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Heavy Metal Toxicity Affecting Fertility and Reproduction of Males
CHAPTER
Heavy Metal Toxicity Affecting Fertility and Reproduction of Males
18 Fouad M. Badr1, Ola El-Habit2
1Suez
Canal University, Ismailia, Egypt; 2Helwan University, Cairo, Egypt
INTRODUCTION A heavy metal is defined as a metallic element, which has a relatively high atomic weight or atomic number and a relatively high density [1]. There are more than 20 heavy metals, but only a few are of particular concern to human health: lead (Pb), cadmium (Cd), mercury (Hg), chromium (Cr), and inorganic arsenic (As) (Table 18.1) [2]. These heavy metals are at the top of most hazardous metals present in many working sites [3]. They are highly toxic and can cause damaging effects even at very low concentrations. They tend to accumulate in the food chain and in the body and can be stored in soft (e.g., kidney) and hard tissues (e.g., bone). They often exist in a positively charged form and can bind on to negatively charged atom [4]. A heavy metal is often assumed to be toxic. Others are relatively harmless but can be toxic in large amounts or certain forms such as silver, indium, and bismuth [5]. Heavy metals such as lead, cadmium, and mercury are “natural” elements but can be harmful to health, especially over a long period of time or in high doses [5]. Heavy metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages.
ESSENTIAL HEAVY METALS Specific heavy metals, typically, iron, copper, zinc, manganese, cobalt, and nickel, are essential nutrients for the human body. Heavy metals essential for life can be toxic if taken in excess amounts. Ingesting more than 5 g of iron can be fatal. Cobalt, a dietary salt, can act at high doses as a carcinogen [6]. Nickel carbonyl (Ni2(CO)4) is lethal at 30 parts per million [7]. Excessive amounts of copper sulfate (Cu(SO4)2) can be fatal and result in major organ damage among survivors [8]. Bioenvironmental Issues Affecting Men's Reproductive and Sexual Health. http://dx.doi.org/10.1016/B978-0-12-801299-4.00018-9 Copyright © 2018 Elsevier Inc. All rights reserved.
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Table 18.1 List of Common Toxic Heavy Metals Sorted by Atomic Number, Weight, and Density Name
Symbol
Atomic Number
Atomic Weight
Density (g/cm3)
Chromium Iron Cobalt Nickel Copper Zinc Arsenic Cadmium Mercury Lead
Cr Fe Co Ni Cu Zn As Cd Hg Pb
24 26 27 28 29 30 33 48 80 82
51.9961 55.845 58.9332 58.6934 63.546 65.39 74.9216 112.411 200.59 207.2
7.19 7.87 8.9 8.9 8.96 7.13 5.72 8.65 13.55 11.35
SOURCES OF HEAVY METAL CONTAMINATION There are many heavy metals that are used in common home products, such as nonstick pans, glazed ceramics, pesticides, soaps, plastic toys, eye shadow, and lipstick. Heavy metals are present in many aspects of modern life. They are used in many industries, for example, cars, plastics, antiseptics, utensils, paints, batteries, solar panels, mobile phones, and particle accelerators [9]. Potential sources of heavy metal poisoning include mining, industrial wastes, agricultural runoff, and occupational exposure to such heavy metals. Lead is present in cigarette smoke, cutlery, hair dyes, lead pipes, car exhaust, and paints. Mercury, a heavy metal, is present in dental amalgams, thermometers, tattooing, fabric softeners, cosmetics, laxatives, insecticides, seafood, and vaccines. Nickel is present in stainless steel cookware, cigarette smoke, fertilizers, jewelry, hydrogenated fats, and margarine. Arsenic is used in car exhausts, colored chalk, household detergents, and certain soil fertilizers. Cadmium is most commonly found in cigarette smoke but is also used in batteries, metal coatings, and plastics [10,11].
BIOLOGICAL AND CHEMICAL EFFECTS OF HEAVY METALS Trace amounts of some heavy metals are required for certain biological processes. It is estimated that an average 70 kg human body contains about 0.01% heavy metals (∼7 g). These are manganese (enzyme regulation or activation), chromium (glucose utilization), iron and copper (oxygen and electron transport), cobalt (complex syntheses and cell metabolism), nickel (cell growth), zinc (hydroxylation), and arsenic (metabolic growth).
Heavy Metals and Reproductive Health
Heavy metals are present in nearly all aspects of modern life. The biocidal effects of some heavy metals have been known for ages [12]. Platinum, osmium, copper, ruthenium, and other heavy metals, including arsenic, are used in anticancer treatments. Antimony (antiprotozoal), bismuth (antiulcer), gold (antiarthritic), and iron (antimalarial) are also important in medicine. Copper, zinc, silver, gold, and mercury are used in antiseptic formulations. Depending on their intended use as fertilizers or biocides, agrochemicals may contain heavy metals, such as chromium, cobalt, nickel, copper, zinc, arsenic, cadmium, mercury, or lead [13]. Selected heavy metals are used as catalysts in fuel processing, chemical production, emission control devices, self-cleaning ovens, soap chemistry, paints, dryers, and fungicides [10,12,13].
