surface water run-off from application sites, aerial drift, rainfall, and sewage effluent. The entry of OPs into the aquatic ecosystems is accompanied by contamination of aquatic habitats through the food web or contact with water. Therefore, female infertility in the aquatic environment can be considered a possible consequence (Ramana et al. 1992, Bernab o et al. 2011, Mir et al. 2011. Due to the great diversity of aquatic animals, it seems impossible and perhaps futile to study the toxic effects of OPs in all of them. However, the induction of infertility in aquatic ecosystems after exposure to OPs is accompanied by devastating alterations in Gonado Somatic Index (Baumert et al. 2022), ovarian structure and function, steroid hormones, and ovarian-related homeostasis, which are discussed below in detail.

GSI and structural-functional efficiency of the ovary
In recent decades, scientists have focused mainly on fish, and evaluated indicators such as the Gonado Somatic Index (Baumert et al. 2022), which indicates the periodicity and maturity of the spawning of fish. GSI increases as the fish mature and reaches the maximum level when the maturity is at the peak and diminishes abruptly upon spawning (Mir et al. 2011). OPs such as dimethoate, monocrotophos, and glyphosate reduce GSI directly proportional to the OPs concentration and duration of the exposure (Ramana et al. 1992, Mir et al. 2011, Armiliato et al. 2014, Sumon et al. 2019, Mohapatra et al. 2021. Further, most OPs, such as chlorpyrifos, malathion, dimethoate, and monocrotophos, are listed as EDCs, a class of compounds that intervene with typical endocrine system function followed by grave adverse developmental, immune, neurological, and reproductive effects, which could interfere with sex differentiation and reproductive development (Bernab o et al. 2011, Mohapatra et al. 2020. Indeed, exposure to OPs leads to drastic alterations in the ovarian structure including vitellogenesis, described as the movement of yolk into the maturing ovarian follicle, presence of myelin-like structures in the cortical regions of the oocytes concentric membranes, increase in the diameter of previtellogenic and vitellogenic oocytes, clumping of cytoplasm, disruption of the follicular wall, and oocyte atresia which in turn upset the physiological balance in the synthesis of sex steroids resulted in the deleterious impairment of spawning performance/breeding fitness (fertilization and hatching rate) (Dutta et al. 1994, Bernab o et al. 2011, Armiliato et al. 2014, Sumon et al. 2019, Mohapatra et al. 2020, Mohapatra et al. 2021.

Steroid hormones
OPs-induced alterations in the expression of steroidogenic factor-1, a main regulator of steroid hormone biosynthesis, could disrupt the production of ovarian hormones (Armiliato et al. 2014). Since the production of estradiol from testosterone requires the appropriate performance of aromatase, increasing ovarian testosterone levels and decreasing estradiol after exposure to OPs indicates the suppressive impact on the enzyme activity (Brandt et al. 2015). Concerning the pivotal impact of ovarian hormones on the maturation of the oocytes, which is an irreplaceable step in the production of fertilizable eggs, acephate could interfere with the nongenomic action of progesterone on the meiotic maturation of oocytes, which is the activation of membrane-receptor associated second messengers, like cAMP or G proteins, through elevating the rate of germinal vesicle breakdown demonstrating the antiestrogenic role of OPs (Das and Thomas 1999, Tokumoto et al. 2005, Ghodageri and Katti 2013. In addition to observing similar changes in the gestational embryonic ovary, a ban on sex steroids may be considered one of the main reasons (Ramana et al. 1992). Unfortunately, long-term exposure to OPs causes mortality in addition to damaging ovarian tissue (Sumon et al. 2019).

Ovarian energy/metabolites homeostasis
Recently, a cohort study, performed in two countries that enrolled 300 participants from each country, revealed that exposure to OPs is followed by metabolic disorder (Leonel Javeres et al. 2021). The optimal function of the ovaries is highly dependent on the balance of metabolites. Indeed, homeostasis of metabolites and the provision of energy are essential because the ovaries consist of highly proliferative cells and are the site of the production and secretion of steroid hormones. It is well established that processes involved in reproduction, such as puberty, pregnancy, and lactation, require significant energy expenditures, all of which depend on the cyclic production of sex hormones. In this regard, the hypothalamus is intended as a center for controlling energy/metabolites homeostasis and fertility, which regulates energy metabolism through various neurons, including AgRP/ NPY and POMC/CART in the arcuate nucleus, and cooperates with GnRH neurons (Estienne et al. 2021). In addition, kisspeptin neurons act as mediators between the reproductive system and energy metabolism . Thus, metabolic disorders, either directly, by targeting follicular cells or oocytes, or indirectly through the hypothalamic-pituitary-ovarian axis, lead to ovarian dysfunction, impaired growth, and maturation of oocytes and oocyte competence acquisition that eventually leads to premature ovarian failure (POF) or polycystic ovary syndrome (PCOS) (Dri et al. 2021, Estienne et al. 2021, Khan et al. 2021. Balance in the levels of various metabolites, including lipids, ketone bodies, glucose, and amino acids, especially histidine, is essential for the health of the reproductive system and pregnancy (Al Rashid 2021, Pishvaei et al. 2021. Furthermore, various studies have shown that known metabolic-regulating hormones could affect the ovaries ability to maintain metabolites/energy homeostasis. Adiponectin, for example, controls fertility through the hypothalamicpituitary-ovarian axis and stimulates estrogen secretion, and to lesser extent progesterone, by increasing the sensitivity of granulosa cells to FSH (Grandhaye et al. 2021, Messini et al. 2021. Concomitantly, the adiponectin agonist, adipRon, activates various signaling pathways, such as AMPK and PPAR in luteinized human granulosa cells, induces granulosa cells to arrest in G1, reduces the proliferation of granulosa cells by activating p53 and PTEN pathways, and in addition, reduces mitochondrial activity and disruption of ATP production, on the other hand, activation of phosphodiesterase and reduction of cAMP levels, reduces aromatase expression and consequently estrogen secretion (Grandhaye et al. 2021). Ovarian reserve, on the other hand, is a target of insulin/IGF (Dri et al. 2021), as insulin resistance is associated with poor metabolic homeostasis in the ovaries and pregnancy output in premenopausal women (Kazemi et al. 2020, Rondanelli et al. 2021. Glucose and glucose transporters are also essential for ovarian development and reproductive maturity, and Glut-4, for example, plays a vital role in oocyte maturation and steroid production by providing energy homeostasis (Li et al. 2022). Previous studies have revealed that fenitrothion and phosphamidon could decline the levels of total proteins, RNA, and ascorbic acid, and increase ovarian cholesterol and phospholipid levels. Interestingly, despite these similarities, different effects have been reported in terms of total lipid levels as phosphamidon increased the total lipid levels, while fenitrothion decreased ovarian total lipid levels. The simultaneous application of fenitrothion and carbofuran, a carbamate, could be assumed one of the main reasons for this contradiction (Saxena et al. 1986, Gill et al. 1990). Importantly, exposure to malathion reduces the ovarian uptake of 32 P that confirms suppressed ovarian activity due to retarded synthesis and release of gonadotrophin . Moreover, some OPs, such as triazophos, could disrupt energy metabolism and osmotic regulation in mussels through inducing increment in glutamate, b-alanine, trimethylamine N oxide, glycine, homarine, aspartate, malonate, ATP, and histidine along with decreasing betaine, taurine, glucose, glycogen, ethanol, and threonine. Interestingly, higher concentrations of OPs disrupted more metabolites homeostasis (Zhang et al. 2017). Also, other OPs, for example malathion, could interfere with lipid metabolism, leading to an increase in fatty acid, glycerol, and lipase activities along with a decrease in total lipid content in the ovary (Gurushankara et al. 2007). It is well documented that energy availability is a major factor in ovarian function, hence ovarian function is responsive to environmental factors that alter the availability of energy for reproduction (Jasienska et al. 2017). Regarding the importance of preserving the energy and metabolite balance within ovaries for suitable and effective biosynthesis of sex steroids (Warzych and Lipinska 2020, Navarro 2020), OPs-induced disruption in the mentioned factors could be considered as another mechanism for insulting ovarian hormone-synthesis performance (Table 1).

