Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies

Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies. Reports of an increase in male reproductive disorders in several countries led to the hypothesis that estrogens during fetal life may cause reduced sperm counts, cryptorchidism, hypospadias and testicular cancer. So far the hypothesis is based on animal studies and reports from the wild life. We systematically searched the epidemiological literature for evidence linking indicators of prenatal serum levels of maternal estrogens with sperm density, hypospadias, cryptorchidism and testicular cancer in humans. Indicators of fetal estrogen exposure included direct measurements, recorded intake of hormones (diethylstilbestrol (DES), oral contraceptives (OCs) and estrogens), pregnancy conditions with known deviant estrogen level as for instance twin pregnancies and some environmental exposures. Among 425 papers we reviewed 81 publications with appropriate information. With the possible exception of testicular cancer there is no strong epidemiological evidence to indicate that prenatal exposure to estrogen are linked to disturbed development of the male reproductive organs.     

Bisphenol A and human health: A review of the literature

There is growing evidence that bisphenol A (BPA) may adversely affect humans. BPA is an endocrine disruptor that has been shown to be harmful in laboratory animal studies. Until recently, there were relatively few epidemiological studies examining the relationship between BPA and health effects in humans. However, in the last year, the number of these studies has more than doubled. A comprehensive literature search found 91 studies linking BPA to human health; 53 published within the last year. This review outlines this body of literature, showing associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. These studies encompass both prenatal and postnatal exposures, and include several study designs and population types. While it is difficult to make causal links with epidemiological studies, the growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental BPA exposure can be harmful to humans, especially in regards to behavioral and other effects in children.     

In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence

In recent years, chemicals with hormone-like properties have become a topic of scientific and public discussion. It has been hypothesized that prenatal exposure of the male fetus to endocrine disruptors may be responsible for a series of outcomes, such as hypospadias and cryptorchidism. The purpose of this study was to review the endocrine disruption hypothesis, to present the relevant supporting evidence, to summarize the current knowledge, to identify gaps and limitations in the interpretation of published data, and to define future directions in research. An update on environmental estrogens was followed by an assessment of the biological plausibility and evidence connecting the environmental chemicalization with adverse reproductive outcomes in males. Subsequently, we carried out a systematic review of human studies attempting to document a direct effect of exogenous estrogens on the male reproductive system. The results do not support with certainty the view that environmental estrogens contribute to an increase in male reproductive disorders, neither do they provide sufficient grounds to reject such a hypothesis.     

Human exposure to environmental contaminants and congenital anomalies: a critical review

Congenital anomalies are an important cause of infant mortality and disability. Developmental exposure to environmental contaminants is thought to increase the risk for congenital anomalies. Herein, we describe a critical review of the literature conducted between February and March 2014 yielding 3057 references from which 97 unique relevant articles published from 2003 through 2014 were evaluated. Common congenital anomalies including hypospadias, cryptorchidism, anogenital distance (AGD), congenital heart defects and oral clefts were well represented in the literature whereas other outcomes such as neural tube defects, limb deficiency defects and gastroschisis were rarely described. While definitions used for congenital anomalies and methods of ascertainment were usually consistent across studies, inconsistencies were frequently found in grouping of different congenital heart defects. Despite strong links between some congenital anomalies and parental occupation, these studies are unable to provide clear insight into the specific chemicals responsible owing to lack of direct measures of exposure. In comparison, data are mixed for contaminant exposures at concentrations representative of results from contemporary biomonitoring studies. Of the environmental contaminants studied, the association between phthalate exposures and developmental abnormalities of the male reproductive tract received the greatest attention. Important limitations of the literature studied relate to adequacy of sample size, absence of or weaknesses in exposure assessment methodologies, failure to account for biological plausibility and grouping of congenital anomalies with divergent mechanisms. We conclude that the literature is inadequate at this time to support a conclusion that exposure to environmental contaminants are or are not associated with increased risks for congenital anomalies in the general population.     

