Untangling the association between environmental endocrine disruptive chemicals and the etiology of male genitourinary cancers.

Endocrine disrupting chemicals disrupt normal physiological function of endogenous hormones, their receptors, and signaling pathways of the endocrine system. Most endocrine disrupting chemicals exhibit estrogen/androgen agonistic and antagonistic activities that impinge upon hormone receptors and related pathways. Humans are exposed to endocrine disrupting chemicals through food, water and air, affecting the synthesis, release, transport, metabolism, binding, function and elimination of naturally occurring hormones. The urogenital organs function as sources of steroid hormones, are targeted end organs, and participate within systemic feedback loops within the endocrine system. The effects of endocrine disruptors can ultimately alter cellular homeostasis leading to a broad range of health effects, including malignancy. Human cancer is characterized by uncontrolled cell proliferation, mechanisms opposing cell-death, development of immortality, induction of angiogenesis, and promotion of invasion/metastasis. While hormonal malignancies of the male genitourinary organs are the second most common types of cancer, the molecular effects of endocrine disrupting chemicals in hormone-driven cancers has yet to be fully explored. In this commentary, we examine the molecular evidence for the involvement of endocrine disrupting chemicals in the genesis and progression of hormone-driven cancers in the prostate, testes, and bladder. We also report on challenges that have to be overcome to drive our understanding of these chemicals and explore the potential avenues of discovery that could ultimately allow the development of tools to prevent cancer in populations where exposure is inevitable.

Systematic review of the association between oil and natural gas extraction processes and human reproduction.

This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.

A review of the carcinogenic potential of bisphenol A.

The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of "carcinogen" put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties.

Diethylstilboestrol--a long-term legacy.

Diethylstilboestrol (DES) is an endocrine disrupter which causes cancer in rodents. It was prescribed in large amounts to treat women with gynaecological problems; some of the daughters of these women subsequently developed a rare cancer (vaginal clear cell adenocarcinoma) while genital abnormalities were found in some of the sons. It was used for decades in livestock feed and this may have contaminated the food chain leading to the exposure of the more general population. DES appears to cause epigenetic effects in animals and there is some evidence that this also occurs in man. The mechanisms of carcinogenesis are complex and the effects are difficult to prove due to the background of dietary and environmental phyto- and xenooestrogens. It has been suggested that, like other endocrine disrupters, DES may have acted as an obesogen in the human population.

Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers.

OBJECTIVE: A retrospective cohort study was conducted in two chlorophenoxy herbicide manufacturing factories, producing mainly 2,4,5-trichlorophenoxyacetic acid (factory A) and 4-chloro-2-methylphenoxyacetic acid, 4-chloro-2-methylphenoxy propanoic acid and 2,4-dichlorophenoxyacetic acid (factory B). Previously, we have shown elevated risks for mortality and cancer mortality in this cohort. The purpose of the current, third follow-up, is to provide an updated assessment of cause-specific mortality for both factories. METHODS: The study population was defined as all persons working in one of the two factories during 1955-1985 for factory A, or during 1965-1986 for factory B. Analyses were performed using Cox proportional hazard models, using attained age as the timescale. Exposure to phenoxy herbicides and dioxins was expected to be different for factory A and factory B and the factories were therefore analysed separately. RESULTS: Previously reported increased risks for respiratory cancer, non-Hodgkin's lymphoma and ischaemic heart disease in factory A could not be confirmed in the present analysis. However, increased risks were observed for all cancers in both factory A (hazard ratio (HR) 1.31; 95% CI 0.86 to 2.01) and factory B (HR 1.54; 95% CI 1.00 to 2.37). Increased risks for urinary cancers (HR 4.2; 95% CI 0.99 to 17.89) and genital cancers (HR 2.93; 95% CI 0.61 to 14.15) were observed in factory A, consistent with earlier reported results in this population. More detailed analyses showed that this increased risk for urinary and genital cancers in exposed workers was not due to selection of healthy controls and could not be attributed to specific products or departments. CONCLUSION: The results of this study showed only slight increases in cancer mortality risk. The increased risk for urinary cancers is noteworthy, but could not be linked to a specific exposure and needs to be confirmed in similar cohorts.