HAZARDS OF HEAVY METAL CONTAMINATION The threats to human health from heavy metals are associated mainly with exposure to lead, cadmium, mercury, and arsenic. These metals have been extensively studied, and their effects on human health are regularly reviewed [3,4].
TOXICITY OF HEAVY METALS Heavy metals are systemic toxicants known to induce adverse health effects in humans. The main pathways of exposure include ingestion, inhalation, and dermal contact. The severity of adverse health effects is related to the type of heavy metal and its chemical form and is also time-dependent and dose-dependent. Among many other factors, speciation plays a key role in the kinetics and dynamics of metal toxicity and is highly influenced by factors such as valence state, particle size, solubility, biotransformation, and chemical form. Recent reports have pointed out that these toxic elements may interfere metabolically with nutritionally essential metals such as iron, calcium, copper, and zinc [7]. Simultaneous exposure to multiple heavy metals may produce a toxic effect that is additive, antagonistic, or synergistic. Coexposure to metal/metalloid mixtures of arsenic, lead, and cadmium produced more severe effects at both relatively high dose and low dose levels in a biomarker-specific manner [3]. These effects were found to be mediated by dose, duration of exposure, and genetic factors. In many areas of metal pollution, chronic low dose exposure to multiple elements is a major public health concern.
HEAVY METALS AND REPRODUCTIVE HEALTH Reproductive toxicants may contribute to a spectrum of adverse effects on reproductive health. These effects include menstrual irregularities, early or delayed puberty, infertility, subfertility, early pregnancy loss, fetal death, impaired fetal growth, low
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birth weight, premature birth, and birth defects [14–16]. Exposures to certain toxicants might result in adverse effects on the male reproductive system, such as an increase in testicular cancer incidence, decreasing sperm counts, a decline in serum testosterone, and fewer males being born. Whether or not an environmental exposure results in adverse effects on reproductive health in an individual ultimately depends on the interaction among various factors, such as the extent of multiple chemical exposures, individual experiences, disease frequency, age status of the population, and genetic variability [17]. The exposure time to environmental toxicants, which includes periods during gestation, childhood, adolescence, and adulthood, is another factor that strongly influences the ultimate biological effect [17–19]. Heavy metal toxicity is believed to be mediated through macromolecules such as proteins with structural, catalytic, or transport function and DNA. Reactive oxygen species are generated by metals, particularly transition metal ions, e.g., of iron, copper, and cobalt, can overcome the spin restriction of O2, and donate a single electron, giving rise to free radical species and chain reaction. Toxicity occurs when such metals are free and reactions become uncontrolled [20]. Metals also inhibit protection mechanism against reactive oxygen species, e.g., SOD, glutathione. Other important cytotoxic mechanism for some metals (e.g., mercury and chromate) are DNA damage and inhibition of cellular respiration (e.g., arsenic and chromate). Metals can bind to a wide variety of cellular legends and the effects produced seem to be relatively specific for each metal [21,22].
HEAVY METALS AND FERTILITY Heavy metals have been identified as factors affecting human fertility. Significant correlations were found between different heavy metals and clinical parameters (age, body mass index, ethnicity) as well as gynecological conditions (uterine fibroids, miscarriages, hormonal disorders). Lowering an increased heavy metal body load improved the spontaneous conception chances of infertile women [23]. A couple’s fertility depends on the fertility of both the man and the woman. Exposure of cadmium to either a man or a woman can delay a woman’s chances of getting pregnant [24]. The more lead there is in a man’s blood, the longer it will take his wife to get pregnant because lead lowers a man’s sperm count and also reduces the sperm mobility [25,26]. Lead or cadmium can affect a woman’s reproductive hormone levels, which, in turn, makes it more difficult to conceive [25,26]. Cadmium (Cd), mercury (Hg), arsenic (As), lead (PB), manganese (Mn), and zinc (Zn) act as endocrine-disrupting chemicals (EDCs). The influence of these metals on the endocrine system and reproductive systems alters possible mechanisms of action and results in consequent health effects, [24,27,28]. Many metals may have adverse effects on the male reproductive function. Metals can lead to the loss of fertility and libido or to impotence by affecting: the testis size, semen quality (e.g., sperm motility and quantity), the secretory function of the prostate and seminal vesicles, and the reproductive endocrine function [29–31].
Environmental Exposures to Heavy Metals
Severe cadmium intoxication provokes injuries to testes, the liver, and lungs [30–33]. Amounts of cadmium exceeding 2.5 mg/kg cause severe placental damage inducing malformations in the newborns and may lead to fetal death. Evidence of cadmium’s effects on pregnancy is inconsistent. Women with higher urinary cadmium levels have increased rates of preterm delivery, and infant weight also was lower than that in mothers with lower levels [24]. Cadmium can seriously damage the reproductive system, as it can mimic estrogen function by virtue of its binding with high affinity to estrogen receptors (ERs) [28], leading to gene activation. Alternatively, ERs can exert their effects through other mechanisms, such as the activation of secondary messengers and enzymatic pathways. Likely, the high incidence of tumors of the genital sphere in industrialized countries can be related to pollutants, such as cadmium, interfering with the hormonal network [26,28]. Although cadmium was associated with the development of prostate and testicular tumors in rats [6], no studies have definitively proved that cadmium can cause prostate cancer in humans [34]. Recent studies suggest that men exposed to heavy metals in their environment make it more difficult for a woman to get pregnant. Some studies have shown the effect of heavy metals on male fertility. There is considerable agreement that high or even moderate concentrations of lead are clearly associated with sperm damage and cause fertility problems in humans [31,32]. Another study found that increased blood lead levels correlated with a 15% decrease in fertility in men and a 28% decline in the probability of pregnancy for each menstrual cycle [35].
