Hormones PCBs and Prostate Function

Hormones, PCBs and Prostate Function

Prostate cancers may be related to hormone levels which have been changed by PCBs in a man’s body. Such hormone changes may be especially critical during a boy’s development in his mother’s womb, leading to cancer later in life. The following studies show that PCBs alter hormone levels.

Summary of Results

(Each entry represents one finding in the 16 studies below, unless otherwise noted. Some studies had multiple findings.)

elevated estrogen levels may be a predisposing factor for prostate diseases
estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to neoplasia [cancer]
hormones and the role of environmental carcinogens (such as PCBs) in prostate cancer are currently under intense investigation
PCBs are estrogenic environmental chemicals
some PCB congeners and hydroxylated PCBs were estrogenic
PCBs competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics
certain PCBs demonstrated greater than 50% displacement of testosterone at binding sites in testicular tissue
environmental estrogens (such as PCBs) affect male offspring but they are not malformed or infertile
administration of an Ah receptor agonist (dioxin or certain PCBs) in the womb produces a different spectrum of effects including reduced ejaculated sperm numbers in male offspring
androgen production was significantly inhibited by PCBs
testosterone production was also decreased by PCBs
aromatase activity decreased in male offspring by maternal exposure to the reconstituted PCB-mixture (aromatase helps determine levels of hormones in the brain)
PCBs reduced testosterone concentrations in adult male testes
PCBs reduce levels of steroid hormones (such as testosterone) in the blood stream
PCBs caused changes in testosterone hydroxylase activities indicative of permanent damage (or imprinting) in androgen metabolism
external factors, such as anti-androgens and oestrogens (such as PCBs), that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus
PCBs caused a significant increase in activities of enzymes
increased enzymes coincided with decreases in hormone levels in the blood stream
disturbances of hormonal regulation by endocrine disruptors (such as PCBs) during fetal or post-natal development induced adverse effects on the animal's reproductive systems
an accelerated onset, peak and decrease of testis-weight that indicates the presence of subtle male reproductive disorders
numerous chemicals working together through several hormone-dependent pathways could prove to be hazardous to human reproductive health
PCBs may induce, by the mechanism of imprinting, alterations of the differentiation of several cell-types, resulting in the development of disease during adulthood
trace amounts of PCBs in human embryos may determine the appearance of tumors later in life, a possibility documented in several animal species including humans

Studies Linking PCBs and Hormone Levels

This is not a complete list of all studies on this topic. For more studies, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts). Keep in mind that these studies are not all equal in size or quality. Some were published in peer-reviewed journals, while others were simply presented at conferences. A few are duplicates by the same author (one conference-based, another published) but we presented both because the descriptions were slightly different.

Study #1

elevated estrogen levels may be a predisposing factor for prostate diseases
estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to neoplasia [cancer]

Three new different aspects of prostate cancer have been considered in this review: the existence of an hereditary form, the role of estrogens as predisposing factors and the efficacy of differentiation therapies. Prostate cancer shows a stronger familial aggregation than colon and breast carcinoma. Hereditary prostate cancer is distinguished by early age at onset and autosomal dominant inheritance within families. However, only 2% of all prostate cancer in United States white men occur in those 55 years old or younger. Thus, the impact of hereditary prostate cancer in the population is the greatest at younger ages but this accounts for only a small proportion of the total disease burden. Using the developmentally estrogenized mouse model, an alternative role for estrogens as a predisposing factor for prostate diseases was proposed: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to neoplasia. A combination therapy employing both differentiation therapy and hormone therapy may be effective in the treatment of advanced prostate cancers. Recent advances in the field of differentiation therapy have resulted in the development of novel retinoic acid metabolism blocking agents. Unlike previous differentiating agents such as the retinoids, these agents increase the endogenous levels of retinoic acid by inhibiting its breakdown in cancer cells. (Sciarra et al, 1998)

Study #2

hormones and the role of environmental carcinogens (such as PCBs) in prostate cancer are currently under intense investigation

