The adrenal cortex and steroidogenesis as cellular and molecular targets for toxicity: critical omissions from regulatory endocrine disrupter screening strategies for human health?

Abstract

Current testing strategies to assess the endocrine disrupting properties of chemicals have omitted examination of the adrenal gland and do not adequately cover the process of steroidogenesis. Steroidogenesis is critical for adrenocortical function as well as that of the testes and ovaries, and presents multiple molecular targets for toxicity, ranging from general effects on all steroidogenic tissues (e.g. via StAR protein or CYP11A1 cholesterol side-chain cleavage) through to specific targets affecting only adrenocortical function (e.g. CYP11beta/18 and glucocorticoid synthesis). Numerous chemicals of environmental relevance are now being shown to affect adrenocortical function both in vivo in aquatic species and in vitro in human cell lines, and given the vital role of the adrenal gland to human health and development, there is a strong case for including dedicated assessment techniques in screening batteries for endocrine-disrupting chemicals, not least to assist in general data interpretation (e.g. whether adrenal hypertrophy is due to stress or to a more sinister adrenocortical insufficiency). Cell lines such as H295R (derived from a human adrenocortical adenocarcinoma) currently exist that will allow assessment of cortisol production and most of the major enzymes and functional proteins in the steroidogenic pathway (e.g. StAR; CYP11A1/scc; CYP11beta/18; CYP17; CYP19; CYP21; 3beta-hydroxysteroid dehydrogenase). Adequate assessment of adrenocortical function, as with any component of the integrated endocrine system, probably also will require the development of specific in vivo methodology to include effects on hypothalamo-pituitary function. Finally, although there is currently no direct evidence that environmental exposure to endocrine-disrupting (oestrogenic) chemicals has actually caused adverse human health effects, lessons have been learned on their potential from the diethylstilboestrol case. Similar evidence exists from aminoglutethimide and etomidate on the lethal impact of unpredicted chemically induced adrenal insufficiency in sensitive human subgroups, and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes.

The stress of being contaminated? Adrenocortical function and reproduction in relation to persistent organic pollutants in female black legged kittiwakes

“…The adrenal gland is one of the most common target for chemically induced lesions (Rosol et al 2001). Because of several characteristics as: its large blood supply, its lipophilicity (allowing the accumulation of lipophilic compounds), its high concentration of cytochrome P450 that can also bioactivate toxicants, and its capacity to synthesize all major classes of steroids (Falco et al 2007;Harvey and Everett 2003;Hinson and Raven, 2006;Rosol et al 2001). Adrenal cells concentrate a number of toxic agents, as DDT (Lund et al 1988) and PCB metabolites (Brandt and Bergman, 1987) that may remain inactive caught into the adrenal tissue until a period of particularly high adrenal steroid demand, as the breeding period.…”

Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis

“…Although these mechanisms are largely relevant to in vivo adrenal toxicology and consequent pathology, effective and relevant in vitro models, such as the H295R cell line, have only very recently been developed and these are now expanding the range of known adrenocortical toxicants and molecular mechanisms of action (e.g. Ohno et al, 2002;Sanderson et al, 2002Sanderson et al, , 2004Li et al, 2004;Hilscherova et al, 2004;Voets et al, 2004;Zhang et al, 2005;Kau et al, 2005;MullerVieira et al, 2005;Li and Wang, 2005;Blaha et al, 2006;Lin et al, 2006;Xu et al, 2006;Hecker et al, 2006;Gracia et al, 2006;Canton et al, 2006;Imagawa et al, 2006;Oskarsson et al, 2006;Sanderson, 2006; see discussion in Harvey and Everett, 2003).…”

“…Etomidate proved to be a potent and selective 11β/18 hydroxlase (cytochrome P450 11B1; CYP11B1; CYP11β/18) inhibitor blocking cortisol production, and although its medicinal use is clearly a worst-case human exposure scenario, the fact that it has prolonged adrenocortical suppressant activity at low doses (in the µg kg −1 body weight dose range) after only a single dose/exposure, raises the question of whether low-level long-term exposures of the human population to environmental chemicals could also produce unrecognised adrenal effects of various degrees. As cortisol production can be affected by chemical action at a number of sites along the steroidogenic pathway (Harvey and Johnson, 2002;Harvey and Everett, 2003) combined exposures to chemicals or mixtures, potentially affecting different sites along a common pathway, may precipitate adrenocortical dysfunction at even lower exposure rates. The lack of a regulatory framework to study adrenal toxicity means that there is a relative paucity of quality standardised data, that data acquisition is slow, and there are no recommended standardised regulatory procedures/protocols for assessment to remedy this situation.…”

OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters as a basis for regulation of substances with endocrine disrupting properties

“…Several chemicals have been identified as EDCs that interfere directly with steroidogenesis. One of these is lindane that inhibits steroid acute regulatory protein (StAR) (Walsh and Stocco, 2000;Harvey and Everett, 2003). The plasticiser di(2-ethylhexyl)phthalate (DEHP) reduces testicular testosterone levels in testis from in utero exposed males and inhibits ex vivo testicular testosterone production (Borch et al, 2003a).…”