title: Adrenocortical endocrine disruption.
abstract: The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'.
authors.affiliation: Toxicology Department, Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, United Kingdom. Electronic address: philip.harvey@covance.com.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Harvey
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects* / Q000503:physiopathology; D000309:Adrenal Insufficiency / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000616:Aminoglutethimide / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000819:agonists / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D052244:Endocrine Disruptors / Q000633:toxicity*; D005045:Etomidate / Q000633:toxicity*; D005786:Gene Expression Regulation; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D052244:Endocrine Disruptors; D018043:Receptors, Corticotropin; D000616:Aminoglutethimide; D003577:Cytochrome P-450 Enzyme System; D003345:Corticosterone; D005045:Etomidate
keywords: Adrenal cortex; Adrenal hypertrophy; Adrenal toxicity; Adrenocortical insufficiency; H295R cell line; Steroidogenesis; Stress; Toxicity