Improving Reproductive Performance and Health of Mammals Using Honeybee Products

Honeybee products have positive effects on the reproductive performance of mammals. Many honeybee product constituents are biologically active, with antioxidant, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, antifungal, wound-healing, and cardio-protective properties. Honeybee products also improve male and female fertility rates by enhancing gamete cryopreservation, in vitro maturation and fertilization, and embryo development. Previously published studies confirmed their efficacy for alleviating reproductive toxicity caused by contaminants and lifestyle habits that impair overall health and well-being. However, high-dose oral administration of honeybee products may adversely affect the reproductive system, and unfavorable effects were alleviated by treatment cessation. For this reason, this review proposes that bioactive components from bee products can be used as a strategy for improving the reproductive performance and health of mammals.


Introduction
Procreation is a pivotal innate physiological event for all creatures. For humankind, reproductive health and fertility are of particular importance for maintaining social, mental, and physical health status. Supporting adequate reproductive performance in foodproducing animals is also important to humans, enabling mass production to maintain food security. However, reproductive events and fertility of individuals/organisms are greatly impacted by modern lifestyle circumstances such as increased exposure to environmental and behavioral stresses. According to a World Health Organization report, 60-80 million couples, representing 8-12% of couples worldwide, are currently experiencing infertility [1][2][3]. Similarly, poor reproductive efficiency is evoked in production animals owing to management practices for producing animal products in massive quantities [4]. Therefore, research endeavors to improve and maintain adequate reproductive health are essential for humankind and animals.
The use of natural products as alternatives to synthetic prophylactic and therapeutic drugs is increasingly recommended to improve many aspects of human and animal health [5]. Honeybee products, including honey, propolis, royal jelly, bee pollen, beeswax, drone brood, bee venom, and bee bread, contain several natural bioactive components with various pharmaceutical and nutritional properties. Given the chemical constitutes of these products, honeybee products may have beneficial prophylactic and therapeutic effects on reproductive health in mammals. For example, honey is an energy-rich product that contains substantial concentrations of polyphenolic compounds with antioxidant activity [6][7][8][9], which can improve reproductive events by improving energy status [10,11] and/or redox Chemically, honey is a natural food substance mainly composed of simple sugars, along with minor constituents such as minerals, vitamins, amino acids, organic acids, flavonoids and other phenolic compounds, and aromatic substances [13]. Generally, sugars comprise 95-99% of honey dry matter, mainly in the form of fructose (32-38% of total sugars). In addition, several other monosaccharides (glucose), disaccharides (sucrose and maltose), and oligosaccharides (maltotriose and panose) are found in honey. Low concentrations of proteins (0.5%) in the form of enzymes (amylase, sucrase or α-glucosidase, and glucose oxidase) and more than 20 individual amino acids (proline is the most important) have also been identified [8]. Organic acids (0.57%; gluconic, acetic, butyric, citric, formic, lactic, malic, pyroglutamic, and succinic acids) as well as major and minor minerals (calcium, magnesium, sodium, potassium, phosphorus, sulfur, zinc, iron, copper, and manganese) are also components of honey. In addition, vitamins such as ascorbic acid (vitamin C), thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), nicotinic acid (vitamin B 3 ), pantothenic acid (vitamin B 5 ), pyridoxine (vitamin B 6 ), biotin (vitamin B 8 ), folic acid (vitamin B 9 ), and cyanocobalamin (vitamin B 12 ) are present in measurable concentrations [40,42]. Honey also contains significant amounts of bioactive polyphenols, including phenolic acids (vanillic, caffeic, syringic, p-coumaric, ferulic, ellagic, 3-hydroxybenzoic, chlorogenic, 4-hydroxybenzoic, rosmarinic, gallic, and benzoic acids) and flavonoids (quercetin, kaempferol, myricetin, pinobanksin, pinocembrin, chrysin, galangin, hesperetin, and others) [8,43]. The unique chemical composition of honey confers several nutritional and medicinal properties [42]. Honey has a long history of use in traditional medicine owing to its antioxidant, hepato-protective, cardio-protective, anti-inflammatory, antidiabetic, hypolipidemic, anticancer, gastrointestinal-protective, and wound-healing properties. In addition, honey produces antibacterial effects against several microorganisms, including Escherichia coli, Shigella spp., Helicobacter pylori, and Salmonella spp. [13].