Malignant transformation of the prostate and progression of carcinoma appear to be the consequence of a complex series of initiation and promotional events under genetic and environmental influences. Increased incidence of the condition may be the result of improved detection, greater awareness of the condition, and possibly an increased life expectancy accompanied by a decrease in competing causes of death rather than a true increase in the prevalence of the disease. The marked racial and geographic differences are probably multifactorial, with genetic, environmental, and possibly social influences affecting progression of the disease. Among several risk factors, evidence for the familial inheritance of some prostate cancers is compelling. Dietary influences, hormonal milieu, and the role of environmental carcinogens are currently under intense investigation. As further risk factors are identified, it will become increasingly important to identify individuals at increased risk for the disease. These men should undergo regular evaluation with state-of-the-art methods. (Haas et al, 1997)

Study #3

PCBs are estrogenic environmental chemicals

A comprehensive review of declining male reproductive health was presented. The review was undertaken at the request of the Danish Environmental Protection Agency with its final content and form decided by a panel of international experts. Trends in male reproductive disorders were discussed, including significant declines in semen quality and volume, and increases in testicular cancer, cryptorchidism, hypospadias and male breast cancer from the 1930s to the present day. African American men had lower rates of testicular cancer than white American men, while Finnish men were less likely to develop testicular or breast cancer than Danish men. The effects of estrogenic pollutants on male reproduction in gastropods, reptiles, fish, birds, porpoises, seals and Florida panthers were described. Reproductive disorders in wildlife were associated with interference of normal prenatal sexual development by estrogenic or other endocrine disrupting environmental pollutants. The function of estrogen in the sexual differentiation in humans and resulting genital development disorders and malignancies was described. The effects of estrogen resistance in mice and man were cited and the effects of overexpression of the estrogen receptor in transgenic mice was described. Structural abnormalities, lower semen quality and incidence of testicular cancer in men prenatally exposed to diethylstilbestrol (56531) were reviewed. Neonatal and prenatal effects of synthetic estrogens in animal models, including effects on Mullerian ducts and developing testis were considered to be dependent on the point in fetal development that exposure occurred. The occurrence and effects of estrogenic environmental chemicals, including organochlorine pesticides, polychlorinated biphenyls, alkylphenol polyethoxylates and phytoestrogens, on male reproductive health were discussed. Existing models and assays for evaluating exposure to estrogenic substances were debated. An appendix describing the reproductive toxicology of numerous pesticides and environmental chemicals was provided. (Toppari et al, 1996)

Study #4

some PCB congeners and hydroxylated PCBs were estrogenic
PCBs competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics

Estrogens are defined by their ability to induce the proliferation of cells of the female genital tract. The wide chemical diversity of estrogenic compounds precludes an accurate prediction of estrogenic activity on the basis of chemical structure. Rodent bioassays are not suited for the large-scale screening of chemicals before their release into the environment because of their cost, complexity, and ethical concerns. The E-SCREEN assay was developed to assess the estrogenicity of environmental chemicals using the proliferative effect of estrogens on their target cells as an end point. This quantitative assay compares the cell number achieved by similar inocula of MCF-7 cells in the absence of estrogens (negative control) and in the presence of 17 beta-estradiol (positive control) and a range of concentrations of chemicals suspected to be estrogenic. Among the compounds tested, several "new" estrogens were found; alkylphenols, phthalates, some PCB congeners and hydroxylated PCBs, and the insecticides dieldrin, endosulfan, and toxaphene were estrogenic by the E-SCREEN assay. In addition, these compounds competed with estradiol for binding to the estrogen receptor and increased the levels of progesterone receptor and pS2 in MCF-7 cells, as expected from estrogen mimics. Recombinant human growth factors (bFGF, EGF, IGF-1) and insulin did not increase in cell yields. The aims of the work summarized in this paper were a) to validate the E-SCREEN assay; b) to screen a variety of chemicals present in the environment to identify those that may be causing reproductive effects in wildlife and humans; c) to assess whether environmental estrogens may act cumulatively; and finally d) to discuss the reliability of this and other assays to screen chemicals for their estrogenicity before they are released into the environment. (Soto et al, 1995)

