Chapter 3: Endocrinology and Endocrine Toxicology 3.1 Introduction to Endocrine Systems intracellular regulators such as second messengers and transcription Endocrine systems of the body play an essential and pervasive role in factors. Even before allowing for the increase in complexity of both the short-and long-term regulation of metabolic processes. “endocrinology” that has resulted from recent recognition of the many Nutritional, behavioral, and reproductive processes are intricately cytocrine/paracrine systems that operate, it had been realized that regulated by endocrine systems, as are growth (including bone there were numerous “classical” endocrine systems in the body that growth/remodeling), gut, cardiovascular, and kidney function and regulate processes as diverse as blood pressure, smooth muscle responses to all forms of stress. Disorders of any of the endocrine contraction, fluid balance, and bone resorption. systems, involving both overactive and underactive hormone It is beyond the scope of this chapter to describe the entire secretion, result inevitably in disease, the effects of which may extend endocrine system; instead, the focus will be on the three major to many different organs and functions and are often debilitating or endocrine axes that affect reproductive development and function. life-threatening. Viewed from this general perspective, the threat This restriction is based on the observations that many manifestations posed from environmental chemicals with endocrine activity (either of endocrine disruption involve the reproductive system, particularly agonist or antagonistic) is potentially serious. However, the fact that during its vulnerable developmental period. The particular aspects of humans and wildlife are exposed to such chemicals does not the endocrine system that are covered include the HPG, the HPT, necessarily mean that clinically manifest disturbance of the relevant and the HPA axes. This restriction is arbitrary and should not imply endocrine system will result, because much depends on the level and that endocrine disruptors cannot affect other endocrine axes. It is also duration of exposure and on the timing of exposure. emphasized that the general principles on which all endocrine (and probably paracrine) axes are first set up and then operate are essentially 3.2 Scope and Terminology identical, and hence, most of what is discussed below can be 3.2.1 Overview transferred in principle to other endocrine axes that are not described. The emphasis will be on the vertebrate endocrine system, with only The endocrine system originally was considered to consist only of minor attention paid to invertebrates. Although there are many glands that secreted hormones into the blood that traveled to distant parallels between vertebrate and invertebrate endocrine mechanisms, target tissues, bound to specific cellular receptors, and produced there are some major differences as well. General discussions of characteristic actions. Currently, our concept of “endocrine” has been invertebrate endocrinology have been reported (Downer and Laufer, broadened by the discovery of other chemical regulators, such as 1983; Matsumoto and Ishii, 1997; Cymborowski, 1992; Nijhout, chemicals secreted into the blood by neurons, that are sometimes 1994). This chapter consists of two main parts: sections 3.1–3.11 termed neurohormones. The term “cytocrine” has been applied to detail the normal functioning of the endocrine system, both in adults numerous local or intercellular chemical regulators, including growth and in the developing organism; sections 3.12–3.16 focus on the factors. Intercellular cytocrines that travel through the extracellular impact of endocrine disruptors on organ systems and disease fluids to other cells in a tissue also are known as paracrine and processes. The largest of the sections deals with effects on reproductive autocrine regulators, depending on whether they affect other cells or system development using several well-characterized examples from themselves, respectively. The term “intracrine” has been suggested for the experimental literature (e.g., MXC, vinclozolin, ketaconazole, List of Abbreviations 17α,20β-P 17α,20β-dihydroxy-4-pregnen-3-one DMP Dimethyl phthalate LOAEL Lowest observed adverse effect level 5-HT Serotonin DOTP Dioctyl phthalate M1, M2 Vinclozolin metabolites ACTH Adrenocorticotropin hormone E2 17β-Estradiol MEHP Mono-ethylhexyl phthalate AGD Anogenital distance EDCs Endocrine-disrupting chemicals MIH Müllerian inhibiting hormone AhR Aryl hydrocarbon receptor ER Estrogen receptor (α and β isoforms) MIS Anti-Müllerian substance AR Androgen receptor FSH Follicle-stimulating hormone mRNA Messenger RNA ARNT AhR nuclear translocator Gal4-HEGO Gal4-human estrogen