In recent years, a number of man-made chemicals have been shown to be able to mimic endogenous hormones, and it has been hypothesized that alterations in the normal pattern of reproductive development seen in some populations of wildlife are linked with exposure to these chemicals. Of particular importance are those compounds that mimic estrogens and androgens (and their antagonists), because of their central role in reproductive function. In fact, the evidence showing that such chemicals actually do mimic (or antagonize) the action of hormones in the intact animal is limited. In only a few cases have laboratory studies shown that chemicals that mimic hormones at the molecular level (in vitro) also cause reproductive dysfunction in vivo at environmentally relevant concentrations. In addition, the reported studies on wild populations of animals are limited to a very few animal species and they have often centered on localized 'hot-spots' of chemical discharges. Nevertheless, many of these xenobiotics are persistent and accumulate in the environment, and therefore a more widespread phenomenon of endocrine disruption in wildlife is possible. This article reviews the evidence, from both laboratory and field studies, that exposure to steroid hormone mimics may impair reproductive function and critically assesses the weight of evidence for endocrine disruption in wildlife.

Endocrine Disruption in Wildlife: A Critical Review of the Evidence

Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors alpha and/or beta and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered "male hormones."

Estrogen and spermatogenesis.

DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. A toxicological Profile for PCBs, Draft for Public Comment, was released in December 1998. This edition supercedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public law 99-499) which amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepared toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous substances was announced in the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions. Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance's relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure. Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure. The following additional material can be ordered through the ATSDR Information Center: Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other …

Toxicological profile for polychlorinated biphenyls (PCBs)

Most research on the effects of chemicals on biologic systems is conducted on one chemical at a time. However, in the real world people are exposed to mixtures, not single chemicals. Although various substances may have totally independent actions, in many cases two substances may act at the same site in ways that can be either additive or nonadditive. Many even more complex interactions may occur if two chemicals act at different but related targets. In the extreme case there may be synergistic effects, in which case the effects of two substances together are greater than the sum of either effect alone. In reality, most persons are exposed to many chemicals, not just one or two, and therefore the effects of a chemical mixture are extremely complex and may differ for each mixture depending on the chemical composition. This complexity is a major reason why mixtures have not been well studied. In this review we attempt to illustrate some of the principles and approaches that can be used to study effects of mixtures. By the nature of the state of the science, this discussion is more a presentation of what we do not know than of what we do know about mixtures. We approach the study of mixtures at three levels, using specific examples. First, we discuss several human diseases in relation to a variety of environmental agents believed to influence the development and progression of the disease. We present results of selected cellular and animal studies in which simple mixtures have been investigated. Finally, we discuss some of the effects of mixtures at a molecular level.

http://www.rachel.org/files/document/Understanding_the_Human_Health_Effects_of_Chem.pdf

Understanding the human health effects of chemical mixtures.

Three major phases compose spermatogenesis: mitotic proliferation of spermatogonia, meiosis of spermatocytes, and spermiogenesis, the restructuring of spermatids into flagellated spermatozoa. The process is fuelled by stem cells that, when dividing, either self-renew or produce spermatogonia that are committed to proliferation, meiosis, and spermiogenesis. During all phases, germ cells are in close contact with and require the structural and functional support of Sertoli cells. In contrast to germ cells, these somatic cells express receptors for sex steroids and follicle-stimulating hormone (FSH), the most important hormones that regulate spermatogenesis. A typical Sertoli cell response to an endocrine stimulus would be to change the release of a growth factor that would then mediate the hormone's effect to the germ cells. Recent studies in the Japanese eel have shown, for example, that in the absence of gonadotropin Sertoli cells produce a growth factor (an orthologue of anti-Mullerian hormone) that restricts stem cell divisions to the self-renewal pathway; also estrogens stimulate stem cell renewal divisions but not spermatogonial proliferation. Gonadotropin or 11-ketotestosterone (11-KT) stimulation, however, induces spermatogonial proliferation, which is in part mimicked by another Sertoli cell-derived growth factor (activin B). Since FSH (besides luteinizing hormone, LH) stimulates steroidogenesis in fish, and since FSH is the only gonadotropin detected in the plasma of sexually immature salmonids, increased FSH signalling may be sufficient to initiate spermatogenesis by activating both Sertoli cell functions and 11-KT production. Another important androgen is testosterone (T), which seems to act via feedback mechanisms that can compromise FSH-dependent signalling or steroidogenesis. The testicular production of T and 11-KT therefore needs to be balanced adequately. Further research is required to elucidate in what way(s) 11-KT stimulates later stages of development, such as entry into meiosis and spermiogenesis. At this period, LH becomes increasingly important for the regulation of androgen production. Results from mammalian models suggest that during the later phases, the control of germ cell apoptosis via Sertoli cell factors is an important regulatory mechanism. In many species, sperm cells cannot fertilize eggs until having passed a maturation process known as capacitation, which includes the acquisition of motility. Progestins that are produced under the influence of LH appear to play an important role in this context, which involves the control of the composition of the seminal plasma (e.g., pH values).

