Effect of Environmental Contaminants on Mammalian ...

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Effect of Environmental Contaminants on Mammalian Testis Faustin Pascal Tsagué Manfo1*, Edouard Akono Nantia2 and Premendu Prakash Mathur3* 1

Department of Biochemistry and Molecular Biology, Faculty of Science, University of Buea, PO Box 63 Buea, Cameroon; 2Department of Biochemistry, Faculty of Science, University of Bamenda, PO Box 39 Bambili, Cameroon; 3KIIT University, Bhubaneshwar-751024, Odisha, India Abstract: Exposure of humans and wildlife to pollutants released in the environment is a centre of attention nowadays. Many of these chemicals (generally referred to as environmental pollutants) have been shown to interfere with normal hormonal signalling and biological functions, Faustin Pascal Tsagué Manfo leading to reproductive disorders or infertility, which has been a matter of concern within the Premendu Prakash Mathur recent decades. The present paper reviews adverse effects of these toxicants on mammalian testes, with emphasis on alteration of steroidogenesis, spermatogenesis, and histopathological effects. From the publications reviewed, it appears that environmental toxicants, especially heavy metals and organic chemicals of synthetic and microbiological origins, disrupt hormone production and action in the mammalian testes. Endocrine disruption leads to disorders of testicular function and thereby compromises the normal p henotypic development of male sexual characteristics, initiation and maintenance of spermatogenesis. The toxicants also induce impairment of testicular cells function, testicular histology, and sperm cells function directly. The release of the toxicants in the environment is still ongoing, despite alarming quantities that already exist in the atmosphere. If appropriate measures are not taken, their impact on the male reproductive function and especially on testicular function will be more serious.

Keywords: Hormone, mammal, spermatogenesis, testis, toxicity. I. INTRODUCTION Chemicals are used in a wide variety of products and processes while they are major contributors to national and world economies. Nowadays, there is hardly any industry where chemicals are not used and there is no single economic sector where chemicals do not play an important role. Chemicals have thus been produced in huge quantities, and have become an integral part of daily life in today’s world. These chemicals include organic chemicals, metals and their complexes, and radionuclides [1-3]. Organic chemicals include products from petrochemical industry (products derived from crude oil and natural gas), plastics, detergents, synthetic fibres, pesticides used in agriculture (herbicides, insecticides, fungicides), substances of microbiological (bacterial and fungal) origin (e.g., aflatoxins from fungi), etc., while metals include cadmium, zinc, copper, iron, etc. [2, 3]. These substances are being released into the environment in the course of their production, use, and disposal [1]. The environmental contaminants have been detected in crops, water, air, ground, etc. [2]. Environmental pollutants are in contact with humans and wildlife, and are thus capable of altering their physiology [4]. The World Health Organization (WHO) estimates that about a quarter of the diseases mankind is facing today occur *Address correspondence to these authors at the Department of Biochemistry and Molecular Biology, Faculty of Science, University of Buea, PO Box 63 Buea, Cameroon, Tel: +237 675 546 276, E-mail: [email protected] KIIT University, Bhubaneshwar-751024, Odisha, India; E-mail: [email protected] 1874-4672/14 $58.00+.00

due to prolonged exposure to environmental risks/pollution. Environmental factors are estimated to contribute for 24% of the global disease burden and 23% of all deaths [5]. Numerous studies have implicated these toxicants inducing dysfunctions such as respiratory difficulties, cancer, neurodegenerative disorders, immune disorders, hepatic damage, reproductive disorders (e.g., hypospadia, cryptorchidism), etc. [1, 6, 7]. Despite these adverse effects on human health, the pollutants are being produced and released in the environment continuously; and this could explain the decline in male fertility, as well as the high impact of environmental factors on human health [5]. Moreover, a 50% world-wide decline in sperm density among humans (from 1940 to 1990) has been reported by Carlsen et al. [8]. The frequency of pathophysiological conditions associated to male infertility are thus increasing, and several studies have shown that exposure to environmental toxicants (e.g., solvents, pesticides) represents one of the major triggering factors [9, 10]. Environmental toxicants affect the male reproductive system by directly interfering with the process of spermatogenesis in testis, or through dysregulation of the hypothalamic-pituitarytesticular (HPT) axis [Box 1]. The testis is among the most sensitive organs to xenobiotics within the male reproductive system. This observation is sustained by several analyses of existing reproductive toxicity study databases [11-13]. The high sensitivity of testis to xenobiotics makes it a good starting point for determination of the no observable adverse effect level (NOAEL) of toxicants in risk assessment studies. To facilitate such studies, the present review paper gathers information on the range of endpoints such as systemic and developmental toxicity of selected groups of environmental © 2014 Bentham Science Publishers

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toxicants that result in impairment of testicular function in mammals, with heavy reliance on animal data. II. PESTICIDES The need to produce more has made the agricultural chemistry more important with the rapid growth of the global population. This has led to extensive use of agrochemical products (pesticides) such as herbicides, insecticides, fungicides and fertilizers, to maximize yields per hectare, through elimination of diseases and sustainment of plant growth. Pesticides can contaminate human directly during farming activities when personal protective equipments are not appropriately used [14, 15]. In addition to lack of protective equipment, occupational exposure to agropesticides is sustained by increased time spent for cropping or spraying the pesticide, frequency and quantity of pesticide sprayed [3, 16]. These chemicals can also get into human system indirectly through contaminated food stuffs or water [14, 15]. Some pesticides have not been produced and used for few years only, but are very persistent and tend to accumulate in soil and sediments (e.g., dichloro-diphenyl-trichloroethane (DDT) and related metabolites). Once pesticides are introduced into the environment, they may travel beyond their point of application or discharge. Some pesticides including triazine group, dichlorophenoxyacetic acid and glyphosate, are used for road and rail weed treatment, gardens, parks and urban woodland areas [17]. Pesticides and related metabolites have been detected in biological samples (blood, urine) of exposed men [16, 18]. Their adverse effects on testicular function have been illustrated in studies involving men or experimental rodents. The nematocide dibromochloropropane (DBCP) is one of the best known pesticides with proven testicular toxicity in men [19, 20]. DBCP was widely used in the United States and other countries such as Costa Rica [19, 21, 22]. The pesticide induced oligozospermia and azoospermia in men involved in its manufacture in the factory, and in farmers who were using it on crops [20, 22, 23]. The deleterious effect was positively correlated with the duration of exposure [10, 23]. DBCP was demonstrated to induce elevation of serum gonadotropins (FSH) [23, 24] and DNA damage [21], and histological analyses in exposed men revealed testicular necrosis [22, 25]. The DBCP –induced adverse effects were confirmed and further clarified in experimental rats. Four daily injections of DBCP produced prolonged oligospermia in rats. Six and 20 weeks after DBCP treatment, about 10% seminiferous tubules were occluded or had morphologic Sertoli cells alterations in the exposed rats, while up to 70% of the tubules showed an epithelium with no differentiating germ cells [26]. The latter tubules without differentiating germ cells contained actively proliferating type A spermatogonia, which underwent apoptosis instead of differentiation; indicating that DBCP act on mammalian testis by inducing loss of stem cells’ ability to undergo differentiation. The proposed action mechanism was comforted by elevated levels of reproductive hormones (FSH levels and intratesticular testosterone concentrations) in the exposed rats [26]. The spermatogenic effects of DBCP are usually irreversible, though suppression of intratesticular testosterone and serum FSH levels with the GnRH agonist Lupron could induce increment