Royal Jelly
Royal jelly is a thick, viscous, and milky natural substance that is formed as a result of incomplete digestion of honeydew in the stomach of a bee worker [44]. In the hive, royal jelly is fed to larvae developing into female workers and male drones until they are three days old, while individuals developing into future queens are fed royal jelly throughout the larval period. Moreover, royal jelly is provided as a special nutrient for adult queens throughout their lives [13,[45][46][47]. Nutritionally, royal jelly is a high-value nutrient, consisting of proteins (27%-41%), carbohydrates (30%), and lipids (3%-19%). It also contains a unique group of nine soluble proteins called major royal jelly proteins (MRJPs), of which MRJPs 1-5 account for approximately 82%. Several antioxidant peptides have been isolated from royal jelly hydrolysate, some with robust hydroxyl radical scavenging activity. Moreover, royal jelly peptides such as jelleines, royalisin, and apisimin exhibit antimicrobial activity [15]. Fatty acids are the major lipid constituents (mainly hydroxydecanoic acid), followed by phenolic lipids, waxes, steroids, and finally phospholipids [48]. Royal jelly also provides a valuable energy source thanks to its enrichment with carbohydrates (3.4%-7.7% glucose, 2.3%-7.8% fructose) and energy-rich molecules such as adenosine monophosphate [15]. In addition, royal jelly contains phytosterols, flavonoids, vitamins (B 9 , B 1 , niacin, B 3 , B 5 , B 2 , B 6 , and beta-carotene), minerals (iron, potassium, zinc, magnesium, and copper), and hormones (prolactin, testosterone, estradiol, and progesterone) [15]. The diverse royal jelly chemical composition confers several pharmaceutical and nutraceutical properties, such as antibacterial, antioxidant, anti-inflammatory, antidiabetic, hypotensive, hepato-protective, antitumor, and hypoglycemic properties [46][47][48][49]. Moreover, immunomodulatory activities and estrogen-like effects have been reported. Accordingly, royal jelly has been widely used in commercial medical products, health foods, and cosmetics for more than 35 years [49].

Propolis
Propolis (bee glue) is a dark-colored resinous substance that honeybees produce by mixing collected plant parts (buds, floral buds, leaves, branches, and barks) and salivary gland secretions. In ancient Greek, propolis means defense of the city; the antiseptic and antimicrobial substance is used in the hive to maintain colony health. Thus, propolis has been identified as a natural antibiotic candidate [50]. Raw propolis is typically composed of 50% plant resin, 30% wax, 10% essential and aromatic oil, 5% pollen, and 5% other organic substances. The color of propolis varies from green to brown and reddish, depending on its botanical source [1]. Propolis cannot be commercialized as a raw material; it must be purified and dewaxed via solvent extraction to remove inert materials and preserve the phenolic fractions [13]. Propolis has been classified into seven main types according to the plant source: (1) poplar propolis: the most widespread type of propolis (Europe, North America, New Zealand, and non-tropical regions of Asia), (2) green propolis or Baccharis propolis, (3) red propolis or Clusia (Brazil, Cuba, Venezuela, and Mexico), (4) eucalyptus propolis, (5) Taiwanese green propolis or Macaranga propolis (Okinawa prefecture in Japan, Taiwan, and Indonesia), (6) birch propolis (Russia), and (7) Mediterranean propolis (Greece, Sicily, and Malta) [13]. Among the types of propolis, poplar and Brazil green propolis are the most commercially available and widely studied [50,51]. The biological activities of propolis, including antioxidant, antimicrobial, antiviral, anti-inflammatory, antifungal, wound-healing, and cardio-protective properties, have been ascribed to the action of phenolic compounds and terpenoids [11,14].