Spermatogenesis and its endocrine regulation

Transient neonatal hypothyroidism in the rat causes prolonged Sertoli cell proliferation, delayed Sertoli cell maturation, and increased adult Sertoli cell number, testis weight, and sperm production. Conversely, neonatal hyperthyroidism decreases Sertoli cell proliferation and ultimate testis size. This suggests that thyroid hormones might normally directly inhibit Sertoli cell proliferation while promoting maturation. However, these Sertoli cell effects could be due to secondary hormonal or metabolic effects of hypo- or hyperthyroidism. In this study, we directly tested thyroid hormone effects on Sertoli cell proliferation and differentiation in vitro. Sertoli cells from 5-day-old rat testes were grown in serum-free medium alone (controls) or with additional triiodothyronine (T3; 1-200 nM) and/or FSH (1 microgram/ml). After 4 days, cultures were used to obtain RNA for Northern hybridization or for thymidine autoradiography. Labeling index (LI) for control cultures and cultures receiving 100 nM T3 alone was 5.2 +/- 0.5% and 5.0 +/- 0.4%, respectively. The LI of FSH-treated cultures increased to 8.4 +/- 0.8% (p < 0.01 vs. control). Cultures treated with FSH and 1, 10, 100, or 200 nM T3 had LIs of 8.0 +/- 0.9%, 6.1 +/- 0.4%, 5.3 +/- 0.6%, and 4.8 +/- 0.6%, respectively; the last three values were less than for cells receiving FSH alone (p < 0.01) or FSH + 1 nM T3 (p < 0.05). Northern hybridization indicated that mRNA levels for clusterin and inhibin-beta B, Sertoli cell secretory proteins whose production normally increases during postnatal differentiation in vivo, were significantly increased by T3 or FSH alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Triiodothyronine inhibits proliferation and stimulates differentiation of cultured neonatal Sertoli cells: possible mechanism for increased adult testis weight and sperm production induced by neonatal goitrogen treatment.

Neonatal polychlorinated biphenyl treatment increases adult testis size and sperm production in the rat.

Erratum: Triiodothyronine inhibits proliferation and stimulates differentiation of cultured neonatal Sertoli cells: Possible mechanism for increased adult testis weight and sperm production induced by neonatal goitrogen treatment (Biology of Reproduction 51:5 (1000-1005))

Yi-dong Zhao

Papers

Triiodothyronine inhibits proliferation and stimulates differentiation of cultured neonatal Sertoli cells: possible mechanism for increased adult testis weight and sperm production induced by neonatal goitrogen treatment.

Neonatal polychlorinated biphenyl treatment increases adult testis size and sperm production in the rat.

Erratum: Triiodothyronine inhibits proliferation and stimulates differentiation of cultured neonatal Sertoli cells: Possible mechanism for increased adult testis weight and sperm production induced by neonatal goitrogen treatment (Biology of Reproduction 51:5 (1000-1005))