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of the percentage of tubules producing differentiating germ cells in DBCP –exposed male rats [19, 27]. The pesticide DDT has been banned in western countries because of its non target effects and its environmental persistence. Most of the endocrine effects induced by DDT and its major metabolite Dichlorodiphenoxydichloroethylene (DDE) result from the ability to mimic 17--estradiol. In experimental animals, DDT and its metabolites trigger their deleterious effect on spermatogenesis through direct action on Sertoli cells. DDE decrease the level of FSH binding sites, modulate expression of androgen binding protein (ABP), and induce mitochondria-mediated apoptosis in Sertoli cells [28-30]. The intracellular mechanism of o,p’-DDT is mediated through the estrogen receptor (ER) pathway [31]. 3Methylsulfonyl-DDE (Me-DDE), which also results from DDT metabolism, down-regulates steroidogenic genes in Leydig cells [32].The deleterious effect of DDE on testicular function in humans was demonstrated in an epidemiological study conduced in malaria endemic-areas in Chiapas (Mexico), where the parent compound DDT was sprayed until 2000. A regression analysis revealed a correlation between reduction of motile sperm cells percentage and increase of plasma p,p'-DDE concentrations in humans [18]. Dichlorvos (2, 2-dichlorovinyl phosphate, DDVP) and Chlorpyrifos are organophosphorus insecticides used worldwide for pest control in agriculture [33, 34]. Subcutaneous injection of DDVP (1 and 4 mg/kg body weight (bwt), 6 days a week) to Wistar rats for 9 weeks induced a decrease in sperm motility [33]. In another study, DDVP (1.6 mg/kg/day) altered sperm morphology, and induced a decrease in testis weights and serum testosterone levels in exposed rats after 4 and 7 weeks treatment. DDVP also induced necrosis, oedema and cellular damage in testicular tissues of the animals [34]. The DDVP–induced effects are likely to occur in male humans. A study conducted in indoor pesticide sprayers who were often using DDVP and other organophoshate (fenitrothion, chlorpyrifos/chlorpyrifos-methyl) and pyrethroid (permethrin) insecticides, revealed reduction in testicular volume and impairment of sperm quality (reduction of sperm motility) in the pesticide sprayers [35]. Chlorpyrifos reduced serum testosterone levels and decreased testicular sperm counts in male rats [36]. Administration of chlorpyrifos (5 and 10 mg/kg bwt) to rats for 30 days induced shrinkage of seminiferous tubules and drastic changes in germ cells, along with plasma levels of hormones that regulate spermatogenesis (testosterone, FSH and LH). Chlorpyrifos induced oxidative stress in the testis (increased levels of testicular lipid peroxidation, and decreased activities of superoxide dismutase (SOD) catalase (CAT), glutathione peroxidise (GPx)). Chlorpyrifos – inhibitory effect on testosterone production involves inhibition of 3-hydroxysteroid dehydrogenase (3-HSD) and 17hydroxysteroid dehydrogenase (17-HSD) enzymes [37]. The deleterious effect of organophosphate pesticides on sperm morphology was also reported in humans. Urinary concentrations of organophosphate metabolites (Diethyldithiophosphate and diethylthiophosphate) were associated to reduction of semen volume and an increased semen pH in pesticide applicators [16, 38]. Testosterone levels were also suppressed in rats by the insecticide Malathion (60 days treatment; 50 - 250 mg/kg/bwt/day) [39]. Parathion is metabolised into p-

Effect of Environmental Contaminants on Mammalian Testis

Nitrophenol (PNP) [40], which is an endocrine disruptor commonly found in water and soil, and capable of estrogenic and anti-androgenic activities [41, 42]. PNP (10 mg/kg/day for 4 weeks) inhibits expression of testicular estrogen receptor (ER) and androgen receptor (AR), reduced ER expression, and induced Leydig cells hyperplasia in immature male rats [42]. Pesticides accumulate in testes, and this may potentiate their deleterious effect on the organ. Examples of such pesticides include the organochlorine compound Lindane, which accumulates in rat testes, where it causes degenerative changes in germinal epithelium. Lindane induced Sertoli cell fragmentation and impaired sperm parameters (decreased sperm counts and increased sperm abnormalities) [43-45], and this was partly attributed to its ability to disrupt androgen synthesis in Leydig cells [44]. Disruption of Leydig cell steroidogenesis was also reported following exposure to methoxychlor. Methoxychlor inhibited cholesterol side-chain cleavage enzyme (cytochrome P450scc) in the cells, reduced steroidogenic acute regulatory (StAR) protein expression and decreased 3-hydroxysteroid dehydrogenase (3-HSD) and 17-HSD activities in rat testes [46, 47]. Methoxychlor is metabolised into 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which also reduced testosterone production in rat Leydig cells, through inhibition of several steroidogenic enzymes (3-HSD, 17-HSD type 3, 11-hydroxysteroid dehydrogenase, and 17-hydroxylase/17,20-lyase (CYP17A1)) [48-50]. Interestingly, HPTE –induced inhibition of CYP17A1 was more efficient in human testicular microsomes, compared to those of rats (with the IC50 values of 1.13±0.10 and 6.87±0.13 μM, for human and rat tests microsomes, respectively); suggesting a high sensitivity of humans to the chemical compared to rats [50]. Synthetic pyrethroid pesticides also induced serious damage on mammalian testis. For instance, exposure of male mice to fenvalerate during lactation (60 mg/kg bwt from postnatal day (PND) 0 to PND 21) decreased the weights of testes, induced apoptosis and spermatogenic failure in the animals. Fenvalerate exposure resulted in decreased mRNA and protein levels of testicular cytochrome P450scc, leading to reduction in serum and testicular testosterone levels [51]. This suggests impairment of spermatogenesis, and the latter pesticide has even been associated with poor semen quality in human beings who were exposed to 21.55 x 10-4 mg fenvalerate /m3 ambient air at the work place [52]. Administration of the insecticide cypermethrin to mature male mice (10 and 20 mg/kg bwt/day, 35 days) induced decrease in testicular weight and altered sperm development in seminiferous tubules. Cypermethrin inhibited serum testosterone concentration through alteration of steroidogenic Leydig cells (degeneration of mitochondria and the smooth endoplasmic reticulum of Leydig cells) [53]. Cypermethrin exposure (25 mg/kg bwt/day by gavage, from PND35 - PND70) also resulted in inhibition of mRNA level of testicular StAR and decrease of testosterone concentrations in serum of male mice [54]. Bifenthrin (2-methylbiphenyl-3-ylmethyl-(Z)(1RS)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropane carboxylate) is one of the most used synthetic pyrethroids for field and household pest control [51]. Administration of 15 mg/kg of Bifethrin for 3 weeks to female mice during pregnancy significantly reduced the