Bee Venom
Bee venom, also known as "apitoxin", is a colorless, acidic liquid that is synthesized in the honeybee venom gland. Honeybee defense mechanisms against threatening attacks involve the injection of bee venom into the body of the attacker, evoking several neurological, immunological, and inflammatory responses [52,53]. The chemical constituents that distinguish bee venom are a group of amphipathic polycationic peptides, predominantly melittin and apamin. Bee venom also contains peptides such as mast-cell degranulating peptide, adolapin, tertiapin, secapin, melittin F, and cardiopep [54], as well as amines such as histamine and catecholamines [55]. Some of these peptides trigger cell lysis, while others act as neurotoxins [56]. Melittin acts as a detergent, binding and breaking down the cell membrane lipid bilayers [57]. Apamin exerts a highly specific toxicity mechanism, blocking the small conductance Ca 2+ -dependent K + channels (SK channels) expressed in the central nervous system, cardiovascular system, and smooth muscle [7]. Despite the toxicity, bee venom has been used as an analgesic, antimutagenic, antinociceptive, and radio-protective immunomodulatory agent and was identified as a potential Parkinson's disease therapy [7]. Furthermore, some substances extracted from bee venom can be included in domestic animal diets as antimicrobial agents to enhance productive performance and health status [36].

Bee Pollen
Bee pollen is a mixture of flower pollen (male germ element), nectar, enzymes, honey, beeswax, and honeybee salivary secretions gathered and produced by worker honeybees [13]. Bee pollen is a rich source of nutrients such as protein (25%), essential amino acids, oil (6%), polyunsaturated fatty acids (13% linoleic acid and 39% linolenic acid), 28 minerals, 12 vitamins, 11 enzymes or coenzymes, carbohydrates (35%-61%; sucrose, glucose, and fructose), carotenoids, flavonoids, and phytosterols [58,59]. Bee pollen is an energy-boosting food that is used by humans as a diet supplement. The high content of protein, fat, and minerals (particularly Ca, Mg, Fe, and P) in bee pollen provides a nutritional value similar to that of dried legumes. B 5 and B 3 , vitamin C, and B 2 levels are comparable to those of beef, vegetables (lettuce and tomatoes), and skimmed milk powder, respectively [60]. Bee pollen is used in complementary and alternative medicine to cure prostatitis, stomach ulcers, and infectious diseases, as well as to prevent and treat high-altitude-sickness syndrome. A wide range of therapeutic properties have been reported, including antimicrobial, antioxidant, hepato-protective, chemo-preventive and anti-carcinogenic, anti-atherosclerotic, anti-inflammatory, antiallergenic, and immunomodulatory activities [60][61][62].
Beeswax is a substance produced by honeybee wax gland complexes to make combs; the greatest quantity is produced during the colony growth phase in late spring [65]. Chemically, beeswax contains more than 300 identified components. Hydrocarbons such as heptacosane, nonacosane, hentriacontane, pentacosane, and tricosane are the main components, along with free fatty acids and fatty alcohols, linear wax monoesters, hydroxymonoesters, complex wax esters, and more than 50 other aromatic components [66]. Beeswax is used as an additive in a variety of industrial, pharmaceutical, and cosmetic products; however, to the best of our knowledge, no specific studies on the relationship between beeswax and reproduction have been published [13].
Bee bread contains abundant high-quality proteins; carbohydrates; fatty acids; vitamins (B-group, C, K, E, and D), especially vitamin P (rutin) and provitamin A (carotene); various minerals; oligo-elements (especially K and Fe); essential oils; enzymes; pigments; and other biologically active natural substances [67]. No other natural product contains such high concentrations of vitamin P (rutin; 13 mg/100 g of bee bread), which can improve the condition of blood vessels. Moreover, bee bread boosts the immune system and has been used to tackle chronic inflammation of the prostate, male sterility and impotence, endocrine glands disorders, and decreased libido, as well as to improve intra-uterine nutrition. Bee bread also produces a strong antiseptic effect on a wide range of pathogenic microorganisms [67]. A summary of the chemical composition of honeybee products is shown in Table 2.

