Chapter 3: Endocrinology and Endocrine Toxicology

1 - 11 Introduction to Endocrine SystemsEndocrine systems of the body play an essential and pervasive role inboth the short-and long-term regulation of metabolic , behavioral, and reproductive processes are intricatelyregulated by Endocrine systems, as are growth (including bonegrowth/remodeling), gut, cardiovascular, and kidney function andresponses to all forms of stress. Disorders of any of the endocrinesystems, involving both overactive and underactive hormonesecretion, result inevitably in disease, the effects of which may extendto many different organs and functions and are often debilitating orlife-threatening.

2 Viewed from this general perspective, the threatposed from environmental chemicals with Endocrine activity (eitheragonist or antagonistic) is potentially serious. However, the fact thathumans and wildlife are exposed to such chemicals does notnecessarily mean that clinically manifest disturbance of the relevantendocrine system will result, because much depends on the level andduration of exposure and on the timing of Scope and OverviewThe Endocrine system originally was considered to consist only ofglands that secreted hormones into the blood that traveled to distanttarget tissues, bound to specific cellular receptors, and producedcharacteristic actions.

3 Currently, our concept of Endocrine has beenbroadened by the discovery of other chemical regulators, such aschemicals secreted into the blood by neurons, that are sometimestermed neurohormones. The term cytocrine has been applied tonumerous local or intercellular chemical regulators, including growthfactors. Intercellular cytocrines that travel through the extracellularfluids to other cells in a tissue also are known as paracrine andautocrine regulators, depending on whether they affect other cells orthemselves, respectively. The term intracrine has been suggested forintracellular regulators such as second messengers and transcriptionfactors.

4 Even before allowing for the increase in complexity of Endocrinology that has resulted from recent recognition of the manycytocrine/paracrine systems that operate, it had been realized thatthere were numerous classical Endocrine systems in the body thatregulate processes as diverse as blood pressure, smooth musclecontraction, fluid balance, and bone is beyond the scope of this Chapter to describe the entireendocrine system; instead, the focus will be on the three majorendocrine axes that affect reproductive development and restriction is based on the observations that many manifestationsof Endocrine disruption involve the reproductive system, particularlyduring its vulnerable developmental period.

5 The particular aspects ofthe Endocrine system that are covered include the HPG, the HPT,and the HPA axes. This restriction is arbitrary and should not implythat Endocrine disruptors cannot affect other Endocrine axes. It is alsoemphasized that the general principles on which all Endocrine (andprobably paracrine) axes are first set up and then operate are essentiallyidentical, and hence, most of what is discussed below can betransferred in principle to other Endocrine axes that are not emphasis will be on the vertebrate Endocrine system, with onlyminor attention paid to invertebrates. Although there are manyparallels between vertebrate and invertebrate Endocrine mechanisms,there are some major differences as well.

6 General discussions ofinvertebrate Endocrinology have been reported (Downer and Laufer,1983; Matsumoto and Ishii, 1997; Cymborowski, 1992; Nijhout,1994). This Chapter consists of two main parts: sections the normal functioning of the Endocrine system, both in adultsand in the developing organism; sections focus on theimpact of Endocrine disruptors on organ systems and diseaseprocesses. The largest of the sections deals with effects on reproductivesystem development using several well-characterized examples fromthe experimental literature ( , MXC, vinclozolin, ketaconazole,List of AbbreviationsChapter 3: Endocrinology and Endocrine TChapter 3.)

7 Endocrinology and Endocrine Toxicology oxicology 17 ,20 -P17 ,20 -dihydroxy-4-pregnen-3-one 5-HTSerotonin ACTHA drenocorticotropin hormone AGDA nogenital distance AhRAryl hydrocarbon receptor ARAndrogen receptor ARNTAhR nuclear translocator AFP -Fetoprotein BBPB utylbenzyl phthalate BNF -Napthoflavone cAMPC yclic AMP CBGC orticotropin-binding globulin CRHC orticotropin-releasing hormone CYPC ytochrome P DBPDi-n-butyl phthalate DDED ichlorodiphenyl dichloroethylene DDTD ichlorodiphenyl trichloroethane DEHPDi-ethylhexyl phthalate DEPD iethyl phthalate DESD iethylstilbestrol DHEAD ihydroepiandrosterone DHPD ihexyl phthalate DHTD ihydrotestosterone DMPD imethyl phthalate DOTPD ioctyl phthalate E217 -Estradiol

8 EDCsEndocrine-disrupting chemicals EREstrogen receptor ( and isoforms) FSHF ollicle-stimulating hormone Gal4-HEGOGal4-human estrogen receptor construct GHGrowth hormone GnRHGonadotropin-releasing hormone GSIG onadal-somatic index GTHG onadotropin (isoforms I and II) HIF-1 Hypoxia inducible factor 1 HPAH ypothalamic-pituitary-adrenal HPGH ypothalamic-pituitary-gonadal HPOAH ypothalamic preoptic area HPTH ypothalamic-pituitary-thyroid HPTE2,2-Bis(p-hydroxyphenyl)-1,1,1-trich loroethane ILInterleukin IUGRI ntrauterine growth retardation LELong-Evans LHLuteinizing hormone LOAELL owest observed adverse effect level M1, M2 Vinclozolin metabolites MEHPMono-ethylhexyl phthalate MIHM llerian inhibiting hormone MISAnti-M llerian substance mRNAM essenger RNA MXCM ethoxychlor NOAELNo observed adverse effect level PCBsPolychlorinated biphenyls PCDFsPolychlorinated dibenzofurans PGsProstaglandins PRLP rolactin SARMsSelective androgen receptor modulatorsSDSprague-Dawley SERMsSelective estrogen receptor modulators SHBGSex hormone binding globulin T3 Triiodothyronine T4 Thyroxine TCDD2,3,7.

9 8-Tetrachlorodibenzyl-p-dioxin TRHT hyrotropin-releasing hormone TSHT hyroid-stimulating hormone US EPAU nited States Environmental Protection AgencyIPCS GLOBALASSESSMENT OFEDCS- 12 -phthalates, and dioxin). These examples were selected to provide abroad view of the basic modes of action that are involved in theinteraction of chemicals with the Endocrine system. In addition todescribing the modes of actions, descriptions of the critical periods,dose sensitivity, and resulting phenotypes seen in experimentalmodels are provided. Similarly to the section on normal endocrinefunction, this section deals primarily with effects on vertebrates, andmammals in particular.

10 Succeeding sections provide examples ofEDC-related modes of action pertinent to carcinogenesis and thefunction of the nervous and immune systems. The final sectionprovides a overall framework to judge whether a particular outcome,whether observed in the laboratory, in the field, or in anepidemiology setting, could be related to an EDC-related mode ofaction. This framework is intended to provide a structure by whichsubsequent observations, either contained in this assessment orreported subsequently in the scientific literature, can be judgedrelative to ascertainment of the mode of HomeostasisThe fundamental role of all Endocrine systems is to enable adynamic, coordinated response of a distant target tissue to signalsoriginating from another organ and, in some instances, cuesoriginating from outside of the body.