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mRNA levels of StAR protein and P450-17 in the testes of 6-week old male offspring [55]. Decreased StAR and serum testosterone level were also observed in rats following oral administration of deltamethrin for 4 weeks (5 mg/kg bwt/day). Moreover, deltamethrin increased testicular total oxidant capacity (TOC), poly (ADP-ribose) polymerase (PARP), lactate dehydrogenase (LDH) and DNA damage, illustrating significant peroxidation and cellular disruptive action of the pesticide. These adverse effects of the pesticide were however alleviated by the co-administration of a carotenoid derivative antioxidant, lycopene [56-58]. A benzimidazole carbamate, carbendazim (methyl-2benzimidazole), is a fungicide used in agriculture. Carbendazin decreased testis weight, reduced Leydig cell activities of the antioxidant enzymes (SOD, CAT, GPx) and nonenzymatic antioxidants (GSH, vitamins E, C and A), when orally administered to male rats at 25 mg/kg bwt/day for 48 days [59]. A decrease in the activities of testicular SOD and CAT was also observed, together with increased lipid peroxidation levels in the rats when orally administered at a single dose of the pesticide (200 mg/kg bwt) [60], and results corroborate the endocrine-disrupting effect of the fungicide. Indeed, carbendazim decreased serum testosterone and estradiol in male rats, through reduction of the activities of steroidogenic enzymes (3-HSD, 17-HSD) in Leydig cells [59], as well as reduction of StAR protein and ABP expressions [60]. The fungicide maneb also prevents release of testosterone precursor (pregnenolone) in Leydig cells of rats after 9 18 days exposure (4 mg/kg), leading to the reduction of plasma testosterone and decreased fertility in the animals [61, 62a]. These results indicate that maneb might contribute to impairment of testicular Leydig cell steroidogenesis in male farmers in Djutitsa (West Cameroon). Indeed, the farmers were using maneb most frequently, and showed imbalances of steroid hormones (increased serum androstenedione and decreased testosterone levels in blood), which are mainly produced by testes [62b]. Carbendazim increased androgen receptor (AR) concentrations in rat testis, and replaced binding of [3H]-5 alphadihydrotestosterone to AR [63]. The insecticides carbaryl induced accumulation of cellular mass in the lumen of seminiferous tubules and loss of sperms in albino rats [64]. Shalaby et al. [65] also reported alteration of spermatogenesis (reduction in sperm count and sperm motility) in rats by the insecticide methomyl, which consequently led to decreased fertility index in the exposed animals. Likewise, Carbofuran induced Sertoli and germ cells alterations, testicular edema and accumulation of cellular debris in the lumen of the seminiferous tubules, leading to decreased sperm count and morphology [66]. Oral administration of Mancozeb to Wistar albino rats (500 mg/kg for 30 days) resulted in the reduction of testicular sperm counts and decrease of the weight of testis [67]. Oyewopo et al. [68] also reported a decreased testicular weight and volume, as well as induction of testicular oxidative stress in adult male rats exposed to Propoxur (2-isopropoxyphenyl-N-methylcarbamate; 10 mg/kg bwt per day) orally for 30 days. This contrasted with observations of Ngoula et al., [69], who reported increase of testicular weight following exposure of rats to Propoxur (5.2 mg/kg bwt) for 90 successive days. However, the pesticide induced modulation of testicular weight, leading to impairment of its function, as evidenced by spermatogenesis impairment in the 2 studies [68, 69].


Administration of atrazine (a tirazine pesticide) to rats for 60 days (60 and 120 mg/kg twice a week), induced degenerative changes in seminiferous tubules in the testes [70], and this corroborate with decreased sperm quality observed in exposed rats [70] and male human workers [71]. Atrazine (25 and 50 μg/mL) induced cell cytotoxicity and decreased the levels of mRNA expression of StAR, and 3-HSD in rat Leydig cells [72]. Atrazine also increased cAMP levels in rat Leydig cells [73]. The carbamate fungicide Benomyl caused occlusion of the efferent ducts, preventing the passage of the sperm from testis into the epididymis [74]. Dichlorophenoxyacetic acid induced germ cells and sperm head abnormalities when administered to male rats (3.3 mg/kg/day, oral) for 3 and 5 consecutive days [75]. The organotin pesticides fentin hydroxide and fenbutatin oxide (25 g/kg bwt, i.p) also induced impairment of sperm cells and function in mice, at least in part, through inhibition of testosterone synthesis (inhibition of testicular steroidogenic enzyme activities (3-HSD and 17-HSD)), which is required for normal spermatogenesis [76]. Alteration of testicular cells by pesticides may be through induction of free radicals production in testes and/or inhibition of the antioxidant enzymes SOD, CAT, GPx, glutathione reductase (GR), and glutathione S-transferase (GST) [77-79]. Examples include methoxychlor, which was introduced as a replacement for the banned pesticide, DDT [50]. A glyphosate-based herbicide Roundup (36 ppm) decreased glutathione and increased Thiobarbituric acid reactive substances (TBARS) levels in pubertal rat testis, leading to Sertoli cell death [80]. Roundup also damaged Leydig cells and decreased testosterone release in the animals after 24 h exposure [81]. Administration of methoxichlor to male rats induced an increased generation of hydrogen peroxide, and reduced the activity of testicular SOD, CAT, GR, and GPx. In addition to oxidative stress, methoxychlor decreased testes weight in the rats [82]. The reactive oxygen species (ROS) -mediated effect of environmental toxicants is most likely to be detrimental to sperm cells, which are particularly vulnerable. Sperm cells contain high levels of polyunsaturated fatty acids that may be subjected to peroxidation by ROS (lipid peroixdation). Moreover, sperm cells have a limited store of antioxidant molecules/enzymes, which could protect against oxidative stress [79, 83]. Prochoraz is an immidazole fungicide, which inhibits aromatase, and act as an estrogen and androgen receptor antagonist in vitro [84]. The fungicide Vinclozolin acts as antiandrogen by inhibiting androgen receptor (AR) activity [85], and induced differential gene expression in developing F1 generation rat testis [86]. III. HEAVY METALS Heavy metals are elements commonly used in industry and generally toxic to animals and to aerobic and anaerobic processes. Heavy metals include cadmium, chromium, copper, mercury, lead, among others [87-89]. Heavy metals can occur naturally in the earth crust at low levels, but mainly from industrial extraction [89, 90]. The general population is exposed to heavy metals via contaminants found in air, drinking water, food, and during occupational exposition [91, 92]. Several studies have correlated their concentrations