Biological Effects of Honeybee Products on Reproduction
Owing to the diversity of chemical constituents in honeybee products, a wide range of biological effects on reproductive functions could be achieved via several biological mechanisms/pathways. For example, most honeybee products contain phenolic compounds, widely known to affect reproduction in mammals. Phenolic compounds can regulate gonadal steroidogenesis and the functionality and metabolism of sex steroid hormones [70,71]. In addition, phenolic compounds can affect the expression of genes and activity of enzymes (aromatase, topoisomerases I and II, and extracellular signal-regulated kinases) involved in the regulation of reproductive events. Phenolic compounds can also contribute to cellular apoptotic/proliferation, epigenetic, antioxidant, and inflammatory pathways [72]. Metabolic status may also be affected by phenols owing to their ability to regulate metabolic hormone signals such as growth hormone, insulin-like growth factors, and triiodothyronine, as well as lipid, protein, and carbohydrate metabolism. Furthermore, sex hormones have been detected in some bee products, such as royal jelly and drone brood, which can thus modulate endocrine system functions [15]. Drone brood is rich in male sex hormones, especially testosterone, producing an androgenic effect that enhances male sex features. Drone brood can also be classified as a natural anabolic agent that can increase body muscle weight in male individuals [63,73]. Additionally, nutrients, vitamins, and minerals can directly affect reproductive tissues, reinforcing their functions and improving gametogenesis and/or the quality of gametes [74]. Therefore, honeybee products can provide effective tools for improving reproductive functions in vivo and assisted reproductive technique (ART) outputs in vitro. The potential effects of honeybee products on mammalian reproductive functions and ARTs are shown in Figure 1.

Applications for Improving Male Fertility
Recent studies on the effects of honeybee products on male reproductive performance in mammalian species are shown in Table 3. Several studies have supported the traditional use of honey as a natural product to enhance reproductive efficiency and fertility in males [31][32][33]. Honey has been demonstrated to improve libido, erectile function, spermatogenesis, epididymal sperm count, and normal sperm percentage, and reduce the percentage of sperm head and tail abnormalities and chromatin damage in mammalian species, including humans [16,17] and rats [31][32][33]. The positive effects of honey on male reproductive performance are attributed to several different mechanisms. Honey can increase the activity of enzymes that affect sperm quality, such as sorbitol dehydrogenase [31], which converts sorbitol into fructose, an important nutrient for sperm metabolism and motility. Additionally, honey administration improves spermatogenesis by enhancing male sex hormones, specifically testosterone. This enhancement was mediated by luteinizing hormone synthesis, Leydig cell viability, upregulation of steroidogenic acute regulatory pro-tein expression, and aromatase activity in the testes [75]. In addition, bioactive compounds with antioxidant activity (e.g., antioxidant polyphenols such as flavonoids and phenolic acids) can provide reproductive organs with a robust defense system against oxidative stress induced by elevated levels of reactive oxygen species (ROS) [33]. Furthermore, honey can treat dysfunctional erection or impotence by modulating the biosynthesis of nitric oxide, a chemical substance involved in vasodilatation that affects erectile function [16,17].   Propolis is another honeybee product shown to improve the reproductive performance of mammalian males. Several studies confirmed that administration of propolis improved sperm count and testis, seminal vesicle, and epididymis weights, and reduced the percentage of sperm head and tail abnormalities [14,[19][20][21][22][23]. Moreover, the administration of propolis extract increased serum testosterone levels, coupled with increased activity and expression of testicular steroidogenesis enzymes including 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD) [24], improving testosterone levels [25]. Propolis also shows strong antioxidant and modulatory activity on cellular mitochondrial energy production [19].
Royal jelly also produced many beneficial effects on male reproductive performance in mammals. As indicated by studies conducted on adult male rats [23,[26][27][28] and rabbits [22,29,30], royal jelly enhanced spermatogenesis, steroidogenesis, sperm quality traits, and libido of treated males. Interestingly, royal jelly contains acetylcholine (1 mg/g dry weight), a peripheral and central neurotransmitter. Acetylcholine can stimulate gonadotropin secretion at both hypothalamic and hypophyseal levels, consequently increasing plasma testosterone levels. Most studies have focused on the major products of honeybees (honey, propolis, and royal jelly); however, beneficial effects of other honeybee products, such as drone brood [34,35], bee venom [36], and bee pollen [18], on male reproductive health have also been reported. These products contain active constituents that can affect reproductive functions, such as apistimul in drone brood [34]. Table 4 summarizes recent studies on the effects of honeybee products on female reproductive performance in mammalian species. Honey [76], royal jelly [46,[77][78][79][80][81], propolis [82,83], and bee pollen [82][83][84][85] were demonstrated to improve female reproductive performance in several mammals. Treatment with royal jelly improved estrus response and pregnancy rate in ewes by enhancing ovarian follicle growth and development and estradiol secretion [80]. Interestingly, Gimenez-Diaz [78] and Kridli [86] reported that royal jelly can mimic the actions of gonadotropins to improve estrus response and conception rate in ewes, providing a promising natural alternative to equine chorionic gonadotropin (eCG). The positive effects of royal jelly on reproductive performance may be partially ascribed to its estrogenic effects [81].