Female mammalian infertility upon exposure to organophosphates
Since fish and mammalian reproductive systems share many similarities, we could assume almost identical toxicity mechanisms. However, due to the existing differences, as well as complexities of the mammalian reproductive system, careful consideration is required. Previous investigations can be classified at two levels,

days
The exposed ovaries of the embryos demonstrated severe damages such as a broken nuclear wall, nondetectable oogonia, unclear cytoplasm, disappeared and broken wall of oocytes, thick wall of ovarian, and shrunken ovaries. (Ramana et al. 1992) 1986 Fenitrothion Channa punctatus 1.5 ppm 120 days OPs could disrupt the metabolites homeostasis as the ovarian levels of total proteins, RNA, ascorbic acid, and total lipids were decreased while the levels of cholesterol and phospholipids were increased upon exposure to the fenitrothion. (Saxena et al. 1986) 1989 Phosphamidon

Puntius conchonius
109.5 ppm 4 weeks Cholesterol and total lipids homeostasis were disrupted in the ovaries. (Gill et al. 1990) 1980 Malathion Heteropneustes fossilis 9 ppm and 45 ppm 96 hours Malathion retarded gonadotropin secretion and thereby decreased ovarian 32 P uptake.  2017 Triazophos Perna viridis 0.5 mg/L and 1 mg/L 24, 48, and 96 hours. The ovaries of mussels exposed to the triazophos revealed the disturbances in energy metabolism and osmotic regulation. The including cellular and animal studies. In the case of cellular studies, the toxicity of exposure to OPs has been studied in two types of cells, including Chinese hamster ovary (CHO) and caprine granulosa cells, which will be discussed earlier (Table 2). In addition to studies on these two cell lines, Rosenmai et al. recently demonstrated, in an in vitro/in silico study, that different OPFRs are able to affect E 2 levels, androgen receptor, aryl hydrocarbon receptor, and transthyretin suggesting endocrine disruptive properties of OPFRs (Rosenmai et al. 2021).

Cellular studies
Estrogen exerts its effects on tissues through two types of receptors, ER-a and ER-b. Interestingly, some OPs have agonistic effects on ER-a (e.g. butamifos) and ER-b (e.g. Prothiofos), while other OPs demonstrate antiandrogenic activity in CHO cells (e.g. fenitrothion, parathion, and methyl parathion). Importantly, some OPs have a selective performance and affect only one type of receptor. Butamifos, for instance, strongly stimulates ER-a while not having such an effect on ER-b (Kouima, Kasrtqa es ak. 2004). In addition to interfering with the interaction of E 2 and its receptors, OPs have severe genotoxicity in CHO cells; for example, monocrotophos can cause chromosomal aberrations and reductions CHO cell proliferation through nucleophilic attack and DNA alkylation (Peitl et al. 1996). Furthermore, dichlorvos, dicrotophos, malathion, parathion, and leptophos demonstrate antiproliferative properties via the induction of sister chromatid exchanges (Nishio and Uyeki 1981). Besides, exposure to OPs leads to cytogenotoxicity due to the induction of DNA double-strand breaks, suppression of mitochondrial activity, and threatens CHO cell viability (Patel et al. 2007). Concomitant to CHO cells, granulosa cells of caprine antral follicles are targeted by OPs. Upon exposure to malathion, cytological, and biochemical alterations, such as condensed chromatin with the fragmented nucleus, pyknosis, disrupted membrane integrity, DNA fragmentation, and impaired antioxidant defense system, occur subsequent to granulosa cells apoptosis and antral follicles atresia . In the case of follicular atresia, particularly in granulosa cells of antral follicles that are vitally involved in the synthesis of sex steroids, exposure to OPs leads to cytogenotoxic alterations, such as diminished cell-cell contact/cellular integrity, presence of a crescent-shaped nucleus, chromatin condensation, and pyknosis, accumulation of lipid droplets, apoptosis, apical localization of lipid bodies, and occurrence of the autophagic body that, altogether, affect overall fertility .