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with occurrence of testicular dysfunction and infertility in living organisms, including humans [92-94]. It is well known that cadmium is a major environmental toxicant that causes adverse effects on male reproductive organs [6, 89, 91]. For assessment its action mechanism on testicular toxicity, adult male rats were administered single dose of cadmium chloride [1 - 1.2 mg ⁄ kg bwt; intraperitoneal injection (i.p)], and followed up for 7 or 56 days. The lower dose caused slight alterations, while the higher dose caused significant reduction in testis weight, gonadosomatic index and length and diameter of seminiferous tubule after 56 days [91]. The tubule lumens were filled with degenerated germ cells and multinucleated spermatid aggregates after 7 days. Vacuolization of the seminiferous epithelium was also observed, and became more pronounced after 56 days, with vacuolated seminiferous tubule consisting only of Sertoli cells [91]. Cadmium induced degeneration in testes and seminiferous tubules, and decreased testicular weights of mice/rats [94, 95]. A cDNA microarray and quantitative realtime RT-PCR analysis in the testes of CD-1 mice injected with CdCl2 (5 micromol/kg, subcutaneous injection) revealed alteration in the expression of some genes that are likely to be important in toxicity responses. Expression of cell cycleregulated cyclin B1 and CDC2 proteins was observed, suggesting G2/M arrest and disturbance of meiosis in the testis following cadmium exposure [96]. Cadmium also induced disruption of cell junctions in the testis, including Sertoli cell blood-testis barrier (BTB), through acceleration of endocytosis of BTB components occludin and N-cadherin [97]. Perturbation of BTB disrupts the microenvironment needed in seminiferous tubules for normal spermatogenesis [Box 1]. Lower doses of Cd ( 5 mol/kg) inhibit spermiation [98], and induced spermatogenic cells apoptosis [99, 100]. Cadmium exposure (0.4 mg/kg) also caused lipid peroxidation and altered the antioxidant defense system (decreased activity of SOD, CAT, GSH-Px, GR and GST) in rat testes. However, these defects on the antioxidant system were reversed by the antioxidants coenzyme Q and vitamin E [93]. Alteration of testicular steroidogenesis by Cd was also reported, as well as imbalances in the levels of gonadotropins that regulate spermatogenesis. In utero exposure of male mice foetuses to Cd (0.5 mg/kg/day, i.p, from gestational day (GD) -13 to GD-17) down regulated expression of steroidogenic enzymes/proteins (StAR protein, cytochrome P450scc and 17-HSD) in testes, leading to decreased serum testosterone levels in the animals [94]. A decreased serum testosterone levels was also observed on male rats and rabbits exposed to cadmium [101, 102]. Moreover, the cadmium -exposed rats showed increased FSH level, and reduction of LH levels [101]. The use of uranium in industrial or military activities has led to its spread in the environment, raising concerns about its toxicity. Histopathological examination of the testes in rats exposed to uranium revealed interstitial alterations, such as focal atrophy, and binucleated cells [103]. Assessment of its reproductive toxicity was conducted using human testes, obtained from 7-12 weeks of gestation foetuses. Incubation of the foetal testes with 0.1 mM uranyl acetate leads to reduced germ cells number, and the effect was more pronounced when compared to mouse germ cells treated in the same experimental conditions [104]. This indicated that ad-


verse effects of the heavy metals may impair the development of human testis and suggest extrapolation of results from mice/rodents to humans. Mercury has been recognized as an environmental pollutant that adversely affects male reproductive systems of animals [92]. Mercuric chloride is one of the most toxic forms of mercury because it easily forms organomercury complexes with proteins [105]. When administered to sexually mature male rats, mercuric chloride (1mg/kg bwt) impaired the antioxidant system (i.e., increase in the TBARS level and a decrease in the SOD, CAT, GPx activities) and histopathological changes on the testes. Mercuric chloride induced increased testicular absolute and relative weight in rats [105]. The histopathological changes induced by mercuric chloride were also observed in mice testes following subchronic administration of the chemical (1-2!mg/kg/day, oral, for 30-60 days), and this was concomitant with alteration of sperm parameters and fertility, as well as inhibition of testicular testosterone levels at the work place [106, 107]. Alteration of testicular function was reported in a 25-year-old infertile (severe oligoasthenoteratospermia) man exposed to mercury for 5 years. The man had high (considerably above levels of unexposed controls) mercury concentrations in hair, blood, and urine samples, and mercury grains in the interstitial Leydig cells. Also, testicular biopsies showed interstitial lymphatic infiltration, Sertoli-cell-only syndrome and tubular atrophy [108]. However, the histopathological changes and oxidative stress induced in rodents by mercury were alleviated when the animals were co-treated with the antioxidants sodium selenite and/or vitamin E [92]. Da Silva et al. [109] also illustrated protective effect of Solanum sessiliflorum Dunal fruit (a source of antioxidants such as zinc and citric acid) on testicular toxicity (decreased testis weights, reduced sperm production, and increased histopathological abnormalities) induced by methylmercury in Wistar rats. Lead, aluminium and chromium also affect testicular cells. When male rats were exposed to lead, a degeneration of spermatogenic and Leydig cells was noticed, as well as testicular atrophy [110, 111]. Further histological examination of the testes revealed perturbation of spermatogenesis, characterized by atrophy of seminiferous tubules, decrease in a number of spermatids and spermatozoa, and alteration of Sertoli cells [110, 112]. Administration of lead (10 mg and 15 mg /kg bwt/day for 20 days) to adult male rats induced a decrease of serum testosterone levels with deformities in testicular morphology, including gross damage within seminiferous tubules [113]. A decrease in serum testosterone levels was also observed after exposure of animals to lead acetate, with concomitant reduction in sperm concentration [110]. Aluminium chloride given orally to male rats at 100 and 200 mg/kg bwt daily for 48 days also altered plasma membrane enzymes (adenosine triphosphatases, alkaline phosphatase, and gamma glutamyl transferase) in testes, which may eventually have an impact on the fertility of the animals [114]. By using the Durand's validated seminiferous tubule culture model, which mimics the in vivo situation, Carette et al. [88] recently reported that hexavalent chromium increase the number of germ cell cytogenetic abnormalities. Exposure to chromium also increased the transepithelial resistance and strongly delocalized the gap junction protein connexin 43 from the membrane


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to the cytoplasm of Sertoli cells, suggesting alteration of BTB dynamics. IV. PHTHALATES Diesters of 1,2-benzenedicarboxylic acid, or phthalates, have been highly produced to be mainly used in a large range of everyday life products, such as construction materials, adhesives, paints, inks, cosmetics, toys, food packaging, clothes, medical materials, and drugs [115]. Phthalates also serve as antifoaming agent in paper production, as an emulsifier for cosmetics, in perfumes and pesticides [116]. Some of these compounds, such as Mono-n- pentyl phthalate (MPP), mono-2-ethylhexyl phthalate (MEPH), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP), have been shown to induce reproductive dysfunction [115, 117-119]. Several studies have reported the in utero deleterious effect of phthalates on testicular function in mammals. When pregnant Wistar rats were exposed to DBP (60 mg/kg bwt/day) from GD-7 to GD-20/21, examination of testes in male offspring at GD-19 or GD-20/21 revealed Leydig cell hyperplasia, Sertoli cell hyperplasia and presence of multinuclear gonocytes. The exposed rats also showed reduction in expression of steroigogenic enzymes (cytochrome P450scc and StAR proteins) in Leydig cells. Downregulation of StAR and cytochrome P450scc mRNA expression was also induced by DBP in fetal Leydig cells [120], and the alteration of steroidogenic proteins/enzymes corroborated reduction in testicular testosterone production [115] and insl3 gene expression in the foetal testis [121]. Moreover, DEHP induced severe spermatogenic disturbance in mice [122]. Exposure of female rats to DBP (500 mg/kg) at GD-11/21 induced cryptorchidism and focal dysgenesis of testicular somatic (Sertoli cells, Leydig cells) and germ (gonocytes) cells in male foetuses [123], and suppressed (approximately 90%) testicular testosterone levels [124]. Suppression of ABP by Sertoli cells by Di-n-pentyl phthalate (DPP) was also observed in immature rats [125]. DPP suppressed secretion of seminiferous tubule fluid (STF) by Sertoli cells, while DEHP induced seminiferous tubular atrophy in rats [125]. MPP and MEPH could penetrate BTB, and this suggests that phthalate esters may act initially to cause injury in Sertoli cells, that will subsequently induce germ cells loss [125]. In rat foetal Leydig cells, MEPH inhibited steroidogenesis by blocking CYP17A1 activity, which converts 17-hydroxyprogesterone (17-OHP) to androstenedione [126]. Detachment of germ cells from the seminiferous epithelium following phthalate exposure was reported in vivo [11, 127]. Mono-2-ethylhexyl phthalate produced specific alterations of gene expression profile in the testes [128], detachment and sloughing of germ cells, and alteration of cytoplasmatic intermediate filament vimentin in Sertoli cells [129] in rodents (mice or rats). This well-known endocrine disruptor has been shown to reduce germ cells number by increasing apoptosis without change in basal and LHstimulated testosterone production in human foetal testes in vitro [130]. Exposure of humans to phthalates may thus induce a deleterious effect on testicular steroidogenesis and spermatogenesis (Table 1).