Applications for Improving Female Fertility
The positive effects of bee pollen on female reproductive performance are welldocumented. Bee pollen can improve rabbit doe reproductive performance and milk production and enhance the immune status and growth performance of their offspring [84][85][86]. These results were attributed to the high micronutrient content (e.g., polyunsaturated fatty acids, minerals, vitamins, amino acids) and biological actions of flavonoids, carotenoids, and phenolic compounds in bee pollen [81]. Furthermore, bee pollen can regulate sex steroidogenesis, specifically progesterone and estradiol [87,88]. Hormonal balance is important for adjusting the mechanisms underlying the fate of ovarian follicles, involving cross-dialog between pro-apoptotic (caspase-3, Bax) and pro-survival anti-apoptotic (Bcl-2) molecules [87,88]. The dose and time of administration of bee pollen can both affect these pathways; positive and negative effects on ovarian follicle development and growth could be obtained using different administration methods [87].  In models designed to study menopausal symptoms, Zaid et al. [76] noticed that daily consumption of Tualang honey for two weeks by ovariectomized female rats suppressed menopause-related reproductive disorders, including uterine atrophy, vaginal epithelium atrophy, and osteoporosis. The positive effects of Tualang honey are likely due to flavonoids, particularly kaempferol and quercetin, which have weak estrogenic activity. Further, flavonoids are strong free radical scavengers, protecting organisms from the destructive actions of ROS [72,76]. Interestingly, local vaginal application of honey and royal jelly before sexual intercourse improved fertility in couples having trouble conceiving [88].