Study #5

certain PCBs demonstrated greater than 50% displacement of testosterone at binding sites in testicular tissue

Two distinct nuclear androgen receptors (ARs) were identified in brain and ovarian tissues of kelp bass, Paralabrax clathratus, termed kbAR1 and kbAR2, which correspond to the two nuclear ARs we have previously characterized in Atlantic croaker, Micropogonias undulatus, termed acAR1 and acAR2. Scat-chard analysis of nuclear fractions of whole brain tissue demonstrated that kbAR1 had a single class of high-affinity binding sites for testosterone (T; Kd of 1.8 nM and Bmax of 1.0 pmol/g tissue), whereas cytosolic fractions of kbAR2 ovarian tissue had a single class of high-affinity binding sites for dihydrotestosterone (DHT; Kd of 0.1 nM and Bmax of 0.5 pmol/g tissue). Competition studies showed that both kbAR1 and kbAR2 were specific for androgens. However, kbAR1 bound only T with high affinity, whereas kbAR2 bound DHT, mibolerone, 17alpha-methyltestosterone, T, and 11-ketotestosterone with high affinity. In addition, we examined the binding affinities of dichlorodiphenyl-trichloroethane and its derivatives, several hydroxylated polychlorinated biphenyl (PCB) congeners, PCB mixtures, and the fungicide vinclozolin and its two metabolites M1 and M2 for the two ARs in Atlantic croaker ovarian, testicular, and brain tissues and in kelp bass ovarian and brain tissues. Only 4,4'-PCB-3-OH and 2',5'-PCB-3-OH demonstrated greater than 50% displacement of (3H)testosterone from either acAR1 or kbAR1. In contrast, with the exception of vinclozolin, all of the xenobiotics examined demonstrated binding to acAR2 in testicular and ovarian tissues. The binding affinities were highest in the testicular tissue with M2, 2,2'5'-PCB-4-OH, and o,p'-DDD all binding with EC50s less than 10 muM. The binding affinities of xenobiotics to kbAR2 in ovarian tissue were similar to their binding affinities f or ovarian acAR2. The finding that AR1 and AR2 possess different binding affinities for natural androgens and synthetic steroids, as well as for xenobiotics, suggests that the activities of androgens and of certain xenobiotics will depend upon the type of AR present within the target tissue. (Sperry et al, 1999)

Study #6

environmental estrogens (such as PCBs) affect male offspring but they are not malformed or infertile
administration of an Ah receptor agonist (dioxin or certain PCBs) in the womb produces a different spectrum of effects including reduced ejaculated sperm numbers in male offspring

Wildlife from ecosystems contaminated with endocrine disrupting chemicals (EDCs) display a variety of reproductive alterations including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. It has been proposed that EDCs also may have contributed to increases in testicular cancer and hypospadias and the reported decline in human sperm counts. Combined in vivo and in vitro studies are necessary to fully characterize EDC induced alterations of reproduction. We have identified several pesticides (vinclozolin, procymidone, p,p'-DDE) which bind rat and human androgen receptors, block androgen-induced gene expression in vitro and in vivo, delay puberty, reduce sex accessory gland size and alter sex differentiation in the male rat. Some of the phthalates, which are estrogenic in vitro but not in vivo, cause malformations in male rats that appear to result from antagonism of androgens in utero. In contrast, xenoestrogens affect male offspring but they are not malformed or infertile. Prenatal administration of an Ah receptor agonist (2,3,7,8-TCDD or PCB 169) produces a different spectrum of effects including reduced ejaculated sperm numbers in male rats. (Gray, 1998)

Study #7

androgen production was significantly inhibited by PCBs
testosterone production was also decreased by PCBs