Table 1. Class

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Adverse effects of selected environmental pollutants on testicular function in humans and rodents Chemical

Studied species

Toxicity and testicular cell(s) affected

Reference(s)

Dibromo-chloropropane (DBCP)

Human, rat

Hormone levels imbalances (elevation of intratesticular testosterone concentrations)

[21, 23, 26, 27]

Dichlorodiphenoxydichloroethylene (DDE)

Rat, mouse

Apoptosis of Sertoli cells

[30]

Dichlorvos

Rat

Proliferating type A spermatogonia, resulting in low sperm count;

Hormone alteration [34] Decrease of testis weight Chlorpyrifos

Rat

Reduction in Sperm count

[36]

Lindane

Rat

Degeneration of germinal epithelium, Sertoli cell Apoptosis

[43]

Fenvalerate

Mouse

Cell apoptosis [51] Decrease of organ weights Pesticides Cypermethrin

Rat

Inhibition of serum testosterone through alteration of testicular /Leydig cells steroidogenesis; decrease in testicular weight and alteration of sperm development in seminiferous tubules

[53, 54]

Carbendazim

Rat

Disruption of antioxidant system, decrease of Leydig cell steroidogenesis

[60]

Maneb

Rat, rabbit

Inhibition of steroid production by Leydig cells, leading to decreased sperm number and reduced fertility

[62a, 62b, 222]

Carbofuran

Rat

Sertoli and germ cells alterations

[66]

Rat

Hyperplasia of testicular Leydig cells

[42]

Roundup

Rat

Disruption of antioxidant system and inhibition of testosterone synthesis

[80, 81]

Methoxichlor

Rat

Disruption of the testicular antioxidant system

[82]

4-Nitrophenol (PNP)

Reduction testis weights degeneration in testes disruption of cell junctions Cadmium

Rat spermatogenic cells apoptosis

[91, 93, 95, 152]

Disruption of antioxidant system, Heavy metals

hormone levels and steroidogenesis Chromium

Rat

Alteration of BTB

[88]

Mercury

Rat, human

Oxidative stress and alteration of sperm parameters in rats; Severe oligoasthenoteratospermia, interstitial lymphatic infiltration in testis, and Sertoli-cell-only syndrome in humans

[105, 108]

Uranium

Rat, mouse, and human

Testicular atrophy in rats, reduced germ cells number in mouse and human fetal testis

[103, 104]



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Table (1) contd….

Class

Chemical

Studied species

Toxicity and testicular cell(s) affected

Reference(s)

Rat

Inhibition of CYP17A1 activity

[126]

Mono-2-ethylhexyl phthalate (MEPH) hyperplasia of Leydig cells and Sertoli cells Dibutyl phthalate Rat Phthalates

(DBP)

"Mouse" inhibition of testicular testosterone production and Please aromatase,include [121, 125, 120] here reduction in expression of cytochrome P450scc, StAR protein and insl3 genes in testis or Leydig cells

Diethylhexyl phthalate Oxidative stress in testis, and inhibition of spermatogenesis

[122]

Alterations of gene expression profile in rodent testes, and increase of apoptosis in germ cells in human foetal testes in vitro

[128-130]

phthalate

Rodents (mice, rats), human foetal testis

Zearalenone

Rat

Decreased serum testosterone

[161]

Mycotoxins

Patulin

Rat

Induction of Leydig cells hyperplasia, increased the plasma level of testosterone levels, and disorganization of seminiferous tubule epithelium

[162, 163]

Dioxins

Tetrachlorodibenzo-p-dioxin (TCDD)

Rat

Inhibition of steroidogenesis and induction of oxidative stress

[131, 138, 139]

Nonylphenol (NP)

Rat

Alteration of Ca2+ homeostasis, inhibition of hCG-induced testosterone release in Leydig cells

[140, 142]

Perfluorododecanoic acid

Rat

Inhibtion of steroidogenesis and testosterone level

[150, 151]

2-methoxyethanol

Rat

spermatocytes necrosis/degeneration

[168-170]

(n-hexane and methyl n-butyl ketone metabolite)

Rat

Testicular atrophy, germ cell loss (detachment from the seminiferous epithelium)

[127, 171, 174, 175]

2,4,6-trinitrotoluene (TNT)

Rat, human

Decrease in sperm number and degeneration of germ cells in rats; decreased serum testosterone levels and impairment of sperm parameters

[165, 166]

Bisphenol A

Rat

(DEHP) Mono-2-ethylhexyl

Sulfactants

Organic solvents

2, 5-hexanedione

Other xenobiotics

Germ cell apoptosis (increased of Fas and FasL, Bax, caspase-9) disruption of BTB, inhibition of steroidogenesis and decrease of testosterone level

[12, 126, 183, 184, 188]

Legend: numbers are references as indicated in references section.