Male-Associated Assisted Reproductive Techniques
The efficiency of ARTs depends on the appropriate manipulation of gametes (sperm cells) during each stage of handling, starting from semen collection, followed by dilution, cooling, cryopreservation, and finally transfer to the female reproductive tract. During these processes, sperm cells might be exposed to thermal and physicochemical stresses, which can cause serious damage to the sperm cell membrane and DNA, thereby decreasing semen quality [89,90].
One of the important factors that can affect sperm cell quality is the medium in which sperm cells are placed for ART. Ideal media should minimize and protect sperm cells against physicochemical stresses; thus, the composition should prevent alterations to the structure and function of sperm cells [90]. Several studies have described the benefits of honey as a natural cryoprotectant agent for maintaining semen quality kinetic parameters, sperm cell membrane and DNA integrity, and sperm cell morphology when included in semen cryopreservation media (human [91], cattle bull semen [92,93], buffalo bull semen [94], and rabbits [95,96]) and liquid storage media [97].
Honey contains a mixture of sugars, proteins, enzymes, amino acids and organic acids, vitamins, phenolic acids, and flavonoids that confer high antioxidant activity. An appropriate mixture of nutrients and bioactive components is necessary for maintaining adequate sperm quality. For example, simple sugars (glucose, fructose, and sucrose) in honey provide sperm cells with a preferable energy source [94,[98][99][100]. Additionally, the presence of components, such as organic acids (gluconic acid), phenolic acids, and flavonoids, with antioxidant and antibacterial activities can play a crucial protective role against the harmful effects of ROS and microbial attack [32]. Thus far, inhibitory effects of honey on 60 species of gram-positive and gram-negative bacteria (Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, and Bacillus cereus) have been reported; these effects are comparable in strength to antibiotics penicillin, streptomycin, and kanamycin [101].
Other studies have reported the beneficial effects of including royal jelly in sperm cellprocessing media on sperm cell quality and, later, fertility in some mammals (rams [102,103], goats [104], and buffalo bull [105,106]). The protective role of royal jelly was mainly ascribed to its unique amino acid profile [107]. Royal jelly contains many vital amino acids, including valine, aspartic acid, isoleucine, tyrosine, glycine, lysine, proline, cysteine, and leucine. Proline has been demonstrated to maintain sperm cell membrane integrity under stressful conditions [108] and both cysteine and proline act as robust antioxidant agents to eliminate ROS and stimulate glutathione enzyme synthesis and activity during semen cooling-freezing processes [108]. Moreover, royal jelly vitamins (C and E) and 10-hydroxy-2-decenoic acid provide protective effects to the sperm cell membrane [109,110]. However, high concentrations of royal jelly produced negative impacts on sperm cell quality [103], thus careful consideration of the concentration in media is essential.
Propolis has also been included in semen preservation media, providing antioxidant and antimicrobial activity [111][112][113] and maintaining semen characteristics such as motility, viability, and DNA integrity [114]. The effects of honeybee products on male ARTs are shown in Table 5.

Female-Associated Assisted Reproductive Techniques
For females (Table 6), in vitro maturation (IVM) and in vitro fertilization (IVF) are the most common ARTs, the outcomes of which relate to oocyte quality. Thus, improving the oocyte microenvironment during IVM and IVF has the potential to improve ART outcomes, with corresponding improvements in reproductive efficiency in humans and animals. Under normal circumstances, oocytes receive essential elements, proteins, growth factors, hormones, antioxidants, and other compounds directly from the female reproductive fluids. Consequently, artificially formulated media for oocyte IVM or IVF should contain elements that correspond to the natural sources in the fluids of the female reproductive tract [115,116]. Given the chemical constituents of honeybee products, the inclusion of the honeybee product(s) in IVM or IVF media may have positive effects on oocyte maturation, oocyte fertilizability, and division and embryo development. The addition of honey (black seed bee honey) to sheep IVM medium has been shown to improve oocyte maturation rate, glutathione levels, and gene expression of GDF-9, BAX, cyclin B, C-MOS, and IGF1 genes. Similarly, the addition of royal jelly to goat oocyte [117] medium or ovine IVM medium [118] improved oocyte and nuclear maturation rate, fertilization rate, and blastocyst formation. These improvements seem to be a result of decreased expression of apoptosis-inducing genes, increased glutathione-S-transferase enzymes content, and enhanced mitochondrial activity, which lead to a reduction in blastocyst apoptosis rates [87,[117][118][119]. The positive effect of royal jelly on oocyte maturation is related to the presence of antioxidant amino acids (cysteine, lysine, and arginine) and polyphenols [117].

