The effect of environmental contaminants on testicular function

Male reproductive health has deteriorated considerably in the last few decades. Nutritional, socioeconomic, lifestyle and environmental factors (among others) have been attributed to compromising male reproductive health. In recent years, a large volume of evidence has accumulated that suggests that the trend of decreasing male fertility (in terms of sperm count, quality and other changes in male reproductive health) might be due to exposure to environmental toxicants. These environmental contaminants can mimic natural oestrogens and target testicular spermatogenesis, steroidogenesis, and the function of both Sertoli and Leydig cells. Most environmental toxicants have been shown to induce reactive oxygen species, thereby causing a state of oxidative stress in various compartments of the testes. However, the molecular mechanism(s) of action of the environmental toxicants on the testis have yet to be elucidated. This review discusses the effects of some of the more commonly used environmental contaminants on testicular function through the induction of oxidative stress and apoptosis.     

基因一环境相互作用与男性生殖功能

由于遗传因素无法解释短时期内发生的改变,环境和生活方式相关因素被认为是引起与时间相关的男性生殖功能衰退的原因。但是,鉴于不同人群之间以及相同人群内部男性生育力存在很大差别,遗传因素可能极大地影响到人们对环境或生活方式的不利影响的个体易感性。尽管我们对这种和生殖系统相关的相互作用的机制还知之甚少,最近已经有研究表明一些特异的基因型会使得男性在接触某些环境因素后生殖疾病风险大大提高。本文对一些基因如何调节环境对男性生殖功能影响的人类和动物学研究进行了回顾和评论。虽然已经发现一些证据支持这一说法,但是研究数量依然有限。这类基因一环境相互作用的研究可以帮助我们更好地了解正常生理学,并且确定男性生殖疾病的风险因素。我们还简短讨论了与生殖相关的其它基因一环境相互作用方面的话题,即环境和生活方式因素引起精子DNA损伤。这些基因到底改变到什么程度,是通过自然方式,还是辅助生殖技术的应用传给下一代,从而引起子代发病率上升？这些问题还有待于研究探讨。     

Environmental erectile dysfunction: can the environment really be hazardous to your erectile health?

The proposal that exposures to environmental or occupational substances may affect erection ability is a tenable one and would add to a growing list of pathogenic risk factors associated with erectile dysfunction. Several lines of evidence gained by clinical epidemiologic and biomedical research investigations lend support. Several environmental toxicants to include lead, organic solvents, and pesticides have been implicated as possibly hazardous agents. Effects on the nervous and hormonal systems have been proposed as the leading mechanisms by which environmental toxicants adversely impact erectile function. Synthesis of the current evidence supports a possible risk association between environmental exposures and erectile dysfunction. However, scientific support is lacking to establish a direct causal association at this time. More scientific work is needed to identify specific environmental agents that may harm erectile function and define their exact mechanisms of action in this regard.     

Reproductive dysgenesis in wildlife: a comparative view

Abnormal reproductive development in males has been linked to environmental contaminant exposure in a wide variety of vertebrates. These include humans, rodent models, and a large number of comparative wildlife species. In human males, abnormal reproductive development can manifest as a suite of symptoms, described collectively as testicular dysgenesis syndrome (TDS). TDS is also described as demasculinization or feminization of the male phenotype. The suite includes cryptorchidism, in situ germ cell carcinoma of the testis and overt testicular cancer, reduced semen quality, and hypospadias. In this paper, we review examples of TDS among comparative species. Wildlife exposed to environmental contaminants are susceptible to some of the same developmental abnormalities and subsequent symptoms as those seen in human males with TDS. There are additional end points, which are also discussed. In some cases, the symptoms are more severe than those normally seen in humans with TDS (i.e. oocytes developing within the testis) because some non-mammalian species exhibit greater innate reproductive plasticity, and are thus more easily feminized. Based on our review, we present an approach regarding the ontogeny of TDS. Namely, we suggest that male susceptibility to the androgynizing influences of environmental contaminants originates in the sexually undifferentiated embryo, which, in almost all species, including humans, consists of bipotential reproductive tissues. These tissues can develop as either male or female and their ultimate direction depends on the environment in which they develop.     