The effects of PCBs (mixture of 2, 3, 4, 5-tetra; 2, 2', 4, 5, 5'-penta; 2, 2', 3, 3', 6, 6'-hexa and 2, 2', 3, 3', 4, 4', 5, 5'-octa congeners) on androgen production were investigated by suspension of Leydig cells from adult rat testis. hCG-stimulated androgen production was significantly inhibited by PCBs while progesterone level was not affected. Progesterone supported testosterone production was also decreased by PCBs, while conversion of androstenedione to testosterone was unchanged. These results suggest that the activity of microsomal enzyme C21 side-chain cleavage P450 was decreased by PCB treatment of Leydig cells in vitro. (Kovacevic et al, 1995)

Study #8

aromatase activity decreased in male offspring by maternal exposure to the reconstituted PCB-mixture (aromatase helps determine levels of hormones in the brain)
PCBs reduced testosterone concentrations in adult male testes

Polychlorinated biphenyls (PCBs) form a class of wide-spread environmental contaminants which accumulate in food chains and are found in breast milk at elevated levels. The developing nervous system is particularly sensitive to PCB exposure. Gestational exposure of rats to a non-ortho-chlorinated, coplanar PCB congener led to changes in haloperidol-induced catalepsy and passive avoidance in adulthood. In addition, the distribution of activity in the open field was altered as rats treated with the coplanar PCB exhibited more activity in the inner zone than controls. Moreover, increases in conditioned ultrasonic vocalizations were found in another experiment using maternal exposure to a mixture of PCBs reconstituted according to the congener pattern found in breast milk. Thyroid hormones and steroids are important regulators of neuronal development and PCBs are reported to interact with these hormones. Therefore, developmental PCB effects on the nervous system might be mediated by influences on hormone-dependent processes. For instance, sexual differentiation of the brain is dependent on aromatase (CYP19) which converts androgens to estrogens. Estradiol has a prominent role in neuronal plasticity and induces a male-like development of brain and behavior. Aromatase activity was determined in newborn male pups and found to be decreased by maternal exposure to the reconstituted PCB-mixture. Adult male littermates exhibited lower testes weights and reduced testosterone concentrations together with a higher, more female-like sweet preference. Finally, a place preference test detected a higher stimulation by testosterone in maternally exposed male rats. (Lilienthal et al, 2000)

Study #9

PCBs reduce levels of steroid hormones (such as testosterone) in the blood stream

Alterations in erythropoiesis induced by exposure to a polychlorinated biphenyl (1336363) (PCB) was studied in rats. Male Sprague-Dawley-rats were injected intraperitoneally with 0, 10, 20, and 40mg/kg Aroclor-1254 (11097691) in a 0.1 milliliter (ml) volume of sesame oil. After 15 days, they were killed, and three 1.0 ml blood samples were obtained from each animal. The average number of red blood cells was reduced by Aroclor-1254 in a dose dependent manner from 9.21 x 10(6) to 7.31 x 10(6) erythrocytes per cubic centimeter (controls and 40mg/kg groups, respectively). The authors interpret their results based on the findings of an earlier study in which androgen specific tissues, such as the testes and accessory glands, were reduced in weight under the influence of phenobarbital by way of hydroxylation of testosterone. Aroclor-1254 has been shown to induce hepatic microsomal enzymes which have the ability to hydroxylate natural steroid hormones, with increased excretion of these polar metabolites reducing plasma steroid concentrations. The authors consider that the same mechanism operated to reduce steroid levels and erythropoiesis in their experiments. (Derr et al, 1979)

Study #10

PCBs caused changes in testosterone hydroxylase activities indicative of permanent damage (or imprinting) in androgen metabolism