Review of reviews on exposures to synthetic organic chemicals and children’s neurodevelopment: Methodological and interpretation challenges

Environmental epidemiology data are becoming increasingly important in public health decision making, which commonly incorporates a systematic review of multiple studies. This review addresses two fundamental questions: What is the quality of available reviews on associations between exposure to synthetic organic chemicals and neurodevelopmental outcomes? What is the value (e.g., quality and consistency) of the underlying literature? Published reviews on associations between synthetic organic environmental chemical exposures and neurodevelopmental outcomes in children were systematically evaluated. Seventy-four relevant reviews were identified, and these were evaluated with respect to four methodological characteristics: (1) systematic inclusion/exclusion criteria and reproducible methods for search and retrieval of studies; (2) structured evaluation of underlying data quality; (3) systematic assessment of consistency across specific exposure–outcome associations; and (4) evaluation of reporting/publication bias. None of the 74 reviews fully met the criteria for all four methodological characteristics. Only four reviews met two criteria, and six reviews fulfilled only one criterion. Perhaps more importantly, the higher quality reviews were not able to meet all of the criteria owing to the shortcomings of underlying studies, which lacked comparability in terms of specific research question of interest, overall design, exposure assessment, outcome ascertainment, and analytic methods. Thus, even the most thoughtful and rigorous review may be of limited value if the underlying literature includes investigations that address different hypotheses and are beset by methodological inconsistencies and limitations. Issues identified in this review of reviews illustrate considerable challenges that are facing assessments of epidemiological evidence.     

Reproductive and developmental effects of phthalate diesters in females

Abstract

Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.     

Reproductive and developmental effects of phthalate diesters in males

Phthalate diesters are a diverse group of chemicals used to make plastics flexible and are found in personal care products, medical equipment, and medication capsules. Ubiquitous in the environment, human exposure to phthalates is unavoidable; however, the clinical relevance of low concentrations in human tissues remains uncertain. The epidemiological literature was inadequate for prior reviews to conclusively evaluate the effects of phthalates on male reproductive tract development and function, but recent studies have expanded the literature. Therefore, we conducted a systematic review of the literature focused on the effects of phthalate exposure on the developing male reproductive tract, puberty, semen quality, fertility, and reproductive hormones. We conclude that although the epidemiological evidence for an association between phthalate exposure and most adverse outcomes in the reproductive system, at concentrations to which general human populations are exposed, is minimal to weak, the evidence for effects on semen quality is moderate. Results of animal studies reveal that, although DEHP was the most potent, different phthalates have similar effects and can adversely affect development of the male reproductive tract with semen quality being the most sensitive outcome. We also note that developmental exposure in humans was within an order of magnitude of the adverse effects documented in several animal studies. While the mechanisms underlying phthalate toxicity remain unclear, the animal literature suggests that mice are less sensitive than rats and potentially more relevant to estimating effects in humans. Potential for chemical interactions and effects across generations highlights the need for continued study.     

Human exposure to endocrine disrupters and semen quality

Reproductive pathology in the male represents about 20% of infertility cases. Male infertility may be attributed to a number of causes, including genetic and congenital abnormalities, infection, multisystemic diseases, varicocele, and others; however, a significant number of cases are idiopathic. Global declines in semen quality were suggested to be associated with enhanced exposure to environmental chemicals that act as endocrine disrupters as a result of our increased use of pesticides, plastics, and other anthropogenic materials. A significant body of toxicology data based upon laboratory and wildlife animals studies suggests that exposure to certain endocrine disrupters is associated with reproductive toxicity, including (1) abnormalities of the male reproductive tract (cryptorchidism, hypospadias), (2) reduced semen quality, and (3) impaired fertility in the adult. There is, however, a relative paucity of studies designed to measure exposure to endocrine disrupters on semen quality parameters (sperm concentration, motility, morphology). An overview of the human semen quality literature is presented that examines the role of endocrine disrupters including organochlorines (OC), dioxins, phthalates, phytoestrogens, and chemical mixtures (pesticides and tobacco smoke).     