Animal studies
Thus far, many studies have been conducted to investigate the harmful effects of exposure to OPs on various mammalian systems, particularly the reproductive system, in different animals, including mice, rats, sheep, etc. Exposure to OPs is evidently associated with changes in fertility-related hormones, ovarian histomorphological structure, estrous cycle phases, follicular homeostasis, and uterine function; the details of which are described below.
Gonadotropins and steroid hormones Both para and autocrine signaling, along with an organized cross-talk between flaggings derived from oocytes and somatic cells, coordinate cellular interactions using gap junctional communication. This highly regulated process leads to the development of folliculogenesis and supports the appropriate acquisition of maturational competence by the oocyte (Biswas et al. 2020, Tesfaye et al. 2020, Dompe et al. 2021. Furthermore, downstream from the surge in gonadotrophins, which is accompanied by the increment in LH, complex cell-cell signaling pathways initiate the development of oocyte nuclear maturation and ovulation (Prasasya and Mayo 2019, Gershon and Dekel 2020). The biosynthesis of sex steroids is dependent on hormonal homeostasis and functional interaction between somatic and germ cells within the follicle.
Damage to mammalian ovaries has been shown via induced cytobiochemical alterations. Indeed, damage to the ovarian follicles, decreasing the number of small, medium, and large follicles, and increasing the number of atretic follicles, accompanied by ovarian weight loss, occurs after exposure to OPs such as monocrotophos, triazophos, tetrachlorvinphos, dimethoate, chlorpyrifos, methyl parathion, and edifenphos (Nishio and Uyeki 1981, Nayudu et al. 1994, Asmathbanu and Kaliwal 1997, Rao and Kaliwal 2002, Nanda and Kaliwal 2003, Sharma et al. 2015. Furthermore, exposure to dimethoate abolishes implantation, induces abortion or fetal resorption in higher doses, and leads to blastotoxicity due to an imbalanced E 2 /progesterone (P 4 ) ratio and interrupted hypothalamic-pituitary axis Kaliwal 2003, Mahadevaswami andKaliwal 2004). Besides, some Ops, like trichlorfon, which dehydrochlorinates to dichlorvos via a nonenzymatic process, Various studies confirm the destructive effects of OPs exposure on mammalian fecundity. What the table specifies are demolished sex hormone biosynthesis, interrupted sex steroid receptors function, altered expression of genes involved in reproduction, disrupted energy and metabolite homeostasis in the ovaries, and pathological changes in ovarian and uterine histoarchitecture which disturb reproductive ability. reduce mucification and ovulation by inhibition of muscarinic acetylcholine esterase receptors that naturally promote P 4 synthesis in granulosa cells (Bodis et al. 2002, Sun et al. 2008. Contrary to previously mentioned, exposure to OPs, such as diazinon, for 2 weeks elicited no effect on the number of primordial, primary, secondary, and graffian follicles, nor on estrogen, LH, and FSH levels, despite causing ovarian weight loss, which was attributed to an increased adrenocorticotropic hormone (ACTH) secretion and promotion of protein catabolism in the ovary. However, diazinon may cause damage to the ovaries by reducing the mean number of corpus luteum and declining P 4 levels (Johari et al. 2010). On the contrary, Sharma, et al. reported an increase in E 2 levels, along with a decrease in P 4 in the plasma, of Wistar rats exposed to triazophos. As the induced alterations are dependent on both concentrations and duration of exposure, these discrepancies could be explained. Indeed, a recent study revealed that exposure to sublethal doses of chlorpyrifos resulted in a significant decrement of E 2 , LH, and FSH levels in a dose-dependent manner. Nevertheless, despite a decrease in P 4 levels in a dose-dependent manner, the results were reported as non-significant (Iheanacho et al., 2020).

Ovarian histomorphological structure
The aneugenic activity of OPs results in histopathological alterations within cells is vital for reproduction. Trichlorfon may be able to induce chromosome nondisjunction and predivision, along with polyploidy and uncoupling of nuclear maturation in oocytes. Moreover, trichlorfon alters the meiosis II spindle that leads to a failure of chromosomes to congress at the spindle equator, which is posited as a reason for trisomy 21 in the Hungarian population (Czeizel et al. 1993, Sun et al. 2008. Similarly, a recent study revealed that exposure to glyphosate deteriorated metaphase II mouse oocyte quality through two distinct mechanisms. The first involved mechanism was disruption of the microtubules and chromosomes organizing centers, including spindle fiber destruction and removal, anomalous pericentrin formation, and defective chromosomal alignment. The second introduced mechanism was suggested to be substantial depletion of intracellular zinc bioavailability and accumulation of reactive oxygen species (Yahfoufi et al. 2020). Interestingly, OPs could change calcium signaling pathways, resulting in progression to anaphase I or II with no polar body formation, which increases polyploidy and oocytes containing two spindles. Ultimately, exposure to OPs leads to apoptosis or necrosis in ovarian follicles in a dose-dependent manner (Sharma et al. 2015, Mazoochi and Ehteram 2018, Regan et al. 2018.