The effects of neonatal exposure to Aroclor 1254 (100 mumol/kg) on the metabolism of testosterone by adult male and female rats were determined by comparing their hepatic microsomal testosterone hydroxylase activities at 60, 90 and 120 days after the initial exposure. The most pronounced effects in male rats were observed 90 days after treatment with Aroclor 1254, whereas in female rats the major changes in testosterone hydroxylase activities were observed after 60 days. Ninety-day-old male rats neonatally treated with Aroclor 1254 exhibited decreased basal testosterone 7 alpha-hydroxylase and increased basal testosterone 16 alpha-, 2 alpha- and 15 beta-hydroxylase activities and androstenedione formation. In addition, the Aroclor 1254-mediated induction of testosterone 7 alpha- and 6 alpha-hydroxylase activities and androstenedione formation was decreased, and that of testosterone 2 beta- and 15 beta-hydroxylase activities was increased. Sixty-day-old female rats exposed neonatally to Aroclor 1254 exhibited increased basal testosterone 16 alpha-, 2 beta-, 6 alpha- and 15 beta-hydroxylase activities and androstenedione formation, and increased Aroclor 1254-induced metabolism of testosterone at all positions except 16 alpha and 2 alpha. Changes in testosterone hydroxylase activities indicative of permanent damage (or imprinting) in androgen metabolism, i.e. altered activities in 120-day-old animals, were observed only in male rats. These activities included basal testosterone 6 beta-, 16 alpha- and 2 alpha-hydroxylase activities and androstenedione formation. (Haake-McMillan et al, 1991)

Study #11

external factors, such as anti-androgens and oestrogens (such as PCBs), that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus

Male sexual differentiation is dependent on normal testicular function, including secretion of testosterone from the Leydig cells, and mullerian-inhibiting substance from the Sertoli cells. External factors, such as anti-androgens and oestrogens, that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus. Oestrogens also cause adverse effects in female fetuses, whereas anti-androgens have little influence. A growing number of chemicals have been found to possess either weak oestrogenic, anti-androgenic or other hormonal activities, and these are often referred to as endocrine disrupters. In animals in the wild, abnormal sexual development has been associated with exposure to mixtures of endocrine disrupters. The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrine disrupters. (Toppari et al, 1998)

Study #12

PCBs caused a significant increase in activities of enzymes
increased enzymes coincided with decreases in hormone levels in the blood stream

Aroclor 1254 was administered i.p. (25 mg kg body wt-1 in 1 ml of Arachis oil) at weekly intervals for 4 wk to trout and carp; Arachis oil was used as the control. Activities of the following hepatic microsomal enzymes, aminopyrine demethylase, p-nitroreductase, UDP-glucuronyl transferase and 1-leucyl-beta-naphthylamide splitting enzyme were measured in both species; cytochrome P450 and microsomal protein contents were also determined. The changes in the levels of androgens, estrogens and corticoid hormones were measured in the circulating blood of control and treated groups at weekly intervals. The blood was obtained by cardiac puncture. Results indicated a significant increase in the activities of all the enzymes measured except 1-leucyl-beta-naphthylamide splitting enzyme, increased cytochrome P450 and microsomal protein contents in trout, but not in carp; a significant reduction in the plasma levels of androgens estrogens and corticoids in the treated groups, particularly at the end of the 4th wk; and a correlation between increased enzyme activities and a decrease in plasma hormone levels. (Sivarajah et al, 1978)

Study #13

disturbances of hormonal regulation by endocrine disruptors (such as PCBs) during fetal or post-natal development induced adverse effects on the animal's reproductive systems
an accelerated onset, peak and decrease of testis-weight that indicates the presence of subtle male reproductive disorders

In recent years, there has been increasing public concern that chemicals in the environment are affecting human health by disrupting normal hormone function. These chemicals mimic or partly mimic the sex steroid hormones estrogens and androgens by binding to hormone receptors or cell signaling pathways. These chemicals are referred to as "endocrine disruptors", or "endocrine disrupting chemicals" in Europe and North America. In Japan, most people including the media call them "Environmental Hormones". Endocrine disruptors include natural products, pharmaceuticals, industrial products and environmental pollutants. Studies of wild shell-fish, fish, alligators, birds, whales, polar bears and experimental rodents have already clearly shown that disturbances of hormonal regulation by endocrine disruptors during fetal or post-natal development induced adverse effects on the animal's reproductive systems. Moreover, etiological studies have reported that a possible cause of regional declines in sperm counts, increases in abnormal spermatogenesis, increases in hypospadias and male reproductive disorders in humans are due to exposure to endocrine disruptors. However, the adverse effects of endocrine disruptors on humans are less clear, and are difficult to research and detect. Therefore we have investigated fetal exposure to endocrine disruptors in Japan by analyzing umbilical cords, and changes of testis weight and spermatogenesis in Japanese men by using analytical data of necropsy. We detected many endocrine disruptors including dioxins, PCBs, bisphenol A and phytoestrogens in human umbilical cords collected from normal newborns in Japan. Moreover, our analysis regarding the male reproductive condition shows an accelerated onset, peak and decrease of testis-weight that indicates the presence of subtle male reproductive disorders in Japan. (Mori, 2001)