HEAVY METALS AND MALE FERTILITY Men with high concentrations of cadmium in seminal plasma (65 μg/dL) had a significant decline in sperm count and in number of motile sperms [33,36]. High concentrations of total mercury (40.6 mmol/L) in whole blood resulted in <50% of progressive sperm motility, and <14% of normal morphology [20]. In another study [31], infertile males were found to have ∼40% higher mercury levels than fertile males of similar age. Analysis of the differences in heavy metals and lead, cadmium, zinc, and copper levels in male semen with normal and low fertilities indicates that men with low fertility have higher semen lead and cadmium levels, lower semen Zn levels, and no significant difference with respect to copper [37].
ENVIRONMENTAL EXPOSURES TO HEAVY METALS AND REPRODUCTIVE HEALTH IN MEN Some chemicals have direct toxic effects on the reproductive system [38]. EDCs can have direct effects on the reproductive system and on hormone-producing glands, such as the thyroid or pituitary, which, in turn, affect reproductive health [39].
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Exposure of germ cells to some chemicals can result in infertility [40]. Depending on the genes affected, mutations can result in an inability to conceive or birth defects in the offspring [6,15]. Exposure to different heavy metals causes irreversible toxic insult to male reproductive system. Heavy metals produce cellular impairments at structural and functional levels in the male reproductive system [41]. Broad-spectrum irreversible toxic actions at the cellular and molecular level were observed mainly on reproductive system of human and experimental animals [39,42]. The potential toxicity of the heavy metals, lead, cadmium, chromium, selenium, and arsenic, caused alteration in sperm morphology, count, and motility as well as biochemical disruptions of enzymes and hormones. A combination of genetic, environmental, and lifestyle factors contributes to adverse effects on the reproductive health in men. Metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages. Studies have generally confirmed that even moderate- to low-level exposure to lead affects certain reproductive parameters [43]. Exposure to cadmium affects the prostate function and serum testosterone levels. Adverse effects of mercury, manganese, chromium and arsenic on semen quality and altered serum hormone levels have been reported [40,42]. Chromium is widely used in refractory, pigment, and stainless steel factory; tannery; welding; engraving; and photo processing unit. It causes severe reproductive injury among the exposed persons. Industrial workers exposed to chromium over a prolonged period showed high metal levels in blood and reduced semen quality leading to infertility [8]. Arsenic compounds are widespread in the environment as a result of natural and anthropogenic occurrence [44]. Arsenic exposure in mice and rats produced steroidogenic dysfunction leading to impairment of spermatogenesis [45,46]. Arsenic (As) has the property to bind to the glucocorticoid receptor, thus disturbing the biological effects of glucocorticoids. Arsenic is widely distributed in the natural environment, both as pure element and within complex compounds [44]. Arsenic is the 20th most prevalent metal in the earth’s crust, with a soil concentration of 1–2 ppm. This heavy metal is part of a large number of pesticides widely used in intensive agriculture. The digestive tract and the skin represent the main ways of contamination with As, which is excreted through urine, sweat, and milk, in both animals and humans [45,46]. Concerning environmental pollution, it was reported that As can accumulate in ground water and well water from natural sources. Cadmium (Cd) interferes with the biological effects of steroid hormones in reproductive organs. The main sources of contamination with Cd are represented by industrial aerosols, water wastes from extraction mines, phosphate-based fertilizers, Cd-containing pesticides, etc. It has been documented that in the industrial area, Cd concentration in the air peaks to 0.03 mg Cd/m3. Fodder plants are the main constituents through which Cd enters the food chain. Interestingly, the accumulation process is age dependent, because of the long half-time of the metals, with up to 20 years needed for Cd to be completely metabolized in human [47]. Significantly higher Cd concentrations were demonstrated in males compared with females, in various tissues and organs such as liver, kidney, muscle, blood, and hair. Cadmium
Environmental Exposures to Heavy Metals
disrupts steroidogenesis by interfering with the biosynthesis of androgens, estrogens, and progesterone, thus leading to disturbed sex differentiation and altered gametogenesis. On the other hand, it may bind both the estrogen and androgen receptor [48–51]. High doses of cadmium chloride exposure caused rapid testicular edema, hemorrhage, and necrosis. Cadmium exerted deleterious effect on the vascular structure of testis that may be the result of varying degrees of cadmium-induced ischemia. The ultimate result is membrane degeneration of spermatozoa leading to abnormal and dead sperm in semen [52]. Mercury is widely used in refineries, plastics and paints, antiseptics, scientific instruments, photography, fuel combustion, and the agricultural field. This metal is a spermato-, steroido- and fetotoxic agent. Organic mercury fungicides are widely used in agriculture. In addition, mercury is used as a catalyst in industrial processes. It is largely spread in the environment in the form of aerosols. Mercury compounds are transported by blood and the lymph and diffuse in practically all tissues. In patients with chronic intoxication, mercury exerts neurotoxic, teratogenic, mutagenic, and endocrine-disrupting effects. It is metabolized and excreted through milk, feces, kidneys, and saliva. Mercury is eliminated completely, after minimum 90 days