V. DIOXINS Dioxins are a mixture of 219 different polychlorinated dibenzo-p-dioxins and furans. The most well-known and hazardous dioxin is tetrachlorodibenzo-p-dioxin (TCDD), an endocrine-disrupting environmental pollutant [131]. Dioxins can arise as unwanted by-products from the production or use of many organochlorine compounds (such as chlorine bleaching of cellulose in paper production and chlorine alkali

electrolysis), from a de-novo synthesis from thermal sources (waste incineration plants and incomplete combustion processes in landfills, combustion plants, iron smelting, sinter plants, non-ferrous smelting and recycling plants), and from incomplete combustions processes involving chlorine [132135]. For example, TCDD is generated during incineration of medical wastes, chlorine bleaching of paper and manufacture of pesticides. It is also generated in exhaust from cars and cigarette smoke [133, 136, 137]. The compound TCDD


induced reproductive toxicity in males. TCDD decreased activities of testicular steroidogenic enzymes (3-HSD and 17-HSD) when administered to rats (100 ng/kg bwt/ day for 15 days) [131], leading to the reduction of serum testosterone level [138]. TCDD increased oxidative stress and suppressed the activities of testicular antioxidant enzymes [138, 139]. TCDD also modulated the gene expression levels of arylhydrocarbon receptor (AhR) and its repressor AhRR in Leydig cells in vitro [135]. VI. SURFACTANTS Nonylphenol (NP) is a widely distributed environment contaminant and has been documented to disrupt testicular development and decrease male fertility [140]. It is a degraded product of alkylphenol polyethoxylates (APEOs), which are non- ionic surfactants used as components of cleaners, detergents and emulsifiers [141]. Amongst possible targets of NP are testicular Sertoli cells, which play a crucial role in supporting and nourishing sperm cells. Nonylphenol alters Ca2+ homeostasis, causing dramatic morphological changes and decreased viability of Sertoli cells, as well as activation of the endoplasmic reticulum -stress signal pathway in the cells [140]. NP inhibited hCG-induced testosterone release both in vitro (rat Leydig cells) and in vivo (in rats) [142]. NP and octylphenol caused downregulation of testicular 3-HSD mRNA when orally administered to 4week-old Sprague-Dawley rats (10-250 mg/kg bwt/day) for 3 weeks [143]. Downregulation of testicular 3-HSD mRNA was also observed in rats exposed to octylphenol (OP; 10250 mg/kg bwt/day for 3 weeks), which is another degradation product of APEOs [143]. OP decreased viability and increased apoptosis of Sertoli cells, induced up-regulation of Bax, and down-regulated the expression of procaspase-3 and Bcl-2 [144]. NP was detected in 51% urine samples (concentration 0.1 g/L) collected from humans [145], and may constitute a potential triggering factor for testicular dycfunction and infertility in men. Perfluoroalkyl acids, including perfluorododecanoic acid, are used as surfactants in industrial and consumer products, and have been detected in environmental matrices, in wildlife and in human samples (blood, tissues) in various countries [146, 147]. Perfluorooctanoate has been used in the production of various fluoropolymers, and is also an end product of many fluorochemical compounds in the environment [148, 149]. Chronic administration of Perfluorododecanoic acid to male rats (0.5mg/kg/day, 110 days) resulted in decreased protein levels of StAR, cytochrome P450scc, along with reduced mRNA levels of insulin-like growth factor I (IGF-I), IGF-I receptor, and interleukin 1 in rat testes [150]. Oral administration of ammonium perfluorooctanoate (1.0-5.0 mg/kg bwt/day) to mice for 6 weeks resulted in reduced plasma testosterone concentrations in the animals. Moreover, perfluorooctanoate decreased testosterone levels in rat testis [151], and the decrease was associated with reduced expression of mitochondrial cytochrome P450scc and StAR protein, which are all involved in the steroidogenesis process [152]. Inhibition of 3-HSD and 17-HSD activities and induction of cell adenomas in rat Leydig cells exposed to perfluorooctanoate were also reported [153, 154]. Per-

Manfo et al.

fluorooctanoate is rapidly absorbed and bioaccumulated in humans (half- life thought to be in the range of 2.3-3.8 years) [147, 155], and this may potentiate its testicular toxicity, regarding the aforementioned adverse effects in other mammalian species. VII. MYCOTOXINS Mycotoxins are toxic secondary metabolites produced by toxigenic fungi species. Mycotoxins commonly contaminate animal feed and human food commodities [156]. Examples of mycotoxins that may be important in connection with foods are aflatoxins, ochratoxin A, patulin, and trichothecenes [156-158]. The administration of mycotoxins (aflatoxin, ochratoxins and zearalenone) to male albino rats at the doses of 0.5, 1.0 and 2.5 ppm in feed, respectively), for 6 months significantly reduced testosterone, LH and FSH levels [159]. Ochratoxin A in particular is commonly found as contaminant in foods such as coffee, grapes, wine, grains, and mainly produced by various species of the Aspergillus genus and one species of Penicillium, Penicillium verrucos [160]. Treatment of H295R cells with Ochratoxin A increased aromatase protein, and leads to enhanced production of estradiol [158]. The effect of this mycotoxin on aromatase may comprise the testicular balance in steroid enzymes thereby negatively affect male reproductive function. Zearalenone is a non-steroidal mycotoxin produced by several species of Fusarium fungi. Zearalenone is frequently found in cereals used for human food stuffs and animal feeds, and capable of altering gene expression profile in the developing testes of mice [128]. Zearalenone decreased serum testosterone in rats after 3 days (i.p, 20 mg/kg bwt). This negative effect of Zearalenone was however alleviated by the simultaneous administration of vitamin E to animals [161]. The mycotoxin Patulin produced in many species (including Aspergillus sp., Penicillium sp., Paecilomyces sp. and Byssochlamys sp.) is found in a variety of food commodities. It increased the plasma level of testosterone, induced hyperplasia of Leydig cells and disorganization of seminiferous tubule epithelium [162, 163]. VIII. OTHER XENOBIOTICS The compound 2,4,6-trinitrotoluene (TNT) is a commonly used explosive. Several studies in both humans and animals have showed its ability to induce testicular toxicity. Toxic effects following administration of TNT to Fischer 344 male rats (125 and 300 mg /kg/day for 13 weeks in the diet) included testicular atrophy with degeneration of the seminiferous tubular epithelium [164]. In another study, TNT administration to rats induced germ cell degeneration and disappearance of spermatozoa in seminiferous tubules, resulting in a significant decrease in sperm number in testis. TNT also increased the formation of 8-oxo-7,8-dihydro-2'deoxyguanosine in sperm without affecting plasma testosterone levels in the animals; suggesting a direct action of the toxicant on sperm cells [165]. Reproductive toxicity of TNT was assessed in male humans occupationally exposed to the chemical in China. The TNT concentrations in the workplace air exceeded maximal allowable concentration (i.e. > 1 mg/m3) [166, 167]. The exposed male workers showed sig-


