In rats exposed to 100 μg/kg TCDD in vivo for 7 days, testicular testosterone secretion ex vivo was decreased by 30–75% after stimulation with human choriogonadotropin (hCG), relative to testes from control rats (Kleeman et al., 1990).
3-MeSO2-DDE was shown to be a relatively potent inhibitor of CYP11B1 in Y-1 mouse adrenocortical tumor cells (Johansson et al., 1998a; Lund and Lund, 1995). T, Morohashi
Similarly, a study using an immortal testis cell line derived from the green sea turtle (Chelonia mydas) showed that p,p′-DDE did not reduce aromatase activity unless exposures were in the cytotoxic range (Keller and McClellan-Green, 2004).
1. They have been reported to have more or less potent antiandrogenic effects (Gray et al., 1994, 1999; Kelce et al., 1994, 1997; Ostby et al., 1999). MC
Azole fungicides (compounds containing an imidazole, triazole, or pyrimidine moiety) and azole antifungal drugs block the biosynthesis of ergosterol in yeasts and fungi by inhibiting the cytochrome P450 enzyme 14α-lanosterol demethylase (CYP51). PW
The same study found a delay in vaginal opening at 50 mg/kg atrazine. Q
Laryngeal size in males was reduced at atrazine concentrations above 1 ppb (5nM), as were testosterone concentrations at 25 ppb.
Direct or indirect effects on steroidogenesis do not appear to play a role in the endocrine disruptive effects caused by DE-71. , 1998 ) but is not or poorly expressed in nonsteroidogenic tissues. However, the researchers point out that several variables such as seminal vesicle weight are also dependent on estrogens, so a possible involvement of prochloraz-mediated CYP19 inhibition (possibly locally in the prostate or seminal vesicle) could not be ruled out.
Each zone is responsible for the synthesis of a specific set of steroid hormones, the mineralocorticoids, glucocorticoids, and weak androgens, respectively (Miller and Tyrell, 1995).
The 17,20-lyase activity of CYP17 is low in the adult adrenal cortex and is exclusive to the zona reticularis, where it converts the two 17α-hydroxylated steroids to the weak androgens dehydroepiandrosterone (DHEA) and androstenedione, respectively. PF
Steroid synthesis inhibitors, including cyanoketone and aminoglutethimide (Snyder and Schuetz, 1973; Mulner and Ozon, 1981) have been used to investigate requirements for steroid synthesis in amphibian oocytes.
Van Der Kraak
Increasingly, key enzymes involved in steroid hormone synthesis and metabolism are being considered as important targets for endocrine-disrupting chemicals. Fujii-Kuriyama
Various chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms.
Interestingly, the female sex hormone, progesterone, is an early intermediate in the pathway. Oie
2004, 2005b; Hilscherova et al., 2004; Johansson et al., 2002; Letcher et al., 2005; Li et al., 2004; Ohno et al., 2002; Sanderson et al., 2000, 2001a,b, 2002, 2004; Zhang et al., 2005). It is relatively persistent to abiotic and biotic breakdowns (Khan and Foster, 1976; Solomon et al., 1996). C
In cultured human luteinized granulosa cells (hLGCs), TCDD has been shown to cause a concentration-dependent decrease in estradiol production in the 0.1–10nM range (Enan et al., 1996; Heimler et al., 1998).
It is not clear whether aromatase induction occurs in vivo or in which target tissues it would occur.
Furthermore, addition of exogenous DHEA abolished the effect on estradiol production, supporting a lack of role for aromatase in reduced estradiol production.
In many cases, perturbations of certain endocrine endpoints have been observed, but their consequences are unknown. JL
De novo synthesis of all steroid hormones starts with the conversion of cholesterol to pregnenolone by CYP11A (cholesterol side-chain cleavage) (Parker and Schimmer, 1995).
TCDD and other persistent halogenated Ah receptor agonists are clearly capable of causing endocrine disruption and are known reproductive and developmental toxicants. Expression of the cyp19a gene is under control of SF-1 which in turn is activated by the cAMP-mediated PKC pathway, opening up the possibility of cyp19a as a target for induction by atrazine. LE
They consist of several specific cytochrome P450 enzymes (CYPs), hydroxysteroid dehydrogenases (HSDs), and steroid reductases (Miller, 1988).
A, various specialized tissues can use cholesterol as the building block for the synthesis of steroid hormones, oxysterols, or bile acids.
In a recent study (Sanderson et al., 2002), vinclozolin was identified as an inducer of aromatase activity and mRNA expression in H295R human adrenocortical cells. X
Up- and/or downregulation of enzyme expression can be determined using techniques such as northern blotting or RT-PCR to determine levels of mRNA expression. Murphy
TCDD decreased CYP17 protein levels by over 50%, without affecting cytochrome P450 reductase levels (Moran et al., 2003).
The process involves conversion of cholesterol (a cholestane, 27 carbons) to a pregnane (21 carbons), then to an androstane (19 carbons), and finally, to an estrane (18 carbons) backbone. The endocrine toxicities and mechanisms of action related to steroidogenesis of a number of classes of drugs and environmental contaminants are discussed. Pregnenolone and progesterone form the precursors for all other steroid hormones. JM
Underlying mechanisms of regulation of aromatase expression in the various tissues of amphibians, reptiles and birds are thus far not well understood, but appear to differ considerably from mammals.
Inhibition potencies (IC50 values) for bifoconazole, clotrimazole, ketoconazole, miconazole, econazole, isoconazole, and tioconazole ranged from 0.6 to 2μM for 17,20-lyase activity and from 1 to 4μM for 17α-hydroxylase activity.
Androgen biosynthesis pathways Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. MD
Organotins have further been reported to inhibit cytochrome P450 (CYP) activities such as CYP1A1 and aromatase in fish. CYP11B1, which is expressed in the zonae fasciculata and reticularis (Erdmann et al., 1995; Ogishima et al., 1992) has strictly 11β-hydroxylase activity, whereas CYP11B2, which is expressed only in the zona glomerulosa (Ogishima et al., 1992; Pascoe et al., 1995), has additional 18-hydroxylase/aldosterone synthetase activity, explaining the zone selectivity of adrenocortical steroid biosynthesis.
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Several of these antifungals compounds also inhibited aromatase activity in rainbow trout ovarian microsomes with IC50 values for clotrimazole, imazalil, prochloraz, and ketoconazole of 0.5, 5, 5, and 50μM, respectively (Monod et al., 1993). van den Berg
Analysis of the currently scattered state of knowledge indicates that still relatively little is known about the underlying mechanisms of interference of chemicals with steroidogenesis and their potential toxicity in steroidogenic tissues, neither in humans nor in wildlife. Consistent with the competitive nature of the triazole fungicides, the clinically used aromatase inhibitor letrozole, notwithstanding its far greater potency, was also found be a competitive inhibitor of microsomal aromatase (Ki = 1.2nM) in guinea pig brain (Choate and Resko, 1996). EA
Lund and coworkers observed a high incidence of bilateral adrenocortical hyperplasia in the declining Baltic gray seal population associated with elevated 3-MeSO2-DDE contamination (Lund, 1994).
Van Den Berg
In amphibians and reptiles, ambient temperature strongly influences aromatase expression during a critical thermosensitive sex-determining period (Crews et al., 2001; Kuntz et al., 2004). SK
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