Systematic review of biomonitoring studies to determine the association between exposure to organophosphorus and pyrethroid insecticides and human health outcomes

For the appropriate protection of human health it is necessary to accurately estimate the health effects of human exposure to toxic compounds. In the present review, epidemiological studies on the health effects of human exposure to organophosphorus (OP) and pyrethroid (PYR) insecticides have been critically assessed. This review is focused on studies where the exposure assessment was based on quantification of specific biomarkers in urine or plasma. The 49 studies reviewed used different epidemiological approaches and analytical methods as well as different exposure assessment methodologies. With regard to OP pesticides, the studies reviewed suggested negative effects of prenatal exposure to these pesticides on neurodevelopment and male reproduction. Neurologic effects on adults, DNA damage and adverse birth outcomes were also associated with exposure to OP pesticides. With regard to exposure to PYR pesticides, there are currently few studies investigating the adverse health outcomes due to these pesticides. The effects studied in relation to PYR exposure were mainly male reproductive effects (sperm quality, sperm DNA damage and reproductive hormone disorders). Studies' findings provided evidence to support the hypothesis that PYR exposure is adversely associated with effects on the male reproductive system. The validity of these epidemiological studies is strongly enhanced by exposure assessment based on biomarker quantification. However, for valid and reliable results and conclusions, attention should also be focused on the validity of the analytical methods used, study designs and the measured toxicants characteristics.     

Perfluoroalkyl and polyfluoroalkyl substances and human fetal growth: A systematic review

Abstract

Background: Exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is ubiquitous in most regions of the world. The most commonly studied PFASs are perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Animal studies indicate that maternal PFAS exposure is associated with reduced fetal growth. However, the results of human studies are inconsistent. Objectives: To summarize the evidence of an association between exposure to PFASs, particularly PFOS and PFOA, and human fetal growth. Methods: Systematic literature searches were performed in MEDLINE and EMBASE. We included original studies on pregnant women with measurements of PFOA or PFOS in maternal blood during pregnancy or the umbilical cord and associations with birth weight or related outcomes according to the PFAS level. Citations and references from the included articles were investigated to locate more relevant articles. Study characteristics and results were extracted to structured tables. The completeness of reporting as well as the risk of bias and confounding were assessed. Results: Fourteen studies were eligible. In utero PFOA exposure was associated with decreased measures of continuous birth weight in all studies, even though the magnitude of the association differed and many results were statistically insignificant. PFOS exposure and birth weight were associated in some studies, while others found no association. Conclusions: Higher PFOS and PFOA concentrations were associated with decreased average birth weight in most studies, but only some results were statistically significant. The impact on public health is unclear, but the global exposure to PFASs warrants further investigation.     

Reproductive health effects of aflatoxins: A review of the literature

ContextAlthough it is known that aflatoxins have many adverse health effects, there is no systematic summary of how it affects the reproductive system or its reproductive health effects.ObjectiveSummarize evidence on the reproductive health effects of aflatoxins.ResultsThe search yielded 121 potential studies, of which 25 were retained. One study found a higher concentration of aflatoxins in the semen of infertile men (40% of cases compared to 8% of controls). Six studies found significant associations or correlations between low birth weight and aflatoxins while one study did not find any correlation. One study found maternal serum aflatoxin to be a risk factor for jaundice in infants (OR, 2.68; CI, 1.18–6.10). Overall, maternal breast milk in developing countries had higher rates of aflatoxin contamination than in high income countries.ConclusionsStakeholders in developing countries need to take steps to reduce exposure of vulnerable populations to the toxic effects of aflatoxins.     

Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are found widespread in the environment and humans. The relation of PFASs to fertility has now been examined in a relatively large number of epidemiologic studies and a synthesis is in order. The aim of this study was to assess the current human epidemiologic evidence on the association between exposure to PFASs and measures of human fertility, with particular emphasis on perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Systematic literature searches were initially conducted in MEDLINE and EMBASE and subsequently in references and citations of included papers. Studies were included if they assessed exposure to PFASs in biological samples in relation to reproductive hormones, semen characteristics, or time to pregnancy (TTP). Study characteristics and results were abstracted to predefined forms, and the studies were assessed for the risk of bias and confounding. Sixteen studies investigated the association between PFAS exposure in men and semen parameters, reproductive hormone levels, or TTP. There was a lack of consistent results among the numerous investigated exposure-outcome combinations. However, subtle associations between higher PFOS and lower testosterone or abnormal semen morphology cannot be excluded. Eleven studies assessed the association between PFAS exposure in women and TTP or reproductive hormones levels. Four of eight studies found prolonged TTP with higher PFOS or PFOA, but only one study found an association when restricting to nulliparous women. In men, there is little evidence of an association between PFAS exposure and semen quality or levels of reproductive hormones. For PFOS and PFOA, the literature indicates an association with female fecundability in parous women, which is most likely not causal.     