Reproductive Toxicity of Pollutants and Heavy Metals
Recently, synthetic chemicals used for different industrial and agricultural purposes have been increasing environmental pollution. Exposure to these chemicals via direct contact during manufacturing and handling, consumption of polluted foods/water, or inhalation of polluted air can cause reproductive toxicity and increase the risk of subfertility/infertility.
Heavy metals such as cadmium chloride (CdCl 2 ) [120], copper (Cu) [121], and aluminum chloride (Al Cl 3 ) [122] have been confirmed to induce subfertility/infertility in male and female mammals. These heavy metals can exert reproductive toxicity through several mechanisms. Heavy metals can accumulate inside vital organs and gonads and can evoke oxidative and inflammatory stress, leading to negative impacts on reproductive function, hormone balance, gamete quality, and fertilizability of gametes, as well as producing teratogenic effects in fetuses [120][121][122][123][124]. The efficacy of honeybee products for alleviating heavy metal reproductive toxicity has been demonstrated. Royal jelly was shown to fix hormonal alterations, oxidative status, inflammatory response, and apoptotic cascades induced following Cd-exposure, presumably due to its potent antioxidant activity [120]. Similarly, propolis protected against the toxic effects of excess Cu [121] or Al Cl 3 [122] on testicular tissue and semen quality traits in rats, as well as by scavenging ROS and improving testicular and blood plasma redox status.
Synthetic pesticides, such as chlorpyrifos (organophosphorus insecticide), cypermethrin, and triphenyltin, are used to control a variety of agricultural, animal farming, and indoor pests [123][124][125][126][127][128]. Such chemicals can induce direct reproductive toxicity and may also act as endocrine disruptors, producing estrogen or androgen-like effects [125] and leading to various health hazards. Several studies have confirmed the protective role of propolis against pesticide-induced reproductive toxicity in males [25,122] and females [126]. The protective role of propolis is ascribed to the antioxidant and anti-inflammatory actions of polyphenols baicalin, lucenin 2, and quercetin against neuroprotective toxicity. Moreover, the anti-inflammatory activity of alkaloids and hepato-protective role of the organosilicon compounds in propolis were proposed as protective mechanisms [125]. Interestingly, honeybee products could also be used to reduce the toxicity of naturally occurring toxins. El-Nekeety et al. [126] reported that royal jelly resulted in a significant reduction in the toxic hazards of fumonisins (mycotoxins), likely due to increased glutathione peroxidase synthesis and suppression of lipid peroxidation and free radical generation by antioxidant enzymes. The protective effects of honeybee products against chemical stress induced reproductive toxicity in mammals are summarized in Table 7.

Unhealthy Lifestyle and Psychological Stresses
Lifestyle factors related to individual habits and ways of life can substantially impact overall health and well-being, including reproductive health. Nutrition, weight, exercise, psychological stress, and other factors can have substantial effects on fertility (Table 8). Lifestyle factors such as cigarette smoking and drug addiction can negatively influence fertility [127]. For instance, smoke from cigarettes, household wood and coal fires, barbecue grills, and automobile exhaust can elevate levels of harmful toxins, such as nicotine [128] and benzo[a]-pyrene [129], in the bloodstream. These toxic compounds are associated with decreased sperm count and motility and an increased percentage of morphologically abnormal sperm, sperm chromatin damage, erectile dysfunction, and early pregnancy loss [130]. Studies using animal models found that the negative impacts of toxins could be mitigated by the consumption of honey [131], royal jelly [128], and propolis [129]. The positive impacts of honeybee products are related to their antioxidant and endocrinemodulating activity, as some bee products, specifically royal jelly, include sex hormones among their constituents [85]. Human exposure to harmful synthetic chemicals may also occur because of the use of chemicals in food and healthcare products, which are considered safe for humans. For example, monosodium glutamate (MSG; flavor enhancer) is used as an ingredient in various food products; however, negative impacts of MSG on male infertility (testicular hemorrhage, degeneration and alteration of sperm cell population and morphology) have been documented [132]. Similarly, sodium fluoride, a main component of toothpaste, can induce reproductive disorders [133]. Bee propolis has been identified as a suitable supplement for alleviating such negative effects [133,134].
Furthermore, psychological stress contributes to many reproductive disorders and dysfunctions. Haron et al. [135] found that administering Tualang honey (1.2 g/kg daily) to restraint-stressed pregnant rats conferred beneficial effects on reproductive parameters, such as corticosterone level and pregnancy outcome. Another study on rats exposed to prenatal restraint stress reported that impaired reproductive function in male rat offspring could be improved by feeding dams honey (1.2 g/kg, three times per day) from day 11 of pregnancy until delivery [136]. Moreover, Rajabzadeh et al. [137] reported that dissolving 0.2 mL of 5% honey in the water of rats exposed to auditory stress significantly improved fertility rates and fetus health.