Endocrine disruptors and male reproductive function – a short review

Semen quality has decline in many countries over the last few decades. There has been an increase in the incidence of testicular cancer world-wide. The incidences of cryptorchidism and hypospadias have also increased in many countries. A biological plausible hypothesis has suggested that man-made chemicals act as endocrine disruptors resulting in altered development of the reproductive tract causing the observed effects. Endocrine disruptors include natural products, pharmaceuticals, industrial products and environmental pollutants. There are limitations in the current in vivo and in vitro assays for the assessment of endocrine disruptors. Epidemiological human studies are necessary to fill in the gap of knowledge. Based on the current knowledge, the impact of endocrine disruptors on the male reproductive function remain to be appreciated.     

Impact of environmental toxin exposure on male fertility potential

Idiopathic infertility is the most common individual diagnosis in male infertility, representing nearly 44% of cases. Research studies dating over the last half-century consistently demonstrate a decline in male fertility that is incompletely explained by obesity, known genetic causes, or diet and lifestyle changes alone. Human exposures have changed dramatically over the same time course as this fertility decline. Synthetic chemicals surround us. Some are benevolent; however, many are known to cause disruption of the hypothalamic-pituitary-gonadal axis and impair spermatogenesis. More than 80,000 chemicals are registered with the United States National Toxicology Program and nearly 2,000 new chemicals are introduced each year. Many of these are known toxins, such as phthalates, polycyclic aromatic hydrocarbons, aromatic amines, and organophosphate esters, and have been banned or significantly restricted by other countries as they carry known carcinogenic effects and are reproductively toxic. In the United States, many of these chemicals are still permissible in exposure levels known to cause reproductive harm. This contrasts to other chemical regulatory legislature, such as the European Union’s REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) regulations which are more comprehensive and restrictive. Quantification of these diverse exposures on an individual level has proven challenging, although forthcoming technologies may soon make this data available to consumers. Establishing causality and the proportion of idiopathic infertility attributable to environmental toxin exposures remains elusive, however, continued investigation, avoidance of exposure, and mitigation of risk is essential to our reproductive health. The aim of this review is to examine the literature linking changes in male fertility to some of the most common environmental exposures. Specifically, pesticides and herbicides such as dichlorodiphenyltrichloroethane (DDT), dibromochloropropane (DBCP), organophosphates and atrazine, endocrine disrupting compounds including plastic compounds phthalates and bisphenol A (BPA), heavy metals, natural gas/oil, non-ionizing radiation, air and noise pollution, lifestyle factors including diet, obesity, caffeine use, smoking, alcohol and drug use, as well as commonly prescribed medications will be discussed.     

Association between chemical pattern in breast milk and congenital cryptorchidism: modelling of complex human exposures

During the past four decades, there has been an increase in the incidence rate of male reproductive disorders in some, but not all, Western countries. The observed increase in the prevalence of male reproductive disorders is suspected to be ascribable to environmental factors as the increase has been too rapid to be explained by genetics alone. To study the association between complex chemical exposures of humans and congenital cryptorchidism, the most common malformation of the male genitalia, we measured 121 environmental chemicals with suspected or known endocrine disrupting properties in 130 breast milk samples from Danish and Finnish mothers. Half the newborns were healthy controls, whereas the other half was boys with congenital cryptorchidism. The measured chemicals included polychlorinated biphenyls (PCBs), polybrominated diphenyl-ethers, dioxins (OCDD/PCDFs), phthalates, polybrominated biphenyls and organochlorine pesticides. Computational analysis of the data was performed using logistic regression and three multivariate machine learning classifiers. Furthermore, we performed systems biology analysis to explore the chemical influence on a molecular level. After correction for multiple testing, exposure to nine chemicals was significantly different between the cases and controls in the Danish cohort, but not in the Finnish cohort. The multivariate analysis indicated that Danish samples exhibited a stronger correlation between chemical exposure patterns in breast milk and cryptorchidism than Finnish samples. Moreover, PCBs were indicated as having a protective effect within the Danish cohort, which was supported by molecular data recovered through systems biology. Our results lend further support to the hypothesis that the mixture of environmental chemicals may contribute to observed adverse trends in male reproductive health.     