Effects of glyphosate exposure on sperm concentration in rodents: A systematic review and meta-analysis

BackgroundCorrelation between exposure to glyphosate and sperm concentrations is important in reproductive toxicity risk assessment for male reproductive functions. Many studies have focused on reproductive toxicity on glyphosate, however, results are still controversial. We conducted a systematic review of epidemiological studies on the association between glyphosate exposure and sperm concentrations of rodents. The aim of this study is to explore the potential adverse effects of glyphosate on reproductive function of male rodents.MethodsSystematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Embase, WANFANG and CNKI databases with different combinations of glyphosate exposure and sperm concentration. 8 studies were eventually identified and random-effect model was conducted. Heterogeneity among study results was calculated via chi-square tests. Ten independent experimental datasets from these eight studies were acquired to synthesize the random-effect model.ResultsA decrease in sperm concentrations was found with mean difference of sperm concentrations(MDsperm) = −2.774 × 10⁶/sperm/g/testis(95%CI = −0.969 to −4.579) in random-effect model after glyphosate exposure. There was also a significant decrease after fitting the random-effect model: MDsperm = −1.632 × 10⁶/sperm/g/testis (95%CI = −0.662 to −2.601).ConclusionsThe results of meta-analysis support the hypothesis that glyphosate exposure decreased sperm concentration in rodents. Therefore, we conclude that glyphosate is toxic to male rodent’s reproductive system.     

In vivo effects of bisphenol A in laboratory rodent studies

Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/(kg day), in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10-1000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system.     

Environmental hazards: evidence for effects on child health

The human fetus, child, and adult may experience adverse health outcomes from parental or childhood exposures to environmental toxicants. The fetus and infant are especially vulnerable to toxicants that disrupt developmental processes during relatively narrow time windows. This review summarizes knowledge of associations between child health and development outcomes and environmental exposures, including lead, methylmercury, polychlorinated biphenyls (PCBs), dioxins and related polyhalogenated aromatic hydrocarbons (PHAHs), certain pesticides, environmental tobacco smoke (ETS), aeroallergens, ambient air toxicants (especially particulate matter [PM] and ozone), chlorination disinfection by-products (DBPs), sunlight, power-frequency magnetic fields, radiofrequency (RF) radiation, residential proximity to hazardous waste disposal sites, and solvents. The adverse health effects linked to such exposures include fetal death, birth defects, being small for gestational age (SGA), preterm birth, clinically overt cognitive, neurologic, and behavioral abnormalities, subtle neuropsychologic deficits, childhood cancer, asthma, other respiratory diseases, and acute poisoning. Some environmental toxicants, notably lead, ionizing radiation, ETS, and certain ambient air toxicants, produce adverse health effects at relatively low exposure levels during fetal or child developmental time windows. For the many associations supported by limited or inadequate epidemiologic evidence, major sources of uncertainty include the limited number of studies conducted on specific exposure-outcome relationships and methodologic limitations. The latter include (1) crude exposure indices, (2) limited range of exposure levels, (3) small sample sizes, and (4) limited knowledge and control of potential confounders. Important knowledge gaps include the role of preconceptual paternal exposures, a topic much less studied than maternal or childhood exposures. Large longitudinal studies beginning before or during early pregnancy are urgently needed to accurately measure and assess the relative importance of parental and childhood exposures and evaluate relatively subtle health outcomes such as neuropsychologic and other functional deficits. Large case-control studies are also needed to assess the role of environmental exposures and their interactions with genetic factors in relatively uncommon outcomes such as specific types of birth defects and childhood cancers. There is also an urgent need to accelerate development and use of biomarkers of exposure and genetic susceptibility in epidemiologic studies. This review supports the priority assigned by international agencies to relationships between child health and air quality (indoor and outdoor), lead, pesticides, water contaminants, and ETS. To adequately address such priorities, governments and agencies must strengthen environmental health research capacities and adopt policies to reduce parental and childhood exposures to proven and emerging environmental threats.     