postexposure [7,9,16]. Mercury chloride exhibited structural alteration of the testicular tissue along with biochemical changes. The prominent features of mercury-induced toxicity are depletion and clogging of different spermatogenic cells, the presence of pyknotic or karyotic pachytene nuclei, the absence of nuclear chromatin at stage XII in dividing cells, the absence of noticeable lumen, and the presence of vacuolated early elongated spermatids along with dispositioning of acrosomes [22,31,53]. Reports indicated that both organic and inorganic mercury compounds highly accumulate in major endocrine glands, for example, the hypothalamus, the pituitary gland, the thyroid, testes, ovaries and the adrenal cortex. Mercury-based compounds disrupt steroidogenesis, including sex hormones synthesis, male and female fertility, and the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal axis [9]. Most data available indicate that mercury may act as a major endocrine disrupter [9,22,54]. The heavy metal nickel (Ni) originates from natural and artificial sources and can be found in practically all environmental compartments: air, water, soil, and living organisms. In the air, it is distributed in the form of aerosols that contain various nickel concentrations, depending on the primary source of metal contamination. Nickel concentrations commonly found in the air vary between 5 and 35 ng/m3, with a 0.1–0.7 μg daily human contamination. Respiratory exposure to Ni carbonyl results in fetal death, intrauterine growth restriction, and congenital anomalies in rats and hamsters. Nickel carbonyl is associated with dominant lethal mutations in rats [3,28,55]. Zinc (Zn) is found in several combinations both in the earth’s crust and vegetal and animal cells. In fact, Zn is one of the most important natural, biologically active constituents, indispensable to life itself. In all tissues, Zn levels are twofold higher compared with iron levels. Zinc contamination results from industrial smoke, with
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the most relevant compounds represented by Zn chloride, Zn chromate, Zn phosphor, Zn sulfate, and Zn oxide [4]. Zn atom from the Zn fingers of the ER can be replaced by several heavy metal molecules, such as copper, cobalt, Ni, and Cd. By replacing the Zn atom with Ni or copper, binding of the ER to the DNA-hormone responsive elements in the cell nucleus is prevented [22,37]. Lead (Pb) is largely found in nature, in rocks, and in several combinations. The terrestrial crust contains on average 1–2 ppm lead. However, because of pollution, lead is largely spread in the environment in air, water, soil, flora, and fauna. In humans, the absorption percent is about 50%. Lead is widely used in acid battery plant refinery, smelter, fuel combustion industry, printing press, and automobile exhaust where tetraethyl lead acts as antiknocking agents [16,20]. Toxicity is manifested in the male reproductive system by deposition of lead in testes, epididymis, vas deferens, seminal vesicle, and seminal ejaculate. Lead has an adverse effect on sperm count and retarded the activity of alive sperm [53,56]. In human study, the semen lead was correspondingly increased with blood lead in the subjects exposed to lead over a period of about 6 years. The sperm analysis from those subjects revealed the morphological abnormalities of sperms (mainly tail abnormality) and a significant decrease in certain key seminal constituents such as fructose and succinic dehydrogenase [27,30]. There is evidence that lead interferes with the enzymes which contain (−SH) group or with the intervening redox systems and tissue respiration. Low fructose content accompanied by decreased activity of succinic dehydrogenase and alkaline phosphatase in seminal plasma was observed among the workers of printing press exposed to lead more than 8 h/day over a period of 10 years [20]. Moreover, workers occupationally exposed to lead exhibited moderately high blood lead levels associated with sexual disorders such as decreased libido. Lead adversely affects the testicular tissues and steroidogenesis either directly or through the endocrine system [27,30]. Lead is a powerful disrupter of adrenal and ovarian steroidogenesis [56,57]. Lead exposure results in disturbed fertility in females, by inhibiting two key proteins in the function of the pituitary–ovarian axis [58,59]. In summary, Pb contamination may alter endocrine-regulated processes such as longevity, development, sexual receptivity, fertility, and locomotion [37,58–60].
CONCLUSION This review provides evidence for the adverse effects of a number of the most toxic heavy metals in the surrounding environment on certain reproductive parameters, as well as the possible mechanisms of action on endocrines and reproductive systems. The adverse effects on aspects of human fertility have been addressed in some detail for certain heavy metals used extensively in industry, agriculture, and medicine. Evidence indicates that exposure to lead, mercury, cadmium, or chromium could adversely affect the male reproductive system and male fertility. There are insufficient data for establishing quantitative dose–response
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[57] Xu DX, Shen HM, Zhu QX, Chua L, Wang QN, Chia SE, Ong CN. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat Res 2003;534:155–63. [58] Roy Chowdhury A. Recent advances in heavy metals induced effect on male reproductive function—a retrospective. Al Ameen J Med Sci 2009. ISSN: 0974-1143;2(2). [special: 37–42]. [59] Erfurth EM, Gerhardsson L, Nilsson A, Rylander L, Schutz A, Skerfving S, Borjesson J. Effects of lead on the endocrine system in lead smelter workers. Arch Environ Health 2001;56:449–55. [60] Benoff S, Centola GM, Millan C, Napolitano B, Marmar JL, Hurley IR. Increased seminal plasma lead levels adversely affect the fertility potential of sperm in IVF. Hum Reprod 2003;18:374–83.