Food safety.

Food can never be entirely safe. Food safety is threatened by numerous pathogens that cause a variety of foodborne diseases, algal toxins that cause mostly acute disease, and fungal toxins that may be acutely toxic but may also have chronic sequelae, such as teratogenic, immunotoxic, nephrotoxic, and estrogenic effects. Perhaps more worrisome, the industrial activities of the last century and more have resulted in massive increases in our exposure to toxic metals such as lead, cadmium, mercury, and arsenic, which now are present in the entire food chain and exhibit various toxicities. Industrial processes also released chemicals that, although banned a long time ago, persist in the environment and contaminate our food. These include organochlorine compounds, such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (dichlorodiphenyl dichloroethene) (DDT), other pesticides, dioxins, and dioxin-like compounds. DDT and its breakdown product dichlorophenyl dichloroethylene affect the developing male and female reproductive organs. In addition, there is increasing evidence that they exhibit neurodevelopmental toxicities in human infants and children. They share this characteristic with the dioxins and dioxin-like compounds. Other food contaminants can arise from the treatment of animals with veterinary drugs or the spraying of food crops, which may leave residues. Among the pesticides applied to food crops, the organophosphates have been the focus of much regulatory attention because there is growing evidence that they, too, affect the developing brain. Numerous chemical contaminants are formed during the processing and cooking of foods. Many of them are known or suspected carcinogens. Other food contaminants leach from the packaging or storage containers. Examples that have garnered increasing attention in recent years are phthalates, which have been shown to induce malformations in the male reproductive system in laboratory animals, and bisphenol A, which negatively affects the development of the central nervous system and the male reproductive organs. Genetically modified foods present new challenges to regulatory agencies around the world because consumer fears that the possible health risks of these foods have not been allayed. An emerging threat to food safety possibly comes from the increasing use of nanomaterials, which are already used in packaging materials, even though their toxicity remains largely unexplored. Numerous scientific groups have underscored the importance of addressing this issue and developing the necessary tools for doing so. Governmental agencies such as the US Food and Drug Administration and other agencies in the USA and their counterparts in other nations have the increasingly difficult task of monitoring the food supply for these chemicals and determining the human health risks associated with exposure to these substances. The approach taken until recently focused on one chemical at a time and one exposure route (oral, inhalational, dermal) at a time. It is increasingly recognized, however, that many of the numerous chemicals we are exposed to everyday are ubiquitous, resulting in exposure from food, water, air, dust, and soil. In addition, many of these chemicals act on the same target tissue by similar mechanisms. "Mixture toxicology" is a rapidly growing science that addresses the complex interactions between chemicals and investigates the effects of cumulative exposure to such "common mechanism groups" of chemicals. It is to be hoped that this results in a deeper understanding of the risks we face from multiple concurrent exposures and makes our food supply safer.

Extramammary Paget's disease--occupational exposure to used engine oil and a new skin grafting technique.

SUMMARY: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma, affecting mainly 50-70-year-olds with a female preponderance of 3:1. Exposure to polyaromatic hydrocarbons (PAHs) is associated with a substantial risk of skin cancer. We report a case of 64-year-old male with longstanding occupational exposure to used engine oil presenting with EMPD of the left scrotum and groin.

Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations.