Precautions and Hazards
As shown through the review, honeybee products have several beneficial effects on the reproductive health of mammals. However, adverse effects of honeybee products on reproduction in mammals have been also reported, specifically when they are consumed during critical periods of the reproductive cycle, such as puberty and pregnancy. The effects of royal jelly on the reproductive system of puberty male rats were investigated in vivo after daily administration of royal jelly at doses of 200, 400, and 800 mg/kg for four weeks. The high-dose royal jelly oral administration adversely affected the reproductive system by decreasing testis weight, changing testis microstructure, and increasing sperm deformity rate of the assayed rats, but the unfavorable effects were alleviated by treatment cessation [37]. The adverse effects of royal jelly were attributed to the estrogenic activity of a high dose of royal jelly. In males, the improper intake of substances with estrogenic activity can adversely affect the reproductive performance of males at different reproductive windows [138,139]. In another study, a low dose of Indonesian propolis (380 mg/kg) and a high-dose of propolis (1400 mg/kg) were provided to mice for 18 days of gestation to confirm the safety of consuming propolis during pregnancy [38]. The low dose of propolis increased weight, crown-rump length, and ossification center thickness compared with the control group. Conversely, the high-dose of propolis reduced weight, crown-rump length, and ossification center thickness and caused hypertrophy of the placenta, inhibiting fetal development. These results may be attributed to the immunomodulatory properties of propolis, as fetal resorption may occur due to rejection via the immune system pathway. Increased macrophage activity in the endometrium during pregnancy leads to increased production of NO and TNF-α, which are toxic to embryo development. Further, it was found that colony-stimulating factor-1 (CSF-1) increased resorption in pregnant mice; CSF-1 plays an important role in the differentiation of macrophages. The anticancer activity of propolis was also proposed as an underlying mechanism of fetal growth retardation in high-dose groups. It is known that most anticancer agents are teratogens, and vice versa. Thus, some natural products that have anticancer effects may also be teratogenic. However, teratogenic effects were not observed after the administration of low doses [38]. Therefore, honeybee product dose should be carefully considered, as high concentrations of royal jelly and propolis can negatively impact sperm cell quality and fetal development [104].

Conclusions
The study of the unique chemical composition of honeybee products and their effects on the reproductive performance of mammals provides opportunities to detect pharmaceutical molecules for safe reproductive health manipulation. The biological activities (e.g., antioxidant, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, antifungal, wound-healing, and cardio-protective) of honeybee products were ascribed to the phenolic compound and terpenoid constituents. Honeybee products have been demonstrated to improve libido, erectile function, spermatogenesis, epididymal sperm count, and normal sperm percentage, as well as to reduce sperm head and tail abnormalities and chromatin damage in many mammalian species. The benefits of using bee honey as a natural cryoprotectant agent in semen cryopreservation and liquid storage media were also reported. Moreover, honeybee products can improve female reproductive performance and milk production and fetal immune status and growth performance. Given the chemical constituents of honeybee products, inclusion in in vitro maturation (IVM) or in vitro fertilization (IVF) media may produce positive effects on oocyte maturation, fertilizability, and division and embryo development. Many studies have also confirmed the efficacy of honeybee products for alleviating the reproductive toxicity of chemical contaminants and pollutants. However, high-dose oral administration of honeybee products may adversely affect the reproductive system; thus, doses should be carefully considered when administering such products. Overall, the bioactive components of honeybee products, when wisely used, can provide a natural approach for improving the reproductive performance and health of mammals.