Reduced seminal parameters associated with environmental DDT exposure and p,p'-DDE concentrations in men in Chiapas, Mexico: a cross-sectional study

In response to mounting concerns about the endocrine-disrupting influence of environmental chemicals on human health, this epidemiological study was initiated to test the hypothesis that nonoccupational exposure to the estrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) affects male reproductive parameters. One hundred and sixteen men aged 27 years (SD = 8.2) living in malaria endemic-areas in Chiapas (Mexico), where DDT was sprayed until 2000, participated in a cross-sectional study. Semen analyses were conducted according to World Health Organization methods and a quality control program was followed. DDT exposure was defined as the level of blood plasma p,p'-dichlorodiphenyl dichloroethylene (DDE), the major metabolite of DDT. The p,p'-DDE concentration adjusted for total lipids was 100 times higher than that reported for nonexposed populations at 45 plus or minus 32 mug/g (mean +/- SD). Crude regression analysis showed that several sperm motion parameters, including the percentage of motile sperm, decreased with higher p,p'-DDE concentrations (beta = -8.38; P = .05 for squared motility), and the percentage of sperm with morphological tail defects increased with higher plasma p,p'-DDE concentration (beta = 0.003; P = .017). Insufficient sperm chromatin condensation was observed in 46.6% of participants, and the most severe category of incomplete DNA condensation was also positively correlated with p,p'-DDE concentration (r = .223; P = .044). Therefore, nonoccupational exposure to DDT, as assessed by plasma p,p'-DDE concentrations, is associated with poorer semen parameters in men, indicating adverse effects on testicular function and/or the regulation of reproductive hormones. Previously, a causal role of environmental toxicants in human male infertility has been lacking because observed effects have been the result of unusually high exposures, either occupationally or as a result of industrial accidents, resulting in unprecedented controversy (reviewed by Cheek & McLachlan, Environmental hormones and the male reproductive system. J Androl. 1998;19:5). This is the first epidemiological study demonstrating effects after nonoccupational exposures to DDT. Based on these findings, the effect of DDT on male reproductive health should not be ignored.     

How work-place conditions,environmental toxicants and lifestyle affect male reproductive function

Major temporal and geographical shifts in male reproductive function is presently an issue worldwide. The hormonal disruption hypothesis has achieved considerable attention but epidemiological evidence in support of the theory is lacking. Several occupational hazards to male reproductive function are known but exposure prevalences are hardly sufficient to play a role for reduced sperm count in the general male population. Sedentary work may be an exception. Perhaps prolonged time in the sedentary position exhausts the testicular heat regulation. But so far studies addressing implications of the heat hypothesis in the general population are few. Neither change of sexual behaviour nor reduced period of sexual continence seems to be a likely explanation. Tobacco smoking and consumption of caffeine and alcoholic beverages in adulthood have a rather marginal impact on spermatogenesis and can hardly explain major shifts or regional differences in male reproductive health. However, prenatal effects following smoking during pregnancy might play a role because we have witnessed a smoking epidemic among fertile women in some countries during the second half of the twentieth century. Moreover, if genetic factors play more than a marginal role for testicular function and sperm count, pregnancy planning resulting in reduced family size during the past 100 years could possibly explain a decline in semen quality because the most fertile part of the population reproduce less while the subfertile probably continue to get a limited number of children.     

Ethnic differences in occurrence of TDS-- genetics and/or environment?

It has been hypothesized that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the so-called testicular dysgenesis syndrome (TDS). TDS was suggested to be a result of disruption of embryonal programming and gonadal development during foetal life and as aetiological factor, an impact of adverse environmental factors such as hormone disrupters, probably acting upon a susceptible genetic background, was suggested. Extensive studies considering the risk of TDS-related diseases in Denmark compared with Finland, showed higher sperm counts and lower risk of cryptorchidism and testicular cancer among Finns. However, when comparing these two populations, the question arises, to which degree this difference might be due to discrepancy in genetic background. A more obvious example of the impact of genetic factors on the risk of TDS concerns Afro-Americans having significantly lower incidence of testicular cancer when compared with Caucasians living in the USA. A yet unexplored scenario is a possible interaction between genetic and environmental/lifestyle-related factors, certain genotypes making individuals more susceptible to adverse exogenous exposures. Studying such interactions has biological, epidemiological and public health-related implications. It will help us to understand the background for the defects in male reproductive organs, facilitate proper design of epidemiological studies and add to identifying individuals susceptible to certain environmental and lifestyle-related hazards. Such 'susceptibility genes' need to be identified, those involved in the synthesis, action and metabolism of sex steroids being strong candidates.     

Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations

Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish-Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be 'whistle blowers' of other reproductive health problems. As cancer registries are often of excellent quality - in contrast to registries for congenital abnormalities - health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising.     

Testicular dysgenesis syndrome and the origin of carcinoma in situ testis

Recent increases in male reproductive disorders have been linked to exposure to environmental factors leading to the testicular dysgenesis syndrome (TDS). Testicular cancer is the most severe condition in TDS and studies have shown a clear correlation between risk of testicular cancer and other components of TDS and that the geographical location of the mother during pregnancy can be a risk factor. This suggests that the dysgenesis has its origin in utero and that TDS is initiated by environmental factors, including possibly hormone-disrupting compounds that act on the mother and the developing foetus, but the genetic background may also play a role. The morphological similarity of carcinoma in situ (CIS) cells (the precursor of the majority of invasive testicular cancers) with primordial germ cells and gonocytes, and overlap in expression of protein markers suggests an origin of CIS from primordial germ cells or gonocytes. CIS cells and germ cell-derived cancers of the human type have so far not been described in any animal model of TDS, which could be caused by species differences in the development of the male gonad. Regardless of this, it is plausible that the dysgenesis, and hence the development of CIS cells, is a result of disturbed signalling between nurse cells and germ cells that allow embryonic germ cells to survive in the pre-pubertal and adult testis. The post-pubertal proliferation of CIS cells combined with aberrant signalling then leads to an accumulation of genetic changes in the CIS cells, which eventually results in the development of invasive testicular cancer in the adult.     

Testicular tumors in mice exposed in utero to diethylstilbestrol

Treatment of pregnant women with diethylstilbestrol (DES) is associated with the subsequent development of reproductive tract abnormalities such as epididymal cysts, retained hypotrophic testes and sperm abnormalities in their male offspring. It recently has been suggested that prenatal DES exposure is associated with development of testicular seminoma in humans. Studies of in utero exposure of laboratory animals to DES are few, but previous reports from our laboratory have described several abnormalities in the reproductive tract of the mouse following prenatal DES exposure. To study the possible association of testicular tumors and prenatal DES exposure in mice, pregnant outbred CD-1 mice were injected subcutaneously with daily doses of DES (100 micrograms./kg.) on days nine through 16 of gestation. DES-exposed and age-matched control male mice were sacrificed at 10 to 18 months of age and examined for testicular lesions. In addition to the nonmalignant abnormalities reported in previous studies such as 91% cryptorchidism and degenerative changes, interstitial cell tumors were observed in nine mice among 277 mice treated prenatally with DES. Two of these lesions were benign tumors and five were interstitial cell carcinomas. Rete testis adenocarcinoma was seen also in 5% of these DES-treated animals and is described in another report. The overall incidence of testicular tumors is 8% in DES-exposed male mice. No comparable lesions were seen in 122 control male mice. These results suggest that the testicular lesions that can occur following prenatal DES exposure include neoplasia. The combined prevalence of DES-induced tumors of the corpus testis and rete testis in mice suggests the male offspring may be more at risk for developing carcinoma of the reproductive tract than the female offspring.     

The male reproductive system and its susceptibility to endocrine disrupting chemicals

In the past years, there has been increased interest in assessing the relationship between impaired male fertility and environmental factors. Human male fertility is a complex process and therefore a great variety of sites may be affected by exogenous noxae. Lifestyle factors as well as various environmental and occupational agents may impair male fertility. Many studies have been published reporting on reproductive dysfunctions in male animals and humans. Especially environmental pollutants with endocrine activity are discussed as a possible cause of this detrimental development. Evidence from animal experiments show that substances with oestrogenic and antiandrogenic properties may cause hypospadia, cryptorchidism, reduction of sperm density and an increase of testicular tumours. Many adverse effects on animal male fertility have been documented for phthalates and some chlorinated hydrocarbons such as polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins. For other chemicals such as bisphenol A and nonylphenols animal data are conflicting. Environmental pollutants may mediate their effects by receptor binding, modulation of hormone-regulated mechanisms or direct toxic effects. Data on environmental chemicals and human male fertility are scarce, and risk assessment is mostly based on the results of animal studies. However, there are indications that exposure to endocrine active chemicals during early development may alter hormone responsiveness in adulthood. Furthermore, some of the chemicals are found in fluids that are associated with human reproduction, such as follicular fluid, seminal fluid and cervical mucus. Recent studies suggest a correlation between pesticide exposure and standard semen parameters as well as in vitro fertilization rates.     