nificant sexual disorders (impotence, loss of libido and hypoesthesia), with increased sperm malformation, reduced semen volume and percentage of motile spermatozoa. The serum testosterone content in the workers was also significantly decreased [166]. TNT exposure induced a decrease of Cu, Zn, Na, Mg, and Se concentrations in the semen of the workers. Moreover, TNT exposure extended the liquefying time of semen, increased the incidence of sperm malformation, and reduced the percentage of motile spermatozoa [167]. Organic solvents are also implicated in testicular dysfunction. Histological alterations were observed in testes of rats following administration of the glycol ether solvent 2methoxyethanol (150 mg/kg bwt/day for 3 days). The induced histopathological changes consisted of degeneration or necrosis of spermatocytes [168]. Spermatocytes degeneration was also observed in rats treated with a single oral dose of 2methoxyethanol [169, 170]. The compound 2,5-hexanedione is a toxic metabolite of industrial solvents such as n-hexane and methyl n-butyl ketone [171], and has been shown to decrease the transport rate of the luminal oil droplets in seminiferous tubules of rats [172]. This suggests the ability of 2,5-hexanedione to reduce production of STF in Sertoli cells, a key factor in maintenance of spermatogenesis and transport sperm from the seminiferous tubule through the rete testis [125, 173]. Exposure to 2, 5-hexanedione (1%, in drinking water) for 3-5 weeks resulted in testicular atrophy, with decreased seminiferous tubule fluid secretion and decline in germ cell number [174, 175]. Bisphenol A (BPA) is a well known environmental estrogen that is most commonly used to produce polycarbonate plastic [12, 79]. BPA has been one of the highest volume chemicals produced worldwide, with over 6 billion pounds produced each year and over 100 tons released into the atmosphere by yearly production [176]. BPA can leach into drinking water from polycarbonate bottles including polycarbonate baby bottles and reusable water bottles. BPA have been detected in serum and urine samples from humans. A study conducted on a reference human population of the United States revealed that BPA concentration was 0.1 g/L in 95% urine samples collected from the participants [145]. BPA was also detected in serum samples from men, with higher concentrations and greater detection rates recorded in males occupationally exposed than those not exposed to the chemical. Interestingly, BPA concentrations were associated with low androstenedione and high sex hormone-binding globuline levels [177], suggesting impairment of testicular function. The BPA-induced reproductive dysfunction in experimental animals is well documented [12, 13, 178]. When administered to rats by oral route at doses of 0.005 - 500 g/kg bwt/day for 45 days, BPA dosedependently decreased the activities of testicular antioxidant enzymes, steroidogenic enzymes (3--HSD, and 17--HSD), and reduced StAR expression; leading to decrease in testosterone secretion by Leydig cells [12]. BPA also decreased LH receptor (LHCGR) in Leydig cells. Moreover, investigations on BPA revealed impairment of insulin signalling and glucose transport in testes of exposed rats, and this dysfunction could lead to impairment of testicular functions and


9

male infertility [12, 179, 180]. BPA showed a mitogenic effect on Leydig cells in the prepubertal period in rats, leading to increased Leydig cell numbers in the testes of adult males [180, 181]. BPA induced germ cell apoptosis through the Fas/FasL signalling pathway and the mitochondrial apoptotic pathway [181]. BPA exposure also evoked the activation of caspase-8 and caspase-3 in testes, induced cytochrome c translocation from mitochondria into cytosol, and upregulated the level of testicular Bax and active caspase-9 [181]. Prenatal or neonatal exposure to BPA disrupts BTB in mice, through down-regulation of genes associated with Sertoli cell function (Msi1h, Ncoa1, Nid1, Hspb2, and Gata6), and modulation in the expression of BTB proteins (increases in the expression of N-cadherin and Zona Occludin-1, and reduction in the expression of Connexin 43) [182, 183]. Considering the importance of BTB for normal spermatogenesis [Box 1], the BTB destruction may explain the decline in total sperm counts in rodents following BPA exposure [182-184]. Acrylonitrile (CH‚CH–CN, ACN) have been widely used in various synthetic chemical industries, including production of plastics. When acrylonitrile was administered daily to male albino rats at a dose of 30 mg/kg bwt for 5 days, a reduction of glutathione content and GST activity was observed in the testes of the animals. Acrylonitrile also induced maturation arrest, depletion and abnormalities (altered cytoplasmic organelles, and deformed spermatids) in spermatogenic cells. Moreover, testosterone –producing Leydig cells exhibited mitochondrial disruption and reduced amount of smooth endoplasmic reticulum [185], and this corroborated the reduction of testosterone concentrations in sera of young and adult male humans exposed to acrylonitrile (vinylcyanid) in a chemical factory [186]. Massive use of Brominated flame retardants (BFRs) in order to reduce the risk of fire accidents, have led to its occurrence in almost all the environmental compartments, including humans and wildlife organisms. BFRs are endocrine disrupting chemicals, and affect mammalian testicular function [187]. These include Hexabromocyclododecane, 1,2,5,6tetrabromocyclooctane and bis-(2-ethylhexyl) tetrabromophthalate. Hexabromocyclododecane induced a decreased weight of the testis in F1 male pups in a one-generation reproduction assay in Wistar rats [188]. Hexabromocyclododecane inhibited steroidogenesis in peripubertal rat Leydig cell cultures [189]. The chemical 1,2,5,6-tetrabromocyclooctane modulated CYP17A1, leading to stimulation of testosterone and estradiol production in primary porcine testicular cells [190]. Environmental toxicants induced impairment on reproductive function in males in general, and particularly on mammalian testis, and this is illustrated by correlations between pollution level and defects in semen samples. For example, a study conducted in Chongqing, China, revealed that air pollution level was more pronounced in urban area compared to rural area, and was associated with male semen quality. Concentrations of particulate matter, sulphur dioxide, and nitrous dioxide were negatively associated with normal sperm morphology percentage and sperm kinetic parameters [96]. These observations were in line with the


earlier report on the evidence that sulphur dioxide, and nitrous dioxide are toxins for the reproductive system of mammals [191]. The alteration of sperm parameters may also occur indirectly through disruption of hormonal regulation of the testicular function. Polychlorinated biphenyls (PCBs) are either manufactured directly by chlorination of biphenyls, or generated during combustion processes (e.g., from waste incineration plants, fossil fuel burning). Manufactured PCBs were used as lubricants, impregnating agents for wood and paper, flame protective substances, in transformers and condensers, as carrier substances for insecticides, etc. [192, 193]. Although banned for several decades, PCBs continue to exist in the environment because of their long half-life, continued presence in items produced before the ban, and poor disposal practices [194]. PCBs are implicated in testicular dysfunction. The PCB Aroclor 1254 decreased testicular weights and reproductive success of male pups in adulthood when given to male rats through lactation (8, 32, or 64 mg/kg to dams) [195, 196]. Treatment of Leydig cells with the PCB Aroclor 1254, resulted in a significant reduction of serum testosterone and estradiol. In addition, the Leydig cell surface LH receptors, activities of the steroidogenic enzymes such as cytochrome P450scc, 3-HSD, 17-HSD, antioxidant enzymes SOD, CAT, GPX, GR, -GT, GST and non-enzymatic antioxidants such as vitamin C and E were significantly diminished, whereas LPO and ROS were markedly elevated. However, the simultaneous administration of vitamin C and E in Aroclor 1254 exposed rats resulted in a significant restoration of all the above-mentioned parameters to the control level [197]. A nitroaromatic intermediate 1,3-Dinitrobenzene, used in manufacture of dyes, plastics and explosives, induced testicular atrophy in male rats [198, 199]. Daily administration of 1,3-Dinitrobenzene (4mg/kg/day) to rats induced testicular injury, particularly to Sertoli cells, and induced apoptosis in the surrounding germinal cells. Plasma testosterone and testicular steroidogenesis-related gene expression were affected in the animals, suggesting an interference with the endocrine system [200]. Environmental toxicants also include diesel exhaust particles (DEPs) and polycyclic aromatic hydrocarbons (PAHs) [201, 202]. DEPs are air pollutants resulting from increased use of vehicles, especially diesel engine- powered cars and trucks. The DEPs may induce hazardous effects on human health, including endocrine disruption [202, 203]. Exposure to nanoparticle-rich diesel exhaust increased serum and testis testosterone levels in male rats [203], through increased StAR protein and cytochrome P450scc mRNA and their protein expressions in the testis of the exposed rats. Interestingly, the exposed rats also showed significant increase in growth hormone receptor expression and increased insulinlike growth factor I-mRNA levels in the testis [202]. PAHs are formed during incomplete combustion of organic matter such as wood, carbon or mineral oil. An example of PAHs source includes car exhaust particles, road runoff, and products originating from incomplete combustion processes in urban landfills, forest and house fires, heat and energy power stations, vehicle traffic, waste incineration and industrial

