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

Abstract

The adrenal is the most common toxicological target organ in the endocrine system in vivo and yet it is neglected in regulatory endocrine disruption screening and testing. There has been a recent marked increase in interest in adrenal toxicity, but there are no standardised approaches for assessment. Consequently, a strategy is proposed to evaluate adrenocortical toxicity. Human adrenal conditions are reviewed and adrenocortical suppression, known to have been iatrogenically induced leading to Addisonian crisis and death, is identified as the toxicological hazard of most concern. The consequences of inhibition of key steroidogenic enzymes and the possible toxicological modulation of other adrenal conditions are also highlighted. The proposed strategy involves an in vivo rodent adrenal competency test based on ACTH challenge to specifically examine adrenocortical suppression. The H295R human adrenocortical carcinoma cell line is also proposed to identify molecular targets, and is useful for measuring steroids, enzymes or gene expression. Hypothalamo-pituitary-adrenal endocrinology relevant to rodent and human toxicology is reviewed (with an emphasis on multi-endocrine axis effects on the adrenal and also how the adrenal affects a variety of other hormones) and the endocrinology of the H295R cell line is also described. Chemicals known to induce adrenocortical toxicity are reviewed and over 60 examples of compounds and their confirmed steroidogenic targets are presented, with much of this work published very recently using H295R cell systems. In proposing a strategy for adrenocortical toxicity assessment, the outlined techniques will provide hazard assessment data but it will be regulatory agencies that must consider the significance of such data in risk extrapolation models. The cases of etomindate and aminoglutethimide induced adrenal suppression are clearly documented examples of iatrogenic adrenal toxicity in humans. Environmentally, sentinel species, such as fish, have also shown evidence of adrenal endocrine disruption attributed to exposure to chemicals. The extent of human sub-clinical adrenal effects from environmental chemical exposures is unknown, and the extent to which environmental chemicals may act as a contributory factor to human adrenal conditions following chronic low-level exposures will remain unknown unless purposefully studied.

In vivo alternative assessment of the chemicals that interfere with anterior pituitary POMC expression and interrenal steroidogenesis in POMC: EGFP transgenic zebrafish

“…This approach was supported by its successful confirmation of known adrenergic agents, such as Dex and AG. The adrenal toxicity of simazine and PCB126 observed in this study might also reflect the effects reported previously (Harvey et al, 2007). The EC50 values of Dex, AG, simazine, and PCB126 for anterior pituitary POMC expression as determined in this study were significantly lower than their NOAECs (Table 1), which might also indicate the fact that the adrenal/interrenal gland is one of their primary targets with regard to endocrine disruption effects.…”

“…These include simazine, PCB126, BADGE, and TCDD (Hinson and Raven, 2006;Hecker et al, 2006;Villeneuve et al, 2007;Harvey et al, 2007). To examine the effects of these chemicals on POMC:EGFP expression in our transgenic fish as well as endogenous POMC expression in zebrafish, Tg (POMC: EGFP) reporter fish and wild-type zebrafish were treated with those chemicals for 4 days starting at 1 dpf (Table 1).…”

“…In contrast, little effort has been made to investigate the underlying mechanisms involved in the adverse influences of environmental EDCs on many other interference effects in endocrine systems other than the reproductive system (Hinson and Raven, 2006;Harvey et al, 2007). The adrenal is a relatively neglected organ in aquatic endocrine toxicology in spite of its importance in the function and overall responses of the adrenal gland to toxic chemicals (Harvey et al, 2007). Over the past decade, numerous studies focused on the estrogenic toxicity of EDCs and utilized the teleost vitellogenin (VTG) assay.…”

“…So far, there are no standard assessment assays for the effects of endocrine-disrupting chemicals on adrenal steroidogenesis and cortex development. Measurements of the relative adrenal organ weights and ACTH levels in plasma are normally utilized in the evaluation of adrenal-associated toxicities (Hinson and Raven, 2006;Harvey et al, 2007). An in vitro steroidogenesis assay using H295R human adenocarcinoma cells has also been suggested as a possible Tier I screening assay.…”

Effects of Pantothenic Acid on Testicular Function in Male Rats

“…Since synthesis of steroid hormones starts from cholesterol [1,7,10,15], the decrease in circulating testosterone in PaA-deficient animals probably results from a decrease in cholesterol synthesis induced by the PaA deficiency. This is also true for steroid hormone synthesis in the adrenal gland.…”