Heavy Metal Toxicity Affecting Fertility and Reproduction of Males
18 Fouad M. Badr1, Ola El-Habit2
1Suez
Canal University, Ismailia, Egypt; 2Helwan University, Cairo, Egypt
INTRODUCTION A heavy metal is defined as a metallic element, which has a relatively high atomic weight or atomic number and a relatively high density [1]. There are more than 20 heavy metals, but only a few are of particular concern to human health: lead (Pb), cadmium (Cd), mercury (Hg), chromium (Cr), and inorganic arsenic (As) (Table 18.1) [2]. These heavy metals are at the top of most hazardous metals present in many working sites [3]. They are highly toxic and can cause damaging effects even at very low concentrations. They tend to accumulate in the food chain and in the body and can be stored in soft (e.g., kidney) and hard tissues (e.g., bone). They often exist in a positively charged form and can bind on to negatively charged atom [4]. A heavy metal is often assumed to be toxic. Others are relatively harmless but can be toxic in large amounts or certain forms such as silver, indium, and bismuth [5]. Heavy metals such as lead, cadmium, and mercury are “natural” elements but can be harmful to health, especially over a long period of time or in high doses [5]. Heavy metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages.
ESSENTIAL HEAVY METALS Specific heavy metals, typically, iron, copper, zinc, manganese, cobalt, and nickel, are essential nutrients for the human body. Heavy metals essential for life can be toxic if taken in excess amounts. Ingesting more than 5 g of iron can be fatal. Cobalt, a dietary salt, can act at high doses as a carcinogen [6]. Nickel carbonyl (Ni2(CO)4) is lethal at 30 parts per million [7]. Excessive amounts of copper sulfate (Cu(SO4)2) can be fatal and result in major organ damage among survivors [8]. Bioenvironmental Issues Affecting Men's Reproductive and Sexual Health. http://dx.doi.org/10.1016/B978-0-12-801299-4.00018-9 Copyright © 2018 Elsevier Inc. All rights reserved.
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Table 18.1 List of Common Toxic Heavy Metals Sorted by Atomic Number, Weight, and Density Name
Symbol
Atomic Number
Atomic Weight
Density (g/cm3)
Chromium Iron Cobalt Nickel Copper Zinc Arsenic Cadmium Mercury Lead
Cr Fe Co Ni Cu Zn As Cd Hg Pb
24 26 27 28 29 30 33 48 80 82
51.9961 55.845 58.9332 58.6934 63.546 65.39 74.9216 112.411 200.59 207.2
7.19 7.87 8.9 8.9 8.96 7.13 5.72 8.65 13.55 11.35
SOURCES OF HEAVY METAL CONTAMINATION There are many heavy metals that are used in common home products, such as nonstick pans, glazed ceramics, pesticides, soaps, plastic toys, eye shadow, and lipstick. Heavy metals are present in many aspects of modern life. They are used in many industries, for example, cars, plastics, antiseptics, utensils, paints, batteries, solar panels, mobile phones, and particle accelerators [9]. Potential sources of heavy metal poisoning include mining, industrial wastes, agricultural runoff, and occupational exposure to such heavy metals. Lead is present in cigarette smoke, cutlery, hair dyes, lead pipes, car exhaust, and paints. Mercury, a heavy metal, is present in dental amalgams, thermometers, tattooing, fabric softeners, cosmetics, laxatives, insecticides, seafood, and vaccines. Nickel is present in stainless steel cookware, cigarette smoke, fertilizers, jewelry, hydrogenated fats, and margarine. Arsenic is used in car exhausts, colored chalk, household detergents, and certain soil fertilizers. Cadmium is most commonly found in cigarette smoke but is also used in batteries, metal coatings, and plastics [10,11].
BIOLOGICAL AND CHEMICAL EFFECTS OF HEAVY METALS Trace amounts of some heavy metals are required for certain biological processes. It is estimated that an average 70 kg human body contains about 0.01% heavy metals (∼7 g). These are manganese (enzyme regulation or activation), chromium (glucose utilization), iron and copper (oxygen and electron transport), cobalt (complex syntheses and cell metabolism), nickel (cell growth), zinc (hydroxylation), and arsenic (metabolic growth).
Heavy Metals and Reproductive Health
Heavy metals are present in nearly all aspects of modern life. The biocidal effects of some heavy metals have been known for ages [12]. Platinum, osmium, copper, ruthenium, and other heavy metals, including arsenic, are used in anticancer treatments. Antimony (antiprotozoal), bismuth (antiulcer), gold (antiarthritic), and iron (antimalarial) are also important in medicine. Copper, zinc, silver, gold, and mercury are used in antiseptic formulations. Depending on their intended use as fertilizers or biocides, agrochemicals may contain heavy metals, such as chromium, cobalt, nickel, copper, zinc, arsenic, cadmium, mercury, or lead [13]. Selected heavy metals are used as catalysts in fuel processing, chemical production, emission control devices, self-cleaning ovens, soap chemistry, paints, dryers, and fungicides [10,12,13].
