Exposure to hazardous substances and male reproductive health: a research framework

The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving.     

On the rumors about the silent spring. Review of the scientific evidence linking occupational and environmental pesticide exposure to endocrine disruption health effects

Occupational exposure to some pesticides, and particularly DBCP and chlordecone, may adversely affect male fertility. However, apart from the therapeutic use of diethylstilbestrol, the threat to human reproduction posed by "endocrine disrupting" environmental contaminants has not been supported by epidemiological evidence thus far. As it concerns other endocrine effects described in experimental animals, only thyroid inhibition following occupational exposure to amitrole and mancozeb has been confirmed in humans. Cancer of the breast, endometrium, ovary, prostate, testis, and thyroid are hormone-dependent, which fostered research on the potential risk associated with occupational and environmental exposure to the so-called endocrine-disrupting pesticides. The most recent studies have ruled out the hypothesis of DDT derivatives as responsible for excess risks of cancer of the reproductive organs. Still, we cannot exclude a role for high level exposure to o,p'-DDE, particularly in post-menopausal ER+ breast cancer. On the other hand, other organochlorine pesticides and triazine herbicides require further investigation for a possible etiologic role in some hormone-dependent cancers.     

Reproductive disorders associated with pesticide exposure

Exposure of men or women to certain pesticides at sufficient doses may increase the risk for sperm abnormalities, decreased fertility, a deficit of male children, spontaneous abortion, birth defects or fetal growth retardation. Pesticides from workplace or environmental exposures enter breast milk. Certain pesticides have been linked to developmental neurobehavioral problems, altered function of immune cells and possibly childhood leukemia. In well-designed epidemiologic studies, adverse reproductive or developmental effects have been associated with mixed pesticide exposure in occupational settings, particularly when personal protective equipment is not used. Every class of pesticides has at least one agent capable of affecting a reproductive or developmental endpoint in laboratory animals or people, including organophosphates, carbamates, pyrethroids, herbicides, fungicides, fumigants and especially organochlorines. Many of the most toxic pesticides have been banned or restricted in developed nations, but high exposures to these agents are still occurring in the most impoverished countries around the globe. Protective clothing, masks and gloves are more difficult to tolerate in hot, humid weather, or may be unavailable or unaffordable. Counseling patients who are concerned about reproductive and developmental effects of pesticides often involves helping them assess their exposure levels, weigh risks and benefits, and adopt practices to reduce or eliminate their absorbed dose. Patients may not realize that by the first prenatal care visit, most disruptions of organogenesis have already occurred. Planning ahead provides the best chance of lowering risk from pesticides and remediating other risk factors before conception.     

Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system,breast, lung,kidney, pancreas,and brain

The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies.     

Maternal pregnancy serum level of heptachlor epoxide, hexachlorobenzene, and beta-hexachlorocyclohexane and risk of cryptorchidism in offspring

Prenatal exposure to environmental endocrine disrupters has been postulated to cause adverse effects on male reproductive health. Exposure to organochlorine pesticides with anti-androgenic and estrogenic potency has been shown to interfere with the sex-hormone-dependent process of testicular descent in animal models. We examined the relation between serum levels of the pesticides heptachlor epoxide (HCE), hexachlorobenzene (HCB), and beta-hexachlorocyclohexane (beta-HCCH) in pregnant women, and the occurrence of cryptorchidism in their sons. These three pesticides were previously suggested as risk factors for cryptorchidism. In a nested case-control design, we compared serum levels between mothers of cases (n = 219) and controls (n = 564), selected from the Collaborative Perinatal Project, a US birth cohort study of pregnancies in 1959-1966. The offspring of mothers with HCE levels above the 90th percentile compared to those below the 10th percentile had an adjusted odds ratio of cryptorchidism of 1.2 (95% confidence interval 0.6-2.6); for beta-HCCH the odds ratio was 1.6 (0.7-3.6). For HCB the adjusted odds ratio was near one. These results provide little support for an association of cryptorchidism with exposure to low levels of HCE or HCB. For beta-HCCH the findings were somewhat suggestive of an association but were inconclusive.     