receptor MXC Methoxychlor AFP α-Fetoprotein construct NOAEL No observed adverse effect level BBP Butylbenzyl phthalate GH Growth hormone PCBs Polychlorinated biphenyls BNF β-Napthoflavone GnRH Gonadotropin-releasing hormone PCDFs Polychlorinated dibenzofurans cAMP Cyclic AMP GSI Gonadal-somatic index PGs Prostaglandins CBG Corticotropin-binding globulin GTH Gonadotropin (isoforms I and II) PRL Prolactin CRH Corticotropin-releasing hormone HIF-1α Hypoxia inducible factor 1α SARMs Selective androgen receptor modulators CYP Cytochrome P HPA Hypothalamic-pituitary-adrenal SD Sprague-Dawley DBP Di-n-butyl phthalate HPG Hypothalamic-pituitary-gonadal SERMs Selective estrogen receptor modulators DDE Dichlorodiphenyl dichloroethylene HPOA Hypothalamic preoptic area SHBG Sex hormone–binding globulin DDT Dichlorodiphenyl trichloroethane HPT Hypothalamic-pituitary-thyroid T3 Triiodothyronine DEHP Di-ethylhexyl phthalate HPTE 2,2-Bis(p-hydroxyphenyl)-1,1,1- T4 Thyroxine DEP Diethyl phthalate trichloroethane TCDD 2,3,7,8-Tetrachlorodibenzyl-p-dioxin DES Diethylstilbestrol IL Interleukin TRH Thyrotropin-releasing hormone DHEA Dihydroepiandrosterone IUGR Intrauterine growth retardation TSH Thyroid-stimulating hormone DHP Dihexyl phthalate LE Long-Evans US EPA United States Environmental DHT Dihydrotestosterone LH Luteinizing hormone Protection Agency - 11 - IPCS GLOBAL ASSESSMENT OF EDCS phthalates, and dioxin). These examples were selected to provide a originating from outside of the body. For most endocrine systems, broad view of the basic modes of action that are involved in the the primary objective is to maintain some form of “homeostasis,” interaction of chemicals with the endocrine system. In addition to avoiding wild swings in hormone levels/responses that might describing the modes of actions, descriptions of the critical periods, otherwise have detrimental metabolic effects (Norman and Litwack, dose sensitivity, and resulting phenotypes seen in experimental 1998). A good example is the role of insulin in maintaining blood models are provided. Similarly to the section on normal endocrine glucose levels within the normal range, that is, a range that does not function, this section deals primarily with effects on vertebrates, and fall so low as to result in unconsciousness and does not rise so high mammals in particular. Succeeding sections provide examples of that wasteful excretion/spillage into urine occurs. When insulin EDC-related modes of action pertinent to carcinogenesis and the levels do not respond to changing blood levels of glucose, diseases function of the nervous and immune systems. The final section such as diabetes are the result. All endocrine systems operate to a provides a overall framework to judge whether a particular outcome, large extent on the “seesaw” principle (Figure 3.1), in which the whether observed in the laboratory, in the field, or in an target cells send feedback signals (usually negative feedback) to the epidemiology setting, could be related to an EDC-related mode of regulating cells, with the result that secretion of the target action. This framework is intended to provide a structure by which cell–stimulating hormone is altered (usually reduced) by one or subsequent observations, either contained in this assessment or more of the products of the target cells (Darlington and Dallman, reported subsequently in the scientific literature, can be judged 1995). However, in reality, there are usually elaborations or relative to ascertainment of the mode of action. refinements of this simple archetypal endocrine system that enable all of the endocrine systems of the body to be integrated via cross 3.2.2 Homeostasis talk. The reasons for this are obvious. For example, reproduction The fundamental role of all endocrine systems is to enable a needs to take account of age, nutritional status, and in most animals, dynamic, coordinated response of a distant target tissue to signals season of the year. Similarly, stress responses, and to a lesser extent, originating from another organ and, in some instances, cues endocrine systems regulating hunger, need to be able to override other endocrine systems when danger threatens. This cross talk is vital for a healthy life and has important implications for the evaluation of endocrine disruptors. Exposure to an estrogenic chemical, for example, may affect not only the reproductive endocrine axis but also several other endocrine systems as well as bone, fat, and cardiovascular systems. 3.2.3 Programming of Endocrine Axes Although homeostasis, via seesaw-type mechanisms, is a central feature of all endocrine systems, it should be stressed that the balance between the two sides of the “seesaw” need to be set up or programmed before the system will work correctly.