The synthetic estrogen diethylstilbestrol (DES) is a potent perinatal endocrine disruptor. In humans and experimental animals, exposure to DES during critical periods of reproductive tract differentiation permanently alters estrogen target tissues and results in long-term abnormalities such as uterine neoplasia that are not manifested until later in life. Using the developmentally exposed DES mouse, multiple mechanisms have been identified that play a role in its carcinogenic and toxic effects. Analysis of the DES murine uterus reveals altered gene expression pathways that include an estrogen-regulated component. Thus, perinatal DES exposure, especially at low doses, offers the opportunity to study effects caused by weaker environmental estrogens and provides an example of the emerging scientific field termed the developmental origin of adult disease. As a model endocrine disruptor, it is of particular interest that even low doses of DES increase uterine tumor incidence. Additional studies have verified that DES is not unique; when other environmental estrogens are tested at equal estrogenic doses, developmental exposure results in increased incidence of uterine neoplasia similar to that caused by DES. Interestingly, our data suggest that this increased susceptibility for tumors is passed on from the maternal lineage to subsequent generations of male and female descendants; the mechanisms involved in these transgenerational events include genetic and epigenetic events. Together, our data point out the unique sensitivity of the developing organism to endocrine-disrupting chemicals, the occurrence of long-term effects after developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations.

The endocrine disrupters: a major medical challenge.

Endocrine disruptors (EDs), chemicals capable of disrupting the normal functioning of the endocrine system, may pose a growing threat to human and wildlife health. These compounds can modulate both the endocrine and immune systems resulting in alteration of homeostasis, reproduction, development and behavior. The hypothesis that chemicals in the environment have caused endocrine disruption is discussed along with important issues in the assessment of the risk of such disruption. Emphasis is put on the most significant pathological effects, namely impacts on the male reproductive tract, female gynecological system, human fertility, thyroid function and the central nervous system.

Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol.

Prenatal exposure to diethylstilbestrol (DES) is associated with reproductive tract abnormalities, subfertility and neoplasia in experimental animals and humans. Studies using experimental animals suggest that the carcinogenic effects of DES may be transmitted to succeeding generations. To further evaluate this possibility and to determine if there is a sensitive window of exposure, outbred CD-1 mice were treated with DES during three developmental stages: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 microg/kg maternal body weight) during major organogenesis; group II was treated once on day 18 of gestation (1000 microg/kg maternal body weight) just prior to birth; and group III was treated on days 1-5 of neonatal life (0.002 microg/pup/day). DES-exposed female mice (F(1)) were raised to maturity and bred to control males to generate DES-lineage (F(2)) descendants. The F(2) males obtained from these matings are the subjects of this report; results in F(2) females have been reported previously [Newbold et al. (1998) CARCINOGENESIS:, 19, 1655-1663]. Reproductive performance of F(2) males when bred to control females was not different from control males. However, in DES F(2) males killed at 17-24 months, an increased incidence of proliferative lesions of the rete testis and tumors of the reproductive tract was observed. Since these increases were seen in all DES treatment groups, all exposure periods were considered susceptible to perturbation by DES. These data suggest that, while fertility of the DES F(2) mice appeared unaltered, increased susceptibility for tumors is transmitted from the DES 'grandmothers' to subsequent generations.

Prostate-seminal vesicle cancers induced in noble rats.

Susceptibility of Noble strain rats to induced cancers in the accessory sex glands was determined. Following an IV inoculation of methylnitrosourea plus three successive SC implants of testosterone propionate, early stage adenocarcinomas were observed in the seminal vesicles and anterior prostates, but not in the dorsolateral nor in the ventral lobes.

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Development of androgen-independent carcinomas from androgen-dependent preneoplastic lesions in the male accessory sex organs of rats treated with 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate.

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.

Mortality from cancer of the male reproductive tract and environmental exposure to the anti-androgen p,p'-dichlorodiphenyldichloroethylene in the United States.

The association of prostate cancer mortality and testicular cancer mortality with environmental exposure to the anti-androgen dichlorodiphenyltrichloroethane (DDT) derivative p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in the USA was explored in the period 1971-1994 using multiple linear regression analysis. Environmental p,p'-DDE contamination by state was estimated by p,p'-DDE concentrations in the subcutaneous fat of population samples and by measurements of p,p'-DDE in tree bark. On average, African Americans had adipose p,p'-DDE levels 74% higher than Whites (8.49 vs. 4.88 microg/g; p < 0.001). Neither prostate cancer mortality nor testicular cancer mortality showed a positive association with either indicator of p,p'-DDE environmental contamination. On the contrary, the regression coefficient for prostate cancer was constantly inverse for adipose p,p'-DDE along the period of study, although it approached statistical significance only for African Americans in 1981-1985 (P=-0.755; 0.10 > p > 0.05). This ecologic study does not provide support to the hypothesis of a link between environmental exposure to DDT derivatives and cancer of the male reproductive tract.