Estrous cycle phases
Hormone secretion, follicle development, and oocyte maturation in rodents are highly regulated processes that occur during the estrus cycle consisting of four phases, including proestrus, estrus, metestrus, and diestrus. The estrous cycle in rodents, particularly in rats and mice, lasts for 4-5 days, which is described as a repetitive, but dynamic, process, as different types of cells appear and recede, representing alterations in steroid hormones levels secreted by ovarian follicles (Cora et al. 2015, Wolcott et al. 2022). The duration of the different stages of the estrous cycle is not the same, such that proestrus and estrus stages in female rats last about 12 h each, while the metestrus lasts 21 h and diestrus lasts for 57 h (Paccola et al. 2018). The rapid rise in E2 levels is characteristic of the proestrus phase, which is associated with the rapid growth of ovarian follicles. After the LH surge, ovulation occurs during the estrus phase. Later, and in the absence of mating, progesterone is produced and secreted by the corpus luteum. As it turns out, the duration of the estrous cycle phases is highly regulated by the secretion of steroid and hypothalamic hormones, so any change in duration reflects abnormal hormone secretion, ovarian follicle abnormalities, and disrupted uterine epithelial development that threaten fertility (Paccola et al. 2018). One of the consequences of damage to the ovarian follicles and impaired secretion of sex steroids is the disrupted duration of the phases of the estrous cycle. Exposure to monocrotophos, dimethoate, and edifenphos can yield a decrease in the duration of proestrus, estrus, and metestrus phases, and decrease the number of cycles with a concomitant increase in the diestrus duration Kaliwal 2002, Rao and. Consistently, methyl parathion causes a significant decrease in the number of estrous cycles and a concomitant increase in diestrus index (Asmathbanu and Kaliwal 1997). Moreover, exposure to chlorpyrifos results in a disrupted estrus cycle with prolonged metestrus (Nishi and Hundal 2013). Some researchers believe that the prolonged estrous cycle demonstrates that OPs have no estrogenic activity which is rejected by others (Asmathbanu andKaliwal 1997, Kojima et al. 2004). However, researchers have observed no pathological alterations regarding germinal vesicle breakdown, first polar body extrusion, the incidence of fetal external malformations, or in the estrous cycle upon exposure to trichlorfon (Ding et al. 2011). The application of low doses of trichlorfon can be considered the best explanation for this inconsistency since the time of exposure and the concentration of OPs have a direct association with the induction of reproductive toxicity. Exposure to dimethoate, for example, in lower doses, has no toxic effects on ovarian follicles and estrous cycle, but higher doses or increased exposure duration could repress follicular development significantly Kaliwal 2002, Ding et al. 2011).

Follicular and energy/metabolites homeostasis
Consistent with what has been mentioned about aquatic inhabitants, OPs can disrupt follicle homeostasis and induce cell death by altering physiological metabolism and decreasing/increasing metabolite levels in rodents' ovaries. For example, exposure to monocrotophos, dimethoate, and methyl parathion, even at low doses, leads to a drastic decrement in the cytoplasmic-and membrane-bound proteins, total lipids, phospholipids, and cholesterol (Kaur and Dhanju 2005). Induction of oxidative stress upon exposure to OPs leads to lipid peroxidation and an increase in the levels of malondialdehyde (Sargazi et al. 2015, Sharma et al. 2015. Interestingly, ovaries, when compared to the testis, are more sensitive to the induction of oxidative stress, which could imply gender-related differences in sensitivity to OPs (Sargazi et al. 2015). Due to the importance and complexity of the effects of oxidative stress on ovarian disease, fullicular apoptosis, and subsequent infertility, we sought to discuss it in detail in the next section.

