Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc)-regulated steroidogenesis as an organ-specific molecular and cellular target for endocrine disrupting chemicals in fish

Abstract

Biologically active steroids are synthesised de novo in specialised cells of several organs, including the adrenal gland, testis, ovary, brain, placenta and adipose tissue. Regardless of organ or tissue, the rate-limiting step in steroid hormone synthesis is the movement of cholesterol across the mitochondrial membrane (i.e. from the outer to the inner membrane) mediated by the steroidogenic acute regulatory (StAR) protein. Subsequent conversion of cholesterol to pregnenolone by cytochrome P450 side-chain cleavage (P450scc) represents the initiation of steroidogenesis. Chemically mediated disruption of StAR and P450scc expression may represent the first step in the sequence of related event cascades underlying xenoestrogen-induced toxicity and transmittable disturbances to the whole organism level. This may include, but is not limited to, alterations in sexual differentiation, growth, reproduction, development and metabolism. Despite the integral role of StAR and P450scc in acute steroidogenesis, and popular demand from regulatory agencies, bioassays for evaluating the effect of endocrine-disrupting chemicals have the potential to overlook chemicals that may modulate estrogenic responses through mechanisms that do not involve direct binding to estrogen receptors (ERs). In addition to their effect as direct ER agonists, the effects of endocrine disruptors may be evaluated and interpreted as interference with steroidogenesis and with the steroidal regulation of the normal development and function of juvenile, male and female individuals. Knowledge of these effects is scarce, indicating that relatively little is known about the mechanisms or mode-of-action of chemical alterations to steroidogenesis and their potential toxicity for wildlife species. In addition, analytical methods for the complete adaptation of these responses as biomarkers of response and effect are yet to be properly validated.

Oestrogen-induced androgen insufficiency results in a reduction of proliferation and differentiation of spermatogonia in the zebrafish testis

“…Since forskolin, an activator of the adenylate cyclase, also induced a much weaker response in tissue from E 2 -treated fish than from control fish, we speculate that oestrogens may target one or more components of the Ga S -adenylate cyclase -protein kinase A (PKA) pathways. Therefore, we conclude that oestrogenic treatment induced a state of androgen-insufficiency in zebrafish by disturbing the testicular steroidogenic system at different levels, as previously suggested for other teleost fish species (Sohn et al 1998, Loomis & Thomas 2000, Andersen et al 2006, Filby et al 2006, Chaves-Pozo et al 2007, Meier et al 2007, Arukwe 2008, Blum et al 2008, Jukosky et al 2008, Zhang et al 2008.…”

Effects of model aromatizable (17α-methyltestosterone) and non-aromatizable (5α-dihydrotestosterone) androgens on the adult mummichog (Fundulus heteroclitus) in a short-term reproductive endocrine bioassay

“…Future work with mummichog could examine a wider range of MT/ DHT concentrations to determine if a similar concentration-dependent negative feedback loop exists in this species. Disruption of StAR may represent the first event in a cascade associated with EDS-induced depressions of plasma hormones (Arukwe, 2008); however, the lack of response in StAR gene expression in the current study indicates other interactions with androgens are responsible for altering hormone levels.…”

The stress response of three-spined sticklebacks is modified in proportion to effluent exposure downstream of wastewater treatment works

“…Chemical impairment of cortisol secretion during stress is reportedly due to modulation of the activity of steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc; Aluru et al, 2005), which are involved with the first step in the synthesis of cortisol, the uptake and conversion of cholesterol to pregnenolone. It has also been suggested (Arukwe, 2008) that contaminants may affect the negative feedback control of steroid hormone synthesis. While these mechanisms are in part consistent with the effects observed in the present study, given the chemical complexity of WWTW effluents it may be the case that as yet unidentified mechanisms and causal factors are involved.…”