HAZARDS OF HEAVY METAL CONTAMINATION The threats to human health from heavy metals are associated mainly with exposure to lead, cadmium, mercury, and arsenic. These metals have been extensively studied, and their effects on human health are regularly reviewed [3,4].
TOXICITY OF HEAVY METALS Heavy metals are systemic toxicants known to induce adverse health effects in humans. The main pathways of exposure include ingestion, inhalation, and dermal contact. The severity of adverse health effects is related to the type of heavy metal and its chemical form and is also time-dependent and dose-dependent. Among many other factors, speciation plays a key role in the kinetics and dynamics of metal toxicity and is highly influenced by factors such as valence state, particle size, solubility, biotransformation, and chemical form. Recent reports have pointed out that these toxic elements may interfere metabolically with nutritionally essential metals such as iron, calcium, copper, and zinc [7]. Simultaneous exposure to multiple heavy metals may produce a toxic effect that is additive, antagonistic, or synergistic. Coexposure to metal/metalloid mixtures of arsenic, lead, and cadmium produced more severe effects at both relatively high dose and low dose levels in a biomarker-specific manner [3]. These effects were found to be mediated by dose, duration of exposure, and genetic factors. In many areas of metal pollution, chronic low dose exposure to multiple elements is a major public health concern.
HEAVY METALS AND REPRODUCTIVE HEALTH Reproductive toxicants may contribute to a spectrum of adverse effects on reproductive health. These effects include menstrual irregularities, early or delayed puberty, infertility, subfertility, early pregnancy loss, fetal death, impaired fetal growth, low
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birth weight, premature birth, and birth defects [14–16]. Exposures to certain toxicants might result in adverse effects on the male reproductive system, such as an increase in testicular cancer incidence, decreasing sperm counts, a decline in serum testosterone, and fewer males being born. Whether or not an environmental exposure results in adverse effects on reproductive health in an individual ultimately depends on the interaction among various factors, such as the extent of multiple chemical exposures, individual experiences, disease frequency, age status of the population, and genetic variability [17]. The exposure time to environmental toxicants, which includes periods during gestation, childhood, adolescence, and adulthood, is another factor that strongly influences the ultimate biological effect [17–19]. Heavy metal toxicity is believed to be mediated through macromolecules such as proteins with structural, catalytic, or transport function and DNA. Reactive oxygen species are generated by metals, particularly transition metal ions, e.g., of iron, copper, and cobalt, can overcome the spin restriction of O2, and donate a single electron, giving rise to free radical species and chain reaction. Toxicity occurs when such metals are free and reactions become uncontrolled [20]. Metals also inhibit protection mechanism against reactive oxygen species, e.g., SOD, glutathione. Other important cytotoxic mechanism for some metals (e.g., mercury and chromate) are DNA damage and inhibition of cellular respiration (e.g., arsenic and chromate). Metals can bind to a wide variety of cellular legends and the effects produced seem to be relatively specific for each metal [21,22].
HEAVY METALS AND FERTILITY Heavy metals have been identified as factors affecting human fertility. Significant correlations were found between different heavy metals and clinical parameters (age, body mass index, ethnicity) as well as gynecological conditions (uterine fibroids, miscarriages, hormonal disorders). Lowering an increased heavy metal body load improved the spontaneous conception chances of infertile women [23]. A couple’s fertility depends on the fertility of both the man and the woman. Exposure of cadmium to either a man or a woman can delay a woman’s chances of getting pregnant [24]. The more lead there is in a man’s blood, the longer it will take his wife to get pregnant because lead lowers a man’s sperm count and also reduces the sperm mobility [25,26]. Lead or cadmium can affect a woman’s reproductive hormone levels, which, in turn, makes it more difficult to conceive [25,26]. Cadmium (Cd), mercury (Hg), arsenic (As), lead (PB), manganese (Mn), and zinc (Zn) act as endocrine-disrupting chemicals (EDCs). The influence of these metals on the endocrine system and reproductive systems alters possible mechanisms of action and results in consequent health effects, [24,27,28]. Many metals may have adverse effects on the male reproductive function. Metals can lead to the loss of fertility and libido or to impotence by affecting: the testis size, semen quality (e.g., sperm motility and quantity), the secretory function of the prostate and seminal vesicles, and the reproductive endocrine function [29–31].