Oxidative stress and follicular apoptosis
Evidently, there is a strictly regulated balance in a healthy body between reactive oxygen species (ROS) and antioxidants. However, when the balance is disrupted toward the overproduction of ROS, a pathological state appears, referred to as oxidative stress (Aitken et al. 2022). Intracellular ROS is considered the main byproduct of mitochondrial function, and contrary to common belief, the presence of ROS is not a biomarker of any pathological conditions, indeed, a certain amount of ROS is needed for cell development and metabolism via activation of different intracellular signaling pathways. However, ROS levels in excess of the cellular antioxidant capacity will be followed by the accumulation of these molecules and subsequent attack on biological macromolecules (Wang et al. 2021). An ovarian follicle, which consists of an individual oocyte encapsulated by specialized somatic cells, is extremely sensitive to oxidative imbalance (Wang et al. 2021, Mousavi et al. 2022. Indeed, oxidative stress in ovarian follicles results in zona hardening, elongation, dispersal, or disruption of the spindle, partial exocytosis of cortical granules, lipid peroxidation in the cell membrane, loss of mitochondrial membrane potential, premature centromere separation, decline in Inositol-3-Phosphate receptor, a decrement in critical cell cycle factors such as MPF and MAPK, depletion of Ca2þ stores, decrease in ATP production, and restricted expression of the antiapoptotic protein named Bcl2, all of which activate/deactivate a variety of signaling pathways that eventually lead to oocyte aging, follicular atresia, and premature ovarian failure (Wang et al. 2021).
OPs are able to induce oxidative stress in the ovaries; indeed, a recent study revealed that different types of OPEs were able to induce oxidative stress accompanied by increased total mitochondria, decreased lysosomes, and increased the total area of lipid droplets in different cell types related to the reproductive system, including KGN human granulosa cells, C18-4 mouse spermatogonial cells, and MA-10 mouse Leydig cells (Wang et al. 2022). In addition, triazophos was able to disrupt the oxidative balance in rat ovaries, which was determined by measuring adverse alterations in related markers, such as catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, and lipid peroxidation. Importantly, triazophos-induced oxidative stress in the ovaries was associated with decreased levels of both sex steroids and increased apoptosis in granulosa cells and follicular atresia, all of which can be ameliorated by antioxidants (Sharma and Sangha 2021). Transcriptome analysis revealed that triazophos induced oxidative stress and reproductive-related endocrine function was sex-specific in green mussels (Zhang et al. 2022). Even exposure to OPs among occupationally exposed researchers has been followed by the induction of oxidative stress markers, malondialdehyde, and total antioxidant capacity, in addition to changes in inflammatory cytokines, including IL-6, IFN-c, and TNF-a (Zahran et al. 2021). Malathion is another example of how induced oxidative stress and ROS accumulation can change the pathways associated with apoptosis and autophagy, and consequently disrupt the estrous cycle and reduce steroid biosynthesis in mice ovaries (Yong et al. 2021). In fact, the autophagy pathway has been described as a double-edged sword, which sometimes plays a protective role against oxidative stress-induced damage and sometimes even participates in oxidative stress-induced apoptosis in granulosa cells (Zhang et al. 2021).
According to the two-cell theory, the biosynthesis of ovarian E 2 requires both theca and granulosa cells (Voutilainen et al. 1986). In this regard, it has been documented that theca cells are responsible for the biosynthesis of androstenedione from cholesterol which is stimulated by LH. The produced androstenedione, in the next step, will be transported to granulosa cells, converted to estrone, and under the stimulation of FSH, will be converted to E 2 (Doshi and Agarwal 2013). Therefore, any dysfunction of these two cells, or irregular secretion of regulatory hormones, will be accompanied by a lack of E 2 production and expectable consequences. Importantly, previous studies have revealed that OPs can cause an oxidative imbalance in both cells, as well as impair the secretion of LH and FSH, hence disrupting the biosynthesis of sex steroids, which, in turn, results in fertility disorders.
As mentioned earlier, the secretion of LH and FSH hormones, which regulate the levels of precursors and the activity of enzymes involved in estrogen production, is disrupted after exposure to OPs, a state characterized by disturbed oxidative balance, altered signaling pathways, accelerated apoptosis, disruption of autophagic pathways, and follicular deformity. Chlorpyrifos, for example, impair reproductive hormones biosynthesis and cause a stress state through induction of oxidative imbalance which was determined by decreased glutathione activity and increased superoxide dismutase enzyme (Oruc¸2010). Moreover, alterations caused by triazophos in oxidative stress markers were accompanied by cytomorphological alterations in the ovaries (Sharma et al. 2015). Pathological alterations have also resulted following exposure to OPFRs and OPEs (Sutha et al. 2022, Wang et al. 2022. Intriguingly, a recent study revealed the induction of autophagy, not cell cycle arrest or apoptosis, is responsible for granulosa cells lost upon exposure to OPFRs. In this regard, granulosa cells, the other party involved in the two-cell theory, were treated by TOCP and the obtained results demonstrated increased levels of LC3-II, LC3-II/LC3-I ratio, ATG5, Beclin1, and the numbers of autophagic vesicles which exerts TOCP-induced autophagy affected mouse ovarian granulosa cells viability, without affecting cell cycle and apoptosis (Wang et al. 2019). Due to the dependency of autophagy on signaling pathways, such as Nrf2 and MAPK and the relationship of these pathways with oxidative stress, OPs-induced granulosa cells loss can be related to disruption of the oxidative balance (Lim et al. 2018, Tantengco et al. 2021. Similarly, TOCP demonstrated inhibitory effects on follicular development and reproductive hormones such as LH, FSH, E 2 , and P 4 via altering levels of proteins such as FoxO1 and Smad2/3 and caused promoted cell death by elevated DNA fragmentation, which happens in concordance with an impaired oxidative stress state (Li et al. 2021). Indeed, the activation of ERK, JNK, and MAPK in ovarian theca and granulosa cells after exposure to OPs results in the disrupted oxidative balance that leads to DNA fragmentation and eventually cell death through either apoptosis or autophagy (Farkhondeh et al. 2020).

Ovarian homeostasis and uterine efficacy
As mentioned earlier regarding aquatic animals, preserving energy/metabolite homeostasis in the ovaries is critical to provide ideal performance in steroids hormone secretion, oocytes development, and preparation for healthy fecundation, etc. In this regard, Walley et. al. in a recent study revealed that maternal exposure to OPFRs could alter the expression of Esr1, the expenditure of energy, and the levels of energyrelated metabolites including fasting glucose, leptin, glucose and insulin tolerance in a sex-and dietdependent manner (Walley et al. 2021).
As the uterus is considered the organ of the generation that plays a crucial role in female fecundity, including sperm migration, embryo implantation, and fetal nourishment (Taylor and Gomel 2008), assessing the destructive effects of OPs on this organ can shed light on how infertility is induced in women (Figure 3). Exposure to OPs, such as methyl parathion and dimethoate, can result in uterine weight loss (Asmathbanu andKaliwal 1997, Mahadevaswami and, and the OPs-induced adverse effects on the uterus could be followed by deleterious consequences on birth outcomes. Exposure to sublethal doses of chlorpyrifos, for instance, resulted in decreased litter birth weight as well as a lower number of pups' survival between parturition and weaning (Iheanacho et al. 2020). In addition, maternal exposure to OPFRs such as tris(1,3-dichloro-2-propyl)phosphate, TCP, and TPHP can have unintended consequences by altering the expression of genes involved in energy homeostasis and reproduction (e.g. Esr1, Foxo1, Dgat2, Fasn, Pdyn, Tac2, and Cyb2b10 in neonates) (Adams et al. 2020). Furthermore, a recent study indicated that chronic exposure to low concentrations of chlorpyrifos caused proliferative alterations in the uterus that suggested the ability of OPs to affect reproduction or act as a risk factor in the intensification of uterine proliferative pathologies (Nieto et al. 2021).