Glutathione S-transferase in hormonal carcinogenesis.

Treatment with testosterone propionate (TP) and diethylstilbestrol (DES) or TP and estradiol (E2) for 8-9 months causes development of leiomyosarcomas in the vas deferens or uterus of Golden Syrian hamsters at a frequency of 100%. In males, treatment with estrogens alone results in renal tumors, fatal within 6 months. No leiomyosarcomas have been detected after treatment with estrogens alone, perhaps due to this high mortality rate. In tissue culture, treatment with the glucocorticoid (GC) triamcinolone acetonide (TA) results in an increased expression of a mu-class glutathione S-transferase (GST) (hGSTYBX). We have characterized this induction as a secondary response, i.e. requiring new protein synthesis. Here we describe homologies to known transcription factor-binding sites in the hGSTYBX promoter which may be involved in the induction event. hGSTYBX is a member of a superfamily of detoxification enzymes, induced by genotoxic compounds and reactive oxygen species (ROS). We also describe the effects of several known inducers of other GST family members on hGSTYBX. While implicated in many chemotherapeutic-resistant tumors, GST enzymes have not yet been characterized as a functional agent in hormonal carcinogenesis. This latter possibility is the focus of our investigations. To study the effects of hormone treatment on GST levels in vivo, we have developed a polyclonal antibody to hGSTYBX, and conducted immunohistochemistry on tissues from control and treated animals. Treatment with TP and E2 causes a loss of hGSTYBX expression in the epithelium of the vas deferens. We hypothesize that the loss of this protective enzyme leaves the cells vulnerable to the genotoxic effects of estrogen or estrogenic metabolites.

Disseminated lipogranulomas and sudden death from self-administered mineral oil injection.

The cosmetic injection of exogenous lipids and more recently of polydimethyl siloxane (injectable silicone) into the scrotum has been described since 1899. Sclerosing lipogranuloma and paraffinoma are terms applied to a complication of this practice in which the injected oils or silicone elicit a marked granulomatous reaction with prominent surrounding fibrosis. Although this complication has been described as a localized process occurring mainly in the scrotal area and regional lymph nodes, few studies have documented systemic manifestations. In this report we describe the autopsy findings of a 48-year-old man who had scrotal and systemic lipogranulomas from repeated self-administered injection of mineral oil. In addition, severe acute pulmonary edema resulted in sudden unexpected death. To our knowledge, this fatal complication of exogenous lipogranuloma has not been previously reported.

Direct effects of testosterone, dihydrotestosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in castrated F344 rats.

The present experiment was carried out to explore the effect of endogenous androgen on rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP) or 5alpha-dihydrotestosterone (DHT) with or without ethinyl estradiol (EE). In order to eliminate the influence of endogenous androgen, F344 rats were orchiectomized just after initiation with the prostate carcinogen, DMAB, and then given TP, DHT, TP plus EE or DHT plus EE for 40 weeks. The results demonstrated that while administration of TP following DMAB treatment causes invasive carcinomas in the lateral and anterior prostate and seminal vesicles, DHT does not exhibit equivalent effects. Synergistic enhancement was also evident with TP plus EE, but not with DHT plus EE. The incidences of prostatic and seminal vesicle lesions in all groups of the present experiment, except for the group given castration without hormonal supplement, were equivalent to those previously found in non-castrated animals. Therefore, the present findings indicate that endogenous testosterone may not be required for promotion by TP/EE of DMAB-initiated prostate carcinogenesis and that it may not contribute to the actions of DHT.