Influence of pesticides on male fertility

Several studies have shown a decline in human semen quality and increased risks of male subfertility. This paper provides an overview of the mechanisms of pesticide-induced reproductive toxicity and the effects on male fertility since exposure to pesticides may be one of the causes of these disorders. Pesticides may directly damage spermatozoa, alter Sertoli cell or Leydig cell function, or disrupt the endocrine function in any stage of hormonal regulation (hormone synthesis, release, storage, transport, and clearance; receptor recognition and binding; thyroid function; and the central nervous system). These mechanisms are described with respect to the effects of pesticide exposure in vitro and in vivo. In epidemiologic studies, effects on sperm quality and time to pregnancy are reviewed. Clear effects on male fertility have been demonstrated for some pesticides [eg, dibromochloropropane, ethylene dibromide]. But results from more recent studies are inconsistent, and no uniform conclusion can be drawn about the effects of pesticides on male reproduction.     

Occupational exposure associated with reproductive dysfunction

Evidence suggestive of harmful effects of occupational exposure on the reproductive system and related outcomes has gradually accumulated in recent decades, and is further compounded by persistent environmental endocrine disruptive chemicals. These chemicals have been found to interfere with the function of the endocrine system, which is responsible for growth, sexual development and many other essential physiological functions. A number of occupations are being reported to be associated with reproductive dysfunction in males as well as in females. Generally, occupations involving the manufacture/or application of some of the persistent chemicals that are not easily degradable as well as bio-accumulative chemicals, occupations involving intensive exposure to heat and radiation, occupations involving the use of toxic solvents as well as toxic fumes are reported to be associated with reproductive dysfunction. Occupational exposure of males to various persistent chemicals have been reported to have male mediated adverse reproductive outcomes in the form of abortion, reduction in fertility etc. with inconclusive or limited evidence. Nevertheless, there is a need for more well designed studies in order to implicate any individual chemical having such effects as in most occupations workers are exposed to raw, intermediate and finished products and there are also several confounding factors associated with lifestyles responsible for reproductive dysfunction. There is an urgent need to look at indiscriminate use of persistent chemicals especially pesticides and persistent organic pollutants (POP's) as these chemicals enter the food chain also and could be potential for exposure during the critical period of development. It is also necessary to impart information, and to educate about the safe use of these chemicals, as a very sensitive reproduction issue is involved with exposure to these chemicals. Occupational exposures often are higher than environmental exposures, so that epidemiological studies should be conducted on these chemicals, on a priority basis, which are reported to have adverse effects on reproduction in the experimental system.     

Self-reported exposure to pesticides and radiation related to pregnancy outcome--results from National Natality and Fetal Mortality Surveys

Although fetal development is known to be sensitive to environmental agents, relatively little epidemiologic research has addressed this concern. Effects on pregnancy outcome of self-reported parental exposure to pesticides and to radiation were examined using data from the National Natality and Fetal Mortality Surveys, large national probability samples of live births and stillbirths occurring in 1980. In case-control analyses, maternal exposure to pesticides at home or work was associated with increased risk of stillbirth (odds ratios (ORs) = 1.5-1.6). Paternal pesticide exposure was associated with stillbirth (ORs = 1.2-1.4) and delivery of small-for-gestational-age infants (ORs = 1.4-2.0). A small increased risk of stillbirth (OR = 1.3) was found in relation to either parent's reported exposure to radiation. In spite of limitations in the quality of exposure data and the possibility of biased recall related to pregnancy outcome, associations of reported pesticide exposure to either parent with risk of stillbirth and small-for-gestational-age infants warrant further evaluation.     

Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat

In mammals, exposure to androgens early in development is essential for masculinization of the male reproductive phenotype. Male fetuses exposed to antiandrogens during perinatal life are permanently demasculinized in their morphology and physiology, whereas exposure to exogenous androgens permanently masculinizes females. In some litter-bearing species, proximity(italic) in utero(/italic) of females to males can partially masculinize female siblings and alter their responsiveness to endocrine-disrupting compounds. However, in our strain of rat (CD-SD Charles River), intrauterine position does not significantly influence testosterone concentrations and anogenital distance of fetuses. In comparison, administration of testosterone propionate to pregnant females, at doses that doubled fetal female testosterone levels, did masculinize the reproductive system. Discovery of androgen-active chemicals in the environment has placed increased emphasis on describing the reproductive and behavioral effects of both natural and environmental androgens and antiandrogens. Recently, the effects of an antiandrogen, vinclozolin, on the brain and behavior were cited as a special concern by the U.S. Environmental Protection Agency in its risk assessment of this pesticide. In rats, one such behavior that is perinatally organized by androgens is social play. Males play more than females, and administration of exogenous androgens during the neonatal period alters the juvenile expression of this sexually dimorphic behavior. Vinclozolin is an androgen receptor antagonist that inhibits androgen-dependent tissue growth in vivo. We were interested in whether developmental exposure to vinclozolin could also alter androgen-dependent behaviors such as play. Neonatal male rats were injected on postnatal days (PNDs) 2 and 3 with corn oil, the pharmacologic antiandrogen flutamide (50 mg/kg), or vinclozolin (200 mg/kg). On PNDs 36-37 animals were observed for social play. Behaviors associated with general social activity such as sniffing and dorsal contact were unaffected by treatment. However, play behavior in males treated with flutamide or vinclozolin was significantly reduced, resembling levels of play characteristic of females rather than untreated males. Therefore, this study demonstrates that perinatal exposure to vinclozolin, an environmental antiandrogen, can alter androgen-dependent play behavior in the male rat.     

Guppy sexual behavior as an effect biomarker of estrogen mimics.

There is widespread concern that some environmental chemicals can reduce the reproductive capability of humans and wildlife by mimicking natural estrogens and disrupting endocrine function. This potential threat to animal populations posed by xenoestrogens has, hardly surprisingly, been met by an intensive global effort to identify and develop biomarkers suitable for screening chemicals for estrogen mimicking capacity. Despite this effort, there are few biomarkers capable of linking exposure to xenoestrogens to impaired reproductive capability. The reproductive success of most animals depends strongly on the ability to perform the appropriate sexual behavior. The sexual display of the male guppy is strongly linked to reproductive success and is readily quantified under laboratory conditions. This preliminary study demonstrates that exposure of adult male guppies to water weakly contaminated with either natural estrogen (17beta-estradiol) or the xenoestrogen (4-tert-octylphenol) causes a dramatic decrease in the rate and intensity of sexual display. It is concluded that quantitative analysis of the sexual display of male guppies holds great promise as a biomarker at the organismal level for the effects of estrogen mimicking xenobiotics.     

The epidemiology of pesticide exposure and cancer: A review

Cancer is a multifactorial disease with contributions from genetic, environmental, and lifestyle factors. Pesticide exposure is recognized as an important environmental risk factor associated with cancer development. The epidemiology of pesticide exposure and cancer in humans has been studied globally in various settings. Insecticides, herbicides, and fungicides are associated with hemopoetic cancers, and cancers of the prostate, pancreas, liver, and other body systems. The involvement of pesticides in breast cancer has not yet been determined. In developing countries, sufficient epidemiologic research and evidence is lacking to link pesticide exposure with cancer development. Agricultural and industrial workers are high-risk groups for developing cancer following pesticide exposure. Children of farm workers can be exposed to pesticides through their parents. Maternal exposure to pesticides can pose a health risk to the fetus and the newborn. The organophosphates are most the commonly used compounds, but the organochlorines are still permitted for limited use in developing countries. Pesticide exposure, independently or in synergism with modifiable risk factors, is associated with several types of cancer.     

Modeling adverse environmental impacts on the reproductive system

When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method.     

Human reproductive system disturbances and pesticide exposure in Brazil

The observation of reproductive disturbances in humans and in the wildlife has been reported in the last decade in different countries. Exposure to different chemicals possibly acting in the endocrine system or endocrine disruptors, including pesticides, has been a hypothesis raised to explain the observed changes. This paper aimed to present results of an epidemiological ecologic study carried out to explore population data on pesticides exposure in selected Brazilian states in the eighties and human reproductive outcomes in the nineties. Pearson correlation coefficients were ascertained between available data pesticides sales in eleven states in Brazil in 1985 and selected further reproductive outcomes or their surrogates. Moderate to high correlations were observed to infertility, testis, breast, prostate and ovarian cancer mortality. Despite the restrains of ecologic studies to establish cause-effect relationships, the observed results are in agreement with evidence supporting a possible association between pesticides exposure and the analyzed reproductive outcomes.     