Manfo et al.

plants [201, 204-206]. Because of rapid increase in the number of automobiles and industrial production, metabolites of PAHs were detected in 100% of test candidates in a recent study in China, and higher levels were associated with male infertility [207]. It is also well established from both human and animal studies that exogenous administration of oestrogens results in increased incidence of male reproductive disorders, such as cryptorchidism [208]. The effect of radionucleoides and temperature on testicular function was also reported. A transient elevation in serum FSH and decreased inhibin B levels was observed in adult men after exposure to radioiodine for thyroid cancer treatment. This reflected severe impairment of spermatogenesis by the radionucleoide [209, 210]. Although the FSH levels normalized within 9-18 months from the last radioiodine administration, this result indicate the potential adverse effect of radonucleoides in spermatogenesis (or HPT axis [Box 1]) in the exposed patients, and particularly those requiring multiple administrations of radionucleoides for persistent cancer treatment [209, 210]. Amara et al. [211] also exposed rats to static magnetic field for 128 mT intensity, 1 h/d for 30 days, and observed a reduction in testosterone concentration with increased oxidative stress in the animals [199].

Box 1: Sertoli cells in spermatogenesis

The overall objective of the reproductive process for the adult male is the production of gametes capable of fertilization and the production of viable offspring [212]. The male gamete results from spermatogenesis, an elaborate process of germ cell proliferation and differentiation that leads to the production and release of spermatozoa from the testis [213]. Spermatogenesis involves mitosis, meiosis, and cellular differentiation that transform spermatogonia into mature spermatozoa [77]. The testis consists of seminiferous tubules that comprise of Sertoli cells, and the interstitial compartment that comprises testosterone-producing Leydig cells [89, 212, 214, 215]. Testicular spermatogenesis and steroidogenesis processes are regulated by the HPT axis which involves the pituitary gonadotropins LH and FSH. In addition to FSH and LH, a number of hormones and growth factors, including androgens, insulin-like growth factor, oxytocin, and transforming growth factor and estrogens, are also proposed to regulate testicular function [124, 216-218]. In addition to hormonal stimulation, spermatogenesis depends upon dynamic interactions between the Sertoli cells and the germ cells of the seminiferous epithelium [213]. Sertoli cells secrete nutritive factors into the adluminal compartment that creates a specialized microenvironment suitable for development and viability of germ cells [213]. Indeed, the BTB formed by tight junctions between adjacent Sertoli cells prevents large molecules from passing directly from the blood into the lumen of the seminiferous tubule and separates spermatogonia in the basal compartment from spermatocytes and spermatids in the adluminal compartment [11]. Sertoli cells also form sites of attachment to germ cells that provide efficient paracrine signaling mechanisms between these cells as well as physical support to developing germ cells [213, 219]. Sertoli cells express androgen receptor and FSH receptor, to which testosterone FSH bind, respectively, to inhibit death signals sent to germ cells [220, 221]. Exposure to Sertoli cell toxicants is likely to induce detachment of germ cells from the seminiferous epithelium [11, 127].

Effect of Environmental Contaminants on Mammalian Testis Box 1. contd….

The BTB comprises ectoplasmic specialization (ES) (in addition to tight junction (TJ), desmosome, and gap junction) which anchors developing spermatids in the seminiferous epithelium until they are fully developed, prior to release into the seminiferous tubule lumen. Thus, disruption of the apical ES by xenobiotics causes the premature release of spermatids that are structurally defective and unable to fertilize the ovum [184]. Sertoli cells produce STF, which is essential to maintain the appropriate nutritional and hormonal environment for spermatogenesis and to transport sperm from the seminiferous tubule through the rete testis and into the epididymis. Changes in fluid production and lack of resorption of fluid in the epididymis can create abnormal conditions in the seminiferous tubules, leading to disrupted spermatogenesis [125, 173]. Maintenance of Sertoli cell population is also a critical factor. Several reports have elucidated the effect of various environmental toxicants on depletion of Sertoli cell population, alteration of their secretary function, induction of germ cells distachment from seminiferous epithelium (Sertoli cells), as well as impairment of the BTB [89, 184, 222].

CONCLUSION This review paper presents updated data on testicular toxicity in mammals. The reviewed literature revealed that


11

rats and mice have been so far the optimal experimental subjects as mammalian species, probably due to their ease of handling and high productivity in short term. Direct effect on human testis have been illustrated also by few studies. Majority of the toxicants reviewed affect the male reproductive system by direct action on testis. This action results in reduction testis weights in general, or decrease of seminiferous epithelial supportive Sertoli cells and interstitial Leydig cells (Fig. 1). The toxicants also induce reduction of sperm parameters (counts, motility, viability and density, and increase in sperm DNA damage and deformity, among others), which represents a key factor for successful fecundation and fertility in males. The available toxicological data on mammalian testis are chiefly based on reduction of testicular size and alteration of sperm cells within the seminiferous epithelium. Induction of oxidative stress is emphasized as another common response after exposure to environmental toxicants, and several reports have suggested the alleviating effect of wellknown antioxidant molecules. Moreover, the reviewed data indicated that xenobiotic –induced alteration of the testicular function may occur from the in utero period throughout elderly life. The environmental toxicants are usually present in the environment as complex mixtures of chemicals that can interact to cause increased effects. The data hereby reviewed are somehow silent on the effect of chemical cocktails on

Fig. (1). Cellular target of different environmental pollutants within mammalian testis. Actions of environmental toxicants include induction of oxidative stress in the testis, inhibition of steroidogenesis in Leydig cells (LC), inhibition of Sertoli cells (SC) function, direct inhibition of spermatogenesis, and alteration of sperm cells. PTC: peritubular cells, SPG: spermatogonia, SPT1: spermatocyte 1, SPT2: spermatocyte 2, RS: round spermatid, ES: elongated spermatid, SPZ: spermatozoa.


testicular function. The deleterious effects reported should thus be considered with stringency, in order to contribute alleviating the burden of xenobiotics around us. This is a prerequisite for preservation of the mammalian specie, as spermatogenesis represents the milestone in reproduction. CONFLICT OF INTEREST

Manfo et al. [16]

[17]

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The authors confirm that this article content has no conflict of interest. [19]

ACKNOWLEDGEMENTS The authors wish to acknowledge the support of the Federation of Indian Chambers of Commerce & Industry (FICCI), the Department of Science and Technology (DST) and Government of India, through CV Raman International Fellowship for African Researchers; and the University of Buea, Cameroon. REFERENCES [1] [2]

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Revised: November 3, 2014

Accepted: December 19, 2014