Environmental Exposures to Heavy Metals
Severe cadmium intoxication provokes injuries to testes, the liver, and lungs [30–33]. Amounts of cadmium exceeding 2.5 mg/kg cause severe placental damage inducing malformations in the newborns and may lead to fetal death. Evidence of cadmium’s effects on pregnancy is inconsistent. Women with higher urinary cadmium levels have increased rates of preterm delivery, and infant weight also was lower than that in mothers with lower levels [24]. Cadmium can seriously damage the reproductive system, as it can mimic estrogen function by virtue of its binding with high affinity to estrogen receptors (ERs) [28], leading to gene activation. Alternatively, ERs can exert their effects through other mechanisms, such as the activation of secondary messengers and enzymatic pathways. Likely, the high incidence of tumors of the genital sphere in industrialized countries can be related to pollutants, such as cadmium, interfering with the hormonal network [26,28]. Although cadmium was associated with the development of prostate and testicular tumors in rats [6], no studies have definitively proved that cadmium can cause prostate cancer in humans [34]. Recent studies suggest that men exposed to heavy metals in their environment make it more difficult for a woman to get pregnant. Some studies have shown the effect of heavy metals on male fertility. There is considerable agreement that high or even moderate concentrations of lead are clearly associated with sperm damage and cause fertility problems in humans [31,32]. Another study found that increased blood lead levels correlated with a 15% decrease in fertility in men and a 28% decline in the probability of pregnancy for each menstrual cycle [35].
HEAVY METALS AND MALE FERTILITY Men with high concentrations of cadmium in seminal plasma (65 μg/dL) had a significant decline in sperm count and in number of motile sperms [33,36]. High concentrations of total mercury (40.6 mmol/L) in whole blood resulted in <50% of progressive sperm motility, and <14% of normal morphology [20]. In another study [31], infertile males were found to have ∼40% higher mercury levels than fertile males of similar age. Analysis of the differences in heavy metals and lead, cadmium, zinc, and copper levels in male semen with normal and low fertilities indicates that men with low fertility have higher semen lead and cadmium levels, lower semen Zn levels, and no significant difference with respect to copper [37].
ENVIRONMENTAL EXPOSURES TO HEAVY METALS AND REPRODUCTIVE HEALTH IN MEN Some chemicals have direct toxic effects on the reproductive system [38]. EDCs can have direct effects on the reproductive system and on hormone-producing glands, such as the thyroid or pituitary, which, in turn, affect reproductive health [39].
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Exposure of germ cells to some chemicals can result in infertility [40]. Depending on the genes affected, mutations can result in an inability to conceive or birth defects in the offspring [6,15]. Exposure to different heavy metals causes irreversible toxic insult to male reproductive system. Heavy metals produce cellular impairments at structural and functional levels in the male reproductive system [41]. Broad-spectrum irreversible toxic actions at the cellular and molecular level were observed mainly on reproductive system of human and experimental animals [39,42]. The potential toxicity of the heavy metals, lead, cadmium, chromium, selenium, and arsenic, caused alteration in sperm morphology, count, and motility as well as biochemical disruptions of enzymes and hormones. A combination of genetic, environmental, and lifestyle factors contributes to adverse effects on the reproductive health in men. Metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages. Studies have generally confirmed that even moderate- to low-level exposure to lead affects certain reproductive parameters [43]. Exposure to cadmium affects the prostate function and serum testosterone levels. Adverse effects of mercury, manganese, chromium and arsenic on semen quality and altered serum hormone levels have been reported [40,42]. Chromium is widely used in refractory, pigment, and stainless steel factory; tannery; welding; engraving; and photo processing unit. It causes severe reproductive injury among the exposed persons. Industrial workers exposed to chromium over a prolonged period showed high metal levels in blood and reduced semen quality leading to infertility [8]. Arsenic compounds are widespread in the environment as a result of natural and anthropogenic occurrence [44]. Arsenic exposure in mice and rats produced steroidogenic dysfunction leading to impairment of spermatogenesis [45,46]. Arsenic (As) has the property to bind to the glucocorticoid receptor, thus disturbing the biological effects of glucocorticoids. Arsenic is widely distributed in the natural environment, both as pure element and within complex compounds [44]. Arsenic is the 20th most prevalent metal in the earth’s crust, with a soil concentration of 1–2 ppm. This heavy metal is part of a large number of pesticides widely used in intensive agriculture. The digestive tract and the skin represent the main ways of contamination with As, which is excreted through urine, sweat, and milk, in both animals and humans [45,46]. Concerning environmental pollution, it was reported that As can accumulate in ground water and well water from natural sources. Cadmium (Cd) interferes with the biological effects of steroid hormones in reproductive organs. The main sources of contamination with Cd are represented by industrial aerosols, water wastes from extraction mines, phosphate-based fertilizers, Cd-containing pesticides, etc. It has been documented that in the industrial area, Cd concentration in the air peaks to 0.03 mg Cd/m3. Fodder plants are the main constituents through which Cd enters the food chain. Interestingly, the accumulation process is age dependent, because of the long half-time of the metals, with up to 20 years needed for Cd to be completely metabolized in human [47]. Significantly higher Cd concentrations were demonstrated in males compared with females, in various tissues and organs such as liver, kidney, muscle, blood, and hair. Cadmium
Environmental Exposures to Heavy Metals