Effects of inhaled combined Benzene,Toluene, Ethylbenzene,and Xylenes (BTEX): Toward an environmental exposure model

Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.     

Chronic low-level hydrogen sulfide exposure and potential effects on human health: A review of the epidemiological evidence

Abstract

The effects of exposure to high concentrations of hydrogen sulfide (H₂S) on human health are well known. However, the potential human health hazards posed by low-level chronic environmental H₂S exposure are being debated. Accordingly, we reviewed the literature regarding the effects of chronic, environmentally-relevant H₂S exposures on human health. All human observational studies using an analytical study design (e.g. cohort, cross-sectional, case-control) to evaluate chronic-duration low-level H₂S exposure (approximately ≤ 10 ppm on average, for 1 year or more), were evaluated for a range of health outcomes. Respiratory symptoms in both adults and children were the most consistently reported symptoms on the increase. When reported, such effects appear to be temporary, given that there is no consistent evidence of pulmonary function deficit in either age group, among those chronically exposed to low H₂S concentrations. While sparse, some data also suggest potential ocular symptoms and disorders associated with chronic ambient level H₂S exposure in adults (not children), but the limited data on H₂S exposures, co-exposures and/or strong odor stimulus of H₂S, temper interpretation. Neurological symptoms and deficits have been reported in some studies, but the highest quality evidence, obtained using objective outcome measures and a reasonably detailed assessment of exposure, does not support a neurological-related risk in adults (only one study in children). For the other endpoints assessed (cardiovascular, reproductive and developmental, and carcinogenicity), the results were mixed and/or conflicting, but did not indicate a potential health hazard, although this literature has several major limitations, particularly with regard to exposure estimation and the ability to assess exposure-response.     

Effects of maternal 4-tert-octylphenol exposure on the reproductive tract of male rats at adulthood

Increases in human male reproductive disorders (testicular cancer, cryptorchidism, hypospadias, and low sperm counts) might stem from increased exposure of the developing male to environmental estrogens. In the present study, we investigated the effects of octylphenol (OP), an estrogenic compound, exposure on the male reproductive system during the fetal period in which the development of reproductive organs and sexual differentiation occurs. Male rats were treated with OP in utero at doses of control (vehicle), 100 or 250 mg/kg/day. After birth, male rats were allowed to grow until adulthood, and then testes, epididymides, and prostate glands were investigated histopathologically. Sperm counts and percentage of abnormal sperm were determined. Seminiferous and epididymal round tubules were evaluated for tubule diameter, lumen diameter, and height of tubule epithelium. Treatment with OP caused abnormalities in the histology of the testis and epididymis and induced atrophy of prostate glands tubules. Although there were no differences in sperm counts among treatment groups, abnormal sperm percentages in the high dose group increased significantly. The results of this study demonstrate that maternally injected OP causes adverse effects on male reproductive tract at adulthood, especially on sperm structure.     

Biomarkers for male reproductive health hazards: are they available?

This review aims to give an overview of some of the biomarkers that have been used for the monitoring of human exposure to xenobiotics as well as to provide a summary of some of the recent epidemiological studies on male reproductive health of exposure to environmental and occupational toxicants. Possible molecular mechanisms on seminal quality change are also suggested. Studies using various biomarkers have no doubt enabled us to better characterize the effect of environmental pollutants on the male reproductive system. However, the sensitivity and specificity of these biomarkers have not been comprehensively validated. Furthermore, many epidemiological findings are difficult to replicate owing to the inherited methodological problems of male reproductive health investigations, such as the small number of study subjects, low compliance rate, substantial intra-individual variability in semen parameters, measurement techniques and misclassifications based on single assay. Oxidative damage, in particular DNA-damage caused by free radicals, generated either by xenobiotics, or endogenously, is now thought to be a key molecular mechanism associated with semen quality and sperm function. Laboratory studies and epidemiological findings have suggested that the male reproductive system is susceptible to reactive oxygen species (ROS). On the other hand, there is so far no single all-encompassing biomarker of reproductive capacity in men. A panel of biomarkers with specific goals should be considered. Collaborative multidisciplinary studies are also needed to overcome some of the issues mentioned here.