Study #14

numerous chemicals working together through several hormone-dependent pathways could prove to be hazardous to human reproductive health

Considerable attention has been given in the past few years to the possibility that man-made chemicals (xenobiotics) in the environment may pose a hazard to human reproductive health. The endocrine-disrupting effects of many xenobiotics can be interpreted as interference with the normal regulation of reproductive processes by steroid hormones. Evidence reviewed here indicates that xenobiotics bind to androgen and oestrogen receptors in target tissues, and to androgen-binding protein and to sex hormone-binding globulin. Although environmental chemicals have weak hormonal activity, their ability to interact with more than one steroid-sensitive pathway provides a mechanism by which their hazardous nature can be augmented. A given toxicant may be present in low concentration in the environment and, therefore, harmless. However, we are not exposed to one toxicant at a time, but, rather, to all of the xenobiotics present in the environment. Therefore, numerous potential agonists/antagonists working together through several steroid-dependent signalling pathways could prove to be hazardous to human reproductive health. (Danzod, 1998)

Study #15

PCBs may induce, by the mechanism of imprinting, alterations of the differentiation of several cell-types, resulting in the development of disease during adulthood

Since the early reports linking the development of clear cell cervicovaginal adenocarcinoma in young women with diethylstilbestrol treatment of their mothers during pregnancy, it became clear that perinatal exposure to several substances may induce irreversible alterations, that can be detected later in life. Current evidence suggests that these substances induce, by the mechanism of imprinting, alterations of the differentiation of several cell-types, resulting in the development of disease during the adult age. The most known delayed effects to prenatal exposure to agents displaying hormone action, pollutants, food additives and natural food components, substances of abuse and stress by the mechanism of imprinting are described. Among them, estrogens, androgens, progestins, lead, benzopyrenes, ozone, dioxins, DDT, DDE, methoxychlor, chlordecone, parathion, malathion, polychlorobiphenyls, pyrethroids, paraquat, food additives, normal food constituents, tetrahydrocannabinol, cocaine and opiates. It is concluded that perinatal exposure to several agents causes irreversible changes that determine health conditions during adulthood. Several diseases developing during adulthood probably were determined during early stages of life, under the effect of exposure or preferential mother's diet during pregnancy. Regulations to avoid these early exposures may contribute to an important improvement of health conditions of humankind. (Tchernitchin et al, 1999)

Study #16

trace amounts of PCBs in human embryos may determine the appearance of tumors later in life, a possibility documented in several animal species including humans

A description of the experimental approaches devised to control the growth of tumors induced by transplacental exposure to carcinogens is given. Due to the massive cell proliferation and differentiation taking place during embryogenesis, fetal tissues are believed to be privileged targets of neoplastic changes. As a consequence, trace amounts of environmental carcinogens capable of accumulating into the conceptuses may determine the appearance of tumors in the offspring, a possibility documented in several animal species including humans. Endogenous and exogenous factors counteracting this process have potential application as regulators of developmental carcinogenesis. Their identification is regarded as a means to chemoprevent pediatric tumors and can be instrumental in the analysis of the aetiopathogenesis of neoplastic phenotypes. (Alexandrov et al, 1990)

Go to:

Back to Human Health Risks

Back to Fox River Watch

To Site Index

Make a Donation