disrupts steroidogenesis by interfering with the biosynthesis of androgens, estrogens, and progesterone, thus leading to disturbed sex differentiation and altered gametogenesis. On the other hand, it may bind both the estrogen and androgen receptor [48–51]. High doses of cadmium chloride exposure caused rapid testicular edema, hemorrhage, and necrosis. Cadmium exerted deleterious effect on the vascular structure of testis that may be the result of varying degrees of cadmium-induced ischemia. The ultimate result is membrane degeneration of spermatozoa leading to abnormal and dead sperm in semen [52]. Mercury is widely used in refineries, plastics and paints, antiseptics, scientific instruments, photography, fuel combustion, and the agricultural field. This metal is a spermato-, steroido- and fetotoxic agent. Organic mercury fungicides are widely used in agriculture. In addition, mercury is used as a catalyst in industrial processes. It is largely spread in the environment in the form of aerosols. Mercury compounds are transported by blood and the lymph and diffuse in practically all tissues. In patients with chronic intoxication, mercury exerts neurotoxic, teratogenic, mutagenic, and endocrine-disrupting effects. It is metabolized and excreted through milk, feces, kidneys, and saliva. Mercury is eliminated completely, after minimum 90 days postexposure [7,9,16]. Mercury chloride exhibited structural alteration of the testicular tissue along with biochemical changes. The prominent features of mercury-induced toxicity are depletion and clogging of different spermatogenic cells, the presence of pyknotic or karyotic pachytene nuclei, the absence of nuclear chromatin at stage XII in dividing cells, the absence of noticeable lumen, and the presence of vacuolated early elongated spermatids along with dispositioning of acrosomes [22,31,53]. Reports indicated that both organic and inorganic mercury compounds highly accumulate in major endocrine glands, for example, the hypothalamus, the pituitary gland, the thyroid, testes, ovaries and the adrenal cortex. Mercury-based compounds disrupt steroidogenesis, including sex hormones synthesis, male and female fertility, and the hypothalamic–pituitary–thyroid axis and the hypothalamic–pituitary–adrenal axis [9]. Most data available indicate that mercury may act as a major endocrine disrupter [9,22,54]. The heavy metal nickel (Ni) originates from natural and artificial sources and can be found in practically all environmental compartments: air, water, soil, and living organisms. In the air, it is distributed in the form of aerosols that contain various nickel concentrations, depending on the primary source of metal contamination. Nickel concentrations commonly found in the air vary between 5 and 35 ng/m3, with a 0.1–0.7 μg daily human contamination. Respiratory exposure to Ni carbonyl results in fetal death, intrauterine growth restriction, and congenital anomalies in rats and hamsters. Nickel carbonyl is associated with dominant lethal mutations in rats [3,28,55]. Zinc (Zn) is found in several combinations both in the earth’s crust and vegetal and animal cells. In fact, Zn is one of the most important natural, biologically active constituents, indispensable to life itself. In all tissues, Zn levels are twofold higher compared with iron levels. Zinc contamination results from industrial smoke, with
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the most relevant compounds represented by Zn chloride, Zn chromate, Zn phosphor, Zn sulfate, and Zn oxide [4]. Zn atom from the Zn fingers of the ER can be replaced by several heavy metal molecules, such as copper, cobalt, Ni, and Cd. By replacing the Zn atom with Ni or copper, binding of the ER to the DNA-hormone responsive elements in the cell nucleus is prevented [22,37]. Lead (Pb) is largely found in nature, in rocks, and in several combinations. The terrestrial crust contains on average 1–2 ppm lead. However, because of pollution, lead is largely spread in the environment in air, water, soil, flora, and fauna. In humans, the absorption percent is about 50%. Lead is widely used in acid battery plant refinery, smelter, fuel combustion industry, printing press, and automobile exhaust where tetraethyl lead acts as antiknocking agents [16,20]. Toxicity is manifested in the male reproductive system by deposition of lead in testes, epididymis, vas deferens, seminal vesicle, and seminal ejaculate. Lead has an adverse effect on sperm count and retarded the activity of alive sperm [53,56]. In human study, the semen lead was correspondingly increased with blood lead in the subjects exposed to lead over a period of about 6 years. The sperm analysis from those subjects revealed the morphological abnormalities of sperms (mainly tail abnormality) and a significant decrease in certain key seminal constituents such as fructose and succinic dehydrogenase [27,30]. There is evidence that lead interferes with the enzymes which contain (−SH) group or with the intervening redox systems and tissue respiration. Low fructose content accompanied by decreased activity of succinic dehydrogenase and alkaline phosphatase in seminal plasma was observed among the workers of printing press exposed to lead more than 8 h/day over a period of 10 years [20]. Moreover, workers occupationally exposed to lead exhibited moderately high blood lead levels associated with sexual disorders such as decreased libido. Lead adversely affects the testicular tissues and steroidogenesis either directly or through the endocrine system [27,30]. Lead is a powerful disrupter of adrenal and ovarian steroidogenesis [56,57]. Lead exposure results in disturbed fertility in females, by inhibiting two key proteins in the function of the pituitary–ovarian axis [58,59]. In summary, Pb contamination may alter endocrine-regulated processes such as longevity, development, sexual receptivity, fertility, and locomotion [37,58–60].
CONCLUSION This review provides evidence for the adverse effects of a number of the most toxic heavy metals in the surrounding environment on certain reproductive parameters, as well as the possible mechanisms of action on endocrines and reproductive systems. The adverse effects on aspects of human fertility have been addressed in some detail for certain heavy metals used extensively in industry, agriculture, and medicine. Evidence indicates that exposure to lead, mercury, cadmium, or chromium could adversely affect the male reproductive system and male fertility. There are insufficient data for establishing quantitative dose–response
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