Organophosphate compounds threaten female fertility and successful pregnancy in humans
Clearly, agricultural fields are the most important areas for the use of OP compounds; where farmers apply these compounds in different volumes as pesticides to protect their crops and eliminate various pests. In many countries, farming is one of the main occupations in which most workers, both men and women, are directly or indirectly involved. In India, for example, 84% of women have relied on the agriculture sector for their livelihood (Thakur et al. 2022). OPs, on the other hand, are considered to be the main pesticides used by farmers (Kongtip et al. 2021). Numerous studies conducted around the world have shown that farmers involved in any of the processes related to planting, holding, and harvesting agricultural products are exposed to high levels of OPs (Manyilizu et al. 2016, Taghavian et al. 2016, Kongtip et al. 2021, Baumert et al. 2022, Medithi et al. 2022, which have faced adverse biological consequences such as metabolic and neurological disorders and diseases related to the cardiovascular system, immune system, and different types of cancer, etc (Yang et al. 2020, Jian et al. 2022, Prihartono et al. 2022, Sombatsawat et al. 2022, Thammachai et al. 2022). In addition, residents of nearby agricultural areas, people who have not been personally involved in the related processes, and even consumers of agricultural products contaminated with OPs will be at risk for exposure to these chemicals and consequently future health risks (Griffith et al. 2019, Hongsibsong et al. 2019, Akande et al. 2020, Sapbamrer et al. 2020, Suarez-Lopez et al. 2020, Budiyono et al. 2021, Madrigal et al. 2021). On the other hand, as mentioned earlier, OPs are not only involved in the production of pesticides but also OPEs are used in the manufacture of OPFRs and plasticizers, which are used in everyday life (Li et al. 2019). Moreover, female firefighters are another occupational group that may expose to these compounds (Clarity et al. 2021, Trowbridge et al. 2022. Alarmingly, a recent study conducted in the US revealed that chronic long-term exposure to OPs represents a dramatically higher health risk for women than for men (Sun et al. 2020).
As noted in the previous sections, OPs damage environmental fertility by different biochemical and histopathological mechanisms. The effects of OPs on aquatic inhabitants and mammals can be used to infer the potentially destructive effects on the women's reproductive system. Over the past decade, human biomonitoring studies in several parts of the world, such as the US, Australia, EU, or China, have found OPs, or metabolites thereof, in urine, placenta, and breast milk, suggesting that human exposure to OPs is widespread. More importantly, this suggests that fetuses and neonates could be exposed through various ways, such as placental transfer or breastfeeding (Figure 4). Despite the undeniable importance of studying the adverse effects of OPs on women's reproductive ability, as well as pregnancy outcome and neonatal health, relatively few human studies have been conducted (Table 3).

Endocrine disruptive properties
In 2021, A.K. Rosenmai and colleagues (Rosenmai et al. 2021) performed an In vitro study to investigate the effects of eleven different OPFRs on the androgen receptor, aryl hydrocarbon receptor, Nrf 2 activity, transthyretin, and steroidogenesis, as well as an In silico study to cover E 2 , thyroid, and CYP3A4 induction related endpoints. Accordingly, the results demonstrated that approximately all of the studied OPFRs, including tris(2-chloroethyl) phosphate, tris(2-chloroisopropyl) phosphate, tris(1,3-dichloro-2-propyl) phosphate, Antiblaze V6, triphenyl phosphate, cresyl diphenyl phosphate, tris(2-isopropyl phenyl) phosphate, TCP, 2-ethylhexyl diphenyl phosphate, and tris(2-ethylhexyl) phosphate reduced androgen receptor activity. Furthermore, increased aryl hydrocarbon receptor activity and displaced transthyretin bound 8anilino-1-naphthalene sulfonic acid ammonium (ANS) were obtained upon exposure to OPFRs. Interestingly, contradictory results have been reported regarding steroidogenesis, including increasing, ineffective, and decreasing E 2 levels; in other words, previous studies have reported the increase, decrease, or even no alteration in estradiol levels upon exposure. Taken together, this information indicates the endocrine disruptive properties of OPFRs in human cell lines (Rosenmai et al. 2021). Moreover, it has been reported that exposure to OPs could lead to endometriosis, a hormone-responsive gynecologic disease that increases the risk of infertility in women of reproductive age (Li et al. 2020). In addition to endometriosis, researchers have shown that premenopausal women exposed to OPEs had a higher risk of uterine fibrosis . Despite the importance of such studies, it is crucial to closely monitor the levels of OPs or metabolites in women, mothers, and infants, and to evaluate the consequences of exposure. In this regard, Figure 4. Organophosphates threaten female fertility followed by deleterious impacts on the fetus. The effects of OPs on female fecundity can be assessed at three levels. 1-Exposure in preconceptional women causes irregular menstrual cycle, shorter duration of menstrual bleeding, longer time to pregnancy, and ultimately infertility. In pregnant women, OPs cause decreased fetal weight, earlier delivery of female infants, and lower pregnancy outcomes such as lower odds of successful implantation and live birth. 2-Due to the placental transfer of OPs, maternal exposure can lead to detrimental consequences such as low birth weight, as well as decreased levels of E2, testosterone, and FSH in cord blood. 3-Since OPs are able to pass on to the newborns upon breastfeeding, they could cause alteration in anthropometry and feeding behaviors. Furthermore, a higher risk of neurological consequences in infants is associated with prenatal exposure to OPs. OPEs could be assumed as metabolic disruptors in infants whose mothers had been exposed to OPEs as higher levels of BDCIPP in maternal urine were associated with a greater ponderal index, lower insulin concentration, and decreased leptin levels in neonates. Kuiper et al revealed that higher urinary maternal concentrations of OPEs, such as bis(1,3-dichloro-2-propyl) phosphate, affected infant outcomes, including a greater ponderal index, which is an index of weight in relation to height or length, lower insulin concentrations, and lower leptin concentrations suggesting OPs as metabolic disruptors (Kuiper et al. 2020).