Neuroendocrine and reproductive effects of contemporary-use pesticides

Work in our laboratory has focused on the hypothesis that certain environmental contaminants will interfere with reproductive function because they disrupt the neuroendocrine regulation of gonadal function. In this article, we review the evidence that certain classes of contemporary-use pesticides alter gonadotropin secretion through a disruption of hypothalamic mechanisms. Specifically, we discuss the effect of formamidine and dithiocarbamate pesticides on the noradrenergic control of pituitary hormone secretion, ovarian function, and pregnancy in the rat. This is followed by a review of studies evaluating the effect of a chlorotriazine herbicide, atrazine, on the hormonal control of ovulation and lactation. We also discuss the physiological consequences of these endocrine alterations in the female, how toxicant-induced endocrine alterations may differ in physiological outcome in the male and female, and the fact that the reproductive risk assessment of some pesticides that act on the central nervous system (CNS) may be influenced by the development of tolerance.     

Ambient air pollution exposure and damage to male gametes: human studies and in situ 'sentinel' animal experiments

Globally there is concern that adverse reproductive outcomes and fertility impairment in humans may be caused by exposure to environmental contaminants. Air pollution in particular has been linked to DNA damage, abnormal sperm morphology, and reduced sperm performance in men. Experimental studies using model species (mice and rats) exposed in situ provide evidence that ambient air pollution can cause damage to the respiratory system and other tissues or organs. This can take the form of DNA damage and other genetic changes throughout the body, including induced mutations, DNA strand breaks, and altered methylation patterns in male germ cells. Human and animal studies together provide strong evidence that air pollution, especially airborne particulate matter, at commonly occurring ambient levels is genotoxic to male germ cells. The mechanistic link between air pollution exposure and induced genetic changes in male germ cells is currently unclear. 'Sentinel' animal experiments explicitly examining air pollution affects on sperm quality in laboratory rodents have not been conducted and would provide a critical link to observations in humans. The importance of air pollution compared to other factors affecting fertility and reproductive outcomes in humans is not clear and warrants further investigation.     

Contaminant-induced feminization and demasculinization of nonmammalian vertebrate males in aquatic environments

Many chemicals introduced into the environment by humans adversely affect embryonic development and the functioning of the male reproductive system. It has been hypothesized that these developmental alterations are due to the endocrine-disruptive effects of various environmental contaminants. The endocrine system exhibits an organizational effect on the developing embryo. Thus, a disruption of the normal hormonal signals can permanently modify the organization and future function of the male reproductive system. A wide range of studies examining wildlife either in laboratories or in natural settings have documented alterations in the development of males. These studies have begun to provide the causal relationships between embryonic contaminant exposure and reproductive abnormalities that have been lacking in pure field studies of wild populations. An understanding of the developmental consequences of endocrine disruption in wildlife can lead to new indicators of exposure and a better understanding of the most sensitive life stages as well as the consequences of exposure during these periods.     

Gliomas and farm pesticide exposure in women: the Upper Midwest Health Study

An excess incidence of brain cancer in male farmers has been noted in several studies, but few studies have focused on women. The National Institute for Occupational Safety and Health Upper Midwest Health Study evaluated effects of rural exposures for 341 female glioma cases and 528 controls, all adult (18-80 years of age) nonmetropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. On average, controls lived longer on farms than did cases. After adjusting for age, age group, education, and farm residence, no association with glioma was observed for exposure to arsenicals, benzoic acids, carbamates, chloroacetanilides, dinitroanilines, inorganics, organochlorines, organophosphates, phenoxys, triazines, or urea-based or estrogenic pesticides. An increased risk of glioma was observed for carbamate herbicides but was not statistically significant (odds ratio = 3.0; 95% confidence interval, 0.9-9.5). No association was observed between glioma and exposure to 12 widely used specific pesticides, after adjustment for age, age group, education, and any other pesticide exposure. These results were not affected after exclusion of proxy respondents (43% of cases, 2% of controls). Women were less likely than men to have applied pesticides, but more likely to have laundered pesticide-contaminated clothes. Storing pesticides in the house was associated with a statistically non-significant increased risk. Results show that exposure to pesticides was not associated with an increased risk of intracranial gliomas in women. Other farm-related factors could be etiologic factors and will be discussed in future reports.     