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??The risk factors and the clinical characteristics of male breast cancer WU Ke-jin, DING Long-long. Department of General Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Corresponding author: WU Ke-jin, E-mail: kejinwu@163.com
Abstract Male breast cancer is a rare malignant tumor, accounting for <1% of all male malignant tumors. Epidemiological risk factors for male breast cancer include family history of breast cancer, BRCA mutation, clinical disorders relating to hormonal imbalances, certain occupational, environmental exposures and alcohol. The most common clinical sign of male breast cancer is painless lump. The main pathological type of male breast tumor is invasive ductal carcinoma with high positive expression rates of hormone receptors. The prognosis of male breast cancer is much awful.     

Combined effects of chronic hyperglycaemia and oral aluminium intoxication on testicular tissue and some male reproductive parameters in Wistar rats

Exposure to either environmental toxicants or chronic hyperglycaemia could impair male reproductive function. However, the extent to which exposure to such toxicants, in the presence of pre‐existing metabolic dysfunction, could affect male reproduction is unclear. Streptozotocin‐induced diabetic Wistar rats (12 weeks old) were exposed to oral aluminium chloride at 250 ppm for 30 days; followed by evaluation of caudal epididymal sperm count and motility, assay for serum follicle stimulating hormone (FSH), testosterone (T) and oestradiol; and assessment of testicular histology. Moreover, blood glucose was evaluated by the glucose oxidase method. In rats treated with streptozotocin (STZ) or aluminium (Al) alone, erosion of testicular parenchyma and stroma was observed. This effect was most severe in diabetic rats simultaneously exposed to Al; coupled with reduced caudal epididymal sperm count that was least in this (STZ+Al) group (18.75 × 10⁶ ml^?1) compared with controls (61.25 × 10⁶ ml^?1; P < 0.05), STZ group or Al group. Moreover, these reproductive perturbations (in the STZ+Al group) were associated with reduced sperm motility and significantly reduced serum FSH (P < 0.05); but elevated serum T and oestradiol (P < 0.05), compared with control. These suggest that diabetes‐induced testicular lesion is exacerbated by simultaneous oral Al toxicity in Wistar rats.     

Oxidative stress: a common factor in testicular dysfunction

Oxidative stress results from the production of oxygen radicals in excess of the antioxidant capacity of the stressed tissue. Many conditions or events associated with male infertility are inducers of oxidative stress. X-irradiation, for example, or exposure to environmental toxicants and the physical conditions of varicocele and cryptorchidism have been demonstrated to increase testicular oxidative stress, which leads to an increase in germ cell apoptosis and subsequent hypospermatogenesis. Such stress conditions can cause changes in the dynamics of testicular microvascular blood flow, endocrine signaling, and germ cell apoptosis. Testicular oxidative stress appears to be a common feature in much of what underlies male infertility, which suggests that there may be benefits to developing better antioxidant therapies for relevant cases of hypospermatogenesis.     

Testicular biopsy: clinical practice and interpretation

Testicular biopsy was considered the cornerstone of male infertility diagnosis for many years in men with unexplained infertility and azoospermia. Recent guidelines for male infertility have limited the indications for a diagnostic testicular biopsy to the confirmation of obstructive azoospermia in men with normal size testes and normal reproductive hormones. Nowadays, testicular biopsies are mainly performed for sperm harvesting in men with non-obstructive azoospermia, to be used for intracytoplasmic sperm injection. Testicular biopsy is also performed in men with risk factors for testicular malignancy. In a subgroup of infertile men, there is an increased risk for carcinoma in situ of the testis, especially in men with a history of cryptorchidism and testicular malignancy and in men with testicular atrophy. Ultrasonographic abnormalities, such as testicular microlithiasis, inhomogeneous parenchyma and lesions of the testes, further increase the risk of carcinoma in situ (CIS) in these men. For an accurate histological classification, proper tissue handling, fixation, preparation of the specimen and evaluation are needed. A standardized approach to testicular biopsy is recommended. In addition, approaches to the detection of CIS of the testis testicular immunohistochemistry are mandatory. In this mini-review, we describe the current indications for testicular biopsies in the diagnosis and management of male infertility.