The menstrual cycle
Disruption of the menstrual cycle may be one of the most important causes of adverse fecundity caused by exposure to OPs. In this regard, higher urinary concentrations of OPs, such as diethyl phosphate and diethyl thiophosphate, have been shown to be related to higher risks of irregular menstrual cycles as well as a shorter duration of menstrual bleeding in preconceptional women (Zhang et al. 2020). A similar study in the USA demonstrated concordant results, suggesting the deteriorative impact of exposure to various pesticides, including OPs, on the alteration of the menstrual cycle among premenopausal women (Farr et al. 2004). Due to the vital connection between the menstrual cycle and healthy fertility, the induced change in exposed women may be associated with decreased fecundability. Indeed, in 615 women who were planning a pregnancy, higher urinary concentrations of OPs, such as diethyl thiophosphate, resulted in a significantly longer time to pregnancy, defined as the number of months taken for a couple to conceive, and infertility, with a strong correlation in nulliparous women (Hu et al. 2018). Therefore, preconception OPs exposures are related to a decreased chance of successful fecundity. Furthermore, in a similar study, Hu et al revealed that among women with infertility who underwent In vitro fertilization, urinary OPs concentrations were associated with pregnancy outcomes since higher levels of diethyl phosphate, dimethyl phosphate, dimethyl thiophosphate, and diethyl thiophosphate yielded lower odds of successful implantation, clinical pregnancy, and live birth (Hu et al. 2020).

Adverse effects on fetal and neonatal
In addition to the importance of fertility, the development and the birth of healthy neonates are vital topics. Unfortunately, exposure to OPs during early life is assumed to be more strongly associated with disrupted endocrine and adverse developmental effects than exposures occurring later in life. A growing number of studies performed in different countries revealed that urinary OP metabolites could be frequently found in different populations, such as the general population, pregnant women, and children (Fromme et al. 2014, Castorina et al. 2017, He et al. 2018, Ospina et al. 2018, Zhang et al. 2018. The widespread occurrence of OPs in the placenta, uterine decidua, chorionic villi, and amniotic fluid confirms that OPs are capable of passing through the placental barrier and transferring from mother to fetus (Ding et al. 2011, Zhao et al. 2017, Bai et al. 2019.
Regrettably, the fetus is not as able as adults to metabolize and detoxify toxic environmental pollutants, thus, the fetus is more susceptible to environmental exposures that consequently cause irreversible effects on the growth and development of the offspring (Gluckman et al. 2008, Barraza 2013.

Newborn low birth weight and spontaneous abortion
A recent cohort study by Crawford et al indicated that higher maternal urinary concentrations of organophosphate ester (OPE) metabolites, including bis-2-chloroethyl phosphate, bis (1,3-dichloro-2-propyl) phosphate, and diphenyl phosphate affected gestational weight gain, increased infant length and feeding speed, elevated both male and female weight, caused weekly growth in iliac skinfold thickness, greater infant thigh skinfold thickness, and subscapular skinfold thickness determined the effects of OPs maternal exposure on infant anthropometry and feeding behavior (Crawford et al. 2020). Accordingly, Hoffman et al. demonstrated that maternal exposure to Ops, such as bis (1,3-dichloro-2-propyl) phosphate, diphenyl phosphate, isopropyl-phenyl phenyl phosphate, and bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate, adversely affected birth-weight and gestational length, and was associated with one week earlier delivery of female infants (Hoffman et al. 2018). In addition, higher levels of OPFRs, such as diphenyl phosphate in maternal urine, were strongly associated with giving birth to infants with low birth weight, defined as a birth weight of <2500 g (Luo et al. 2020). Interestingly, the indicated adverse effects of maternal exposure to OPs reported in all of the above studies on newborns were more severe in female infants, which implies sex-specific detriments in offspring (Hoffman et al. 2018, Crawford et al. 2020, Luo et al. 2020. Moreover, a recent population-based study documented that prenatal exposure is followed by lower estimated fetal weight in the mid-pregnancy period, which continued until late pregnancy, resulting in lower birth weight (van den Dries et al. 2021).
Concordantly, higher maternal exposure to 4-nitrophenol, a metabolite of parathion and methyl parathion, resulted in an increased risk of having a child born small for gestational age and was more likely to deliver preterm (Jaacks et al. 2019). Widyawati et al. have determined that low birth weight upon pesticides exposure during pregnancy was due to umbilical serum insulin-like growth hormone-1 reduction pathway (Widyawati et al. 2020). Moreover, the inverse association between maternal exposure to OPFRs and different molecular biomarkers, including integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1), revealed that these compounds are capable of inducing placental stress, abnormal placentation, and future health risks (Varshavsky et al. 2021). Although Alvarez-Silvares and colleagues have linked high levels of prenatal exposure to OPs to appropriate newborn birth weight ( Alvarez-Silvares et al. 2021), whilst other studies have identified spontaneous abortion and whether the newborns' weight were low or appropriate as a consequence of exposure to OPs (Luo et al. 2020, Cecchi et al. 2021, Zhao et al. 2021).

Disruption of maternal and fetal endocrine hormones and neurological function
Importantly, maternal-fetal transfer of OPs could affect fetal reproductive hormones. For example, Qin et al indicated that prenatal exposure to OPPs resulted in lower levels of E 2 , testosterone, testosterone/E 2 ratio, and FSH in cord blood. In addition, the researchers emphasized the greater vulnerability of female infants than males (Qin et al. 2020). Furthermore, multiple studies have reported that exposure to OPs during pregnancy could impair the function of thyroid hormones in both mothers and neonates by altering T 3 , T 4, and TSH levels , Percy et al. 2021, Tao et al. 2021, Yao et al. 2021). An endocrine disruptive consequence that has been attributed to the induction of oxidative stress, due to the significant correlation between dibutyl phosphate and diphenyl phosphate levels in maternal urine samples with 8-OHdG and MDA levels, eliciting damage to DNA and lipid peroxidation (Yao et al. 2021).
More seriously, neurological consequences could occur upon prenatal exposure to OPs. For instance, a recent study indicated that pregnancy exposure to OPEs is associated with a higher risk of attention-deficit hyperactivity disorder (ADHD) in offspring . Moreover, researchers have recently measured the maternal urinary levels of three dimethyl alkyl phosphate and three diethyl alkyl phosphate metabolites, and assessed children's IQ scores with generalized estimating equations (GEEs) when they were 3 to 4 years old. Accordingly, the results demonstrated that maternal exposure to OPs during pregnancy could lead to poorer Verbal IQ in boy children (Nkinsa et al. 2020). Therefore, the outcomes of exposure to OPs are not limited to damaging female fecundity but can be followed by catastrophic consequences due to the possibility of motherfetus transfer.
Antioxidants as preventive agents against OPs-Induced female reproductive toxicity Due to the vital importance of preventing OPsinduced toxicity in the female reproductive system, many experimental studies have been conducted to find an ideal solution. Due to the fact that toxicity in female reproductive tissues upon exposure to OPs is induced by biochemical mechanisms, such as promotion of oxidative imbalance, acceleration of apoptosis, and disruption of sex steroid biosynthesis, various experimental studies have shown the preventive effects of antioxidant compounds, such as vitamins, herbal adjuvants, and phytoestrogens. In the following section, we will briefly discuss some of these studies.