The influence of occupational exposure on male reproductive function

Recently, many studies have found a decrease in semen quality which has increased the focus on male reproductive health. Occupational hazards are by far the best documented in reproductive epidemiological research. Generally, occupational exposures have been divided into physical exposures (heat and radiation), chemical exposures (solvents and pesticides), psychological exposures (distress), exposure to metals and welding. The recent and/or most important epidemiological studies exploring the effect of occupational exposures on semen quality and fecundity, the ability to conceive, are reviewed. The evidence for an adverse effect on male reproduction of several occupational and environmental exposures and toxicants, such as heat, ionizing radiation, inorganic lead, dibromochloropropane, ethylene dibromide, some ethylene glycol ethers, carbon disulfide and welding operations, is strongly supported in well-designed epidemiological studies. For other agents, the association is only suspected or suggested and needs further evaluation before conclusions can be drawn. It is also important to bear in mind that many workers in the non-Western world still are exposed to substances that are banned in the Western world, sometimes in high concentrations.     

Pesticide/Environmental Exposures and Parkinson's Disease in East Texas

ABSTRACT

Epidemiological evidence suggests that pesticides and other environmental exposures may have a role in the etiology of idiopathic Parkinson's disease (PD). However, there is little human data on risk associated with specific pesticide products, including organic pesticides such as rotenone with PD. Using a case-control design, this study examined self-reports of exposure to pesticide products, organic pesticides such as rotenone, and other occupational and environmental exposures on the risk of PD in an East Texas population. The findings demonstrated significantly increased risk of PD with use of organic pesticides such as rotenone in the past year in gardening (OR = 10.9; 95% CI = 2.5–48.0) and any rotenone use in the past (OR = 10.0; 95% CI = 2.9–34.3). Use of chlorpyrifos products (OR = 2.0; 95% CI = 1.02–3.8), past work in an electronics plant (OR = 5.1; 95% CI = 1.1–23.6), and exposure to fluorides (OR = 3.3; 95% CI = 1.03–10.3) were also associated with significantly increased risk. A trend of increased PD risk was observed with work history in paper/lumber mill (OR = 6.35; 95% CI = 0.7–51.8), exposure to cadmium (OR = 5.3; 95% CI = 0.6–44.9), exposure to paraquat (OR = 3.5; 95% CI = 0.4–31.6), and insecticide applications to farm animals/animal areas and agricultural processes (OR = 4.4; 95% CI = 0.5–38.1). Cigarette smoking, alcohol use, and fish intake were associated with reduced risk. In summary, this study demonstrates an increased risk of PD associated with organic pesticides such as rotenone and certain other pesticides and environmental exposures in this population.     

Ocular toxicity from pesticide exposure: A recent review

Toxic effects on eyes result from exposure to pesticides via inhalation, ingestion, dermal contact and ocular exposure. Exposure of unprotected eyes to pesticides results in the absorption in ocular tissue and potential ocular toxicity. Recent literature on the risks of ocular toxicity from pesticide exposure is limited. Ocular toxicity from pesticide exposure, including the dose-response relationship, has been studied in different animal species. Cholinesterase enzymes have been detected in animal ocular tissue, with evidence of organophosphate-induced inhibition. Pathological effects of pesticides have been observed in conjunctiva, cornea, lens, retina and the optic nerve. Pesticide exposure has been associated with retinopathy in agricultural workers and wives of farmers who used pesticides. Saku disease, an optico-autonomic peripheral neuropathy, has been described in Japan in people living in an area where organophosphates were used. Pesticide exposure is also associated with abnormal ocular movements. Progressive toxic ocular effects leading to defective vision are a serious health concern. Agricultural workers are at high risk of exposure to pesticides and associated ocular toxicity. Primary prevention is the appropriate method of protecting eyes from pesticide-related damage. This includes improved eye safety and care in workplaces, and effective pesticide regulation for maintenance of public eye health.