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.