Vitamins
Vitamins E and C have surprisingly been the most important vitamins to prevent OPs toxic effects on the female fecundity. In this regard, it is demonstrated that vitamin E could inhibit diazinon-induced apoptosis in rat ovarian tissue (Sargazi et al. 2016). Concomitantly, the reduction of glutathione content and increased levels of malondialdehyde following exposure to diazinon were modified by vitamin E (Sargazi et al. 2014). More importantly, vitamin E was able to protect proliferative cells within ovarian follicles against diazinon (Sargazi et al. 2019). Meanwhile, ascorbic acid (vitamin C) reduced lipid peroxidation and increased glutathione content in the ovaries of animals exposed to malathion (Arab et al. 2018).
In addition, a number of studies have examined the effects of co-administration of vitamins E and C on the improvement of OPs-induced reproductive toxicity. A study by Oral et al. depicted that the co-administration of these two antioxidative vitamins with dichlorvos could recover histopathological alterations, increased levels of caspase-3 and À9 (indices of apoptosis), and elevated levels of lipid peroxidation, hence alleviating OPs-induced endometrial damage (Oral et al. 2006). Similarly, an ultrastructural and histopathological study revealed that these vitamins were capable of preventing fallopian damage caused by methyl parathion (Guney et al. 2007). Furthermore, the supplementation of these vitamins mitigated glyphosate-induced toxicity in caprines granulosa cells via reducing apoptosis and oxidative stress (Bhardwaj et al. 2019).

Herbal compounds and phytoestrogens
It has been suggested that green tea, which contains polyphenolic compounds with several free OH-groups, such as catechins and Epigallocatechin-3-gallate, flavonoid phytoestrogens, is capable of ameliorating adverse effects of malathion via modulating serum levels of E 2 , P 4 , LH, and FSH, and preserving ovarian primary and secondary follicles (Sadat et al. 2015). Similarly, a recent study by Farag et al. demonstrated that green tea polyphenol epigallocatechin-3-gallate could ameliorate adverse effects of chlorpyrifos on reproductive hormones biosynthesis, oxidative balance, and ovarian weight and follicular reserve (Farag et al. 2020).
Moreover, the anti-oxidative, anti-inflammatory, and antiapoptotic properties of 6-Gingerol have been sought after for protecting against chlorpyrifosinduced toxicity in the ovaries and uterus (Abolaji et al. 2017). In addition, the extract of Broccoli Sprouts, a natural plant product rich in antioxidants, has been revealed to be effective in preventing triazophosinduced ovarian toxicity via modulating the levels of oxidative stress markers such as catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, and lipid peroxidation. Concomitantly, improved ovarian histoarchitecture, reduced apoptotic granulosa cells and follicular atresia, and preserved sex steroids resulted (Sharma and Sangha 2021). Furthermore, Chebab et al. demonstrated that Pistacia lentiscus contain protective properties against chlorpyrifos-induced alterations in LH, FSH, E 2 , and P 4 levels, and oxidative markers such as malondialdehyde and protein content (Chebab et al. 2017). Interestingly, when Kumar et al. studied the bioremedial properties of Withania somnifera (Ashwagandha) and Curcuma longa (Turmeric) against chlorpyrifos exposed animals, the findings showed that the levels of E2 and cholesterol were restored, and the degenerated germinal epithelium, Graafian follicles, and corpus luteum were ameliorated (Kumar et al. 2015). The amelioration of malathion-induced estrus cycle disorder via attenuating oxidative stress, apoptosis, and autophagy in the ovarian tissue resulted upon administration of resveratrol, a non-flavonoid polyphenol compound abundantly presents in grape leaves (Yong et al. 2021).

Conclusion
The application of OPs continues to rise all over the world as these chemicals are attractive alternatives to formerly used compounds. However, global widespread and unlimited application of various OPs, that effortlessly leak into the environment, is associated with devastating consequences on the fertility of aquatic inhabitants, mammals, and women. Such effects may occur via the induction of detrimental alterations in reproductive organs histoarchitecture, damaging oocytes, changing the physiological levels of sex hormones and gonadotropins, interruption in oxidative balance, disruption of signaling pathways, and interfering with metabolites homeostasis and energy metabolism, followed by poor pregnancy outcomes that threaten the health of subsequent generations. Thus, the present review advocates that there is a necessity to make immediate and appropriate efforts to restrict the current widespread application of OPs, or to change their chemical structure to make them more water-soluble to disseminate, in an affordable manner, into the environment through dissolution, abrasion, and volatilization, which would lead to a reduction in the probability of persistence or bioaccumulation in the environment, a lower possibility of movement in the ecosystem via food webs, and lower risk in causing reproductive toxicity.

Author contributions
MSN contributed conception and design of the study, MSN, AS, and SV directed the study, AS, SV, AA, and NK wrote sections of the manuscript, MSN wrote the first draft of the manuscript and designed figures and tables, MSN, BNJ, NJ, SV, CC, MM, and NK critically revised the manuscript. All authors contributed to manuscript revision, and read and approved the submitted version.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.