scispace - formally typeset
Search or ask a question
Topic

Steroid biosynthesis

About: Steroid biosynthesis is a research topic. Over the lifetime, 1721 publications have been published within this topic receiving 58977 citations.


Papers
More filters
Journal ArticleDOI
TL;DR: Data support the hypothesis that regulation of the biosynthetic pathway by PTTH occurs at the step immediately following the formation of 7-dehydrocholesterol, and suggest that RH5849 is a specific ecdysteroid substrate/product mimic in this reaction.

100 citations

Journal ArticleDOI
TL;DR: The need to consider compensation/adaptation and recovery when developing and interpreting short-term bioassays or biomarkers or when trying to predict the effects of chemical exposures based on mode of action is highlighted.
Abstract: In a recent report, Toxicity Testing in the 21st Century, the National Research Council Committee on Toxicity Testing and Assessment of Environmental Agents (2007) proposed that improved scientific understanding of toxicity pathways was central to the expanded use of predictive, pathway-based bioassays in risk assessment. Toxicity pathways can be viewed as the series of biological changes, spanning across multiple levels of biological organization, that lead from some molecular initiating event (perturbation) to an adverse outcome. A major challenge associated with dose–response modeling and extrapolation from laboratory to real-world conditions has been to understand under what conditions an organism may compensate for, or recover from, a given perturbation and under what conditions the perturbation will lead to an adverse outcome (Andersen et al. 2005). Thus, in developing useful predictive models of toxicity, we need to understand not only the direct effects of a chemical and how they translate into adverse effect, but also the potential mechanisms for compensation and recovery and how they may intersect with other biological pathways and processes. Previous studies with the fathead minnow (Pimephales promelas) have suggested potential compensatory responses to the direct effects of chemicals whose primary mode of action was inhibition of one or more enzymes involved in steroid biosynthesis. For example, the chemical fadrozole (FAD) inhibits aromatase, the enzyme that catalyzes the rate-limiting conversion of testosterone (T) to 17β-estradiol (E2) (Miller 1988). Villeneuve et al. (2006) observed significant, concentration-dependent up-regulation of transcripts coding for the ovarian isoform of aromatase (CYP19A) in female fathead minnows exposed to FAD for 7 days. The increased CYP19A gene expression was associated with an inverted U-shaped concentration–response profile for ovary aromatase activity. Although that study did not examine effects on plasma E2 concentrations, it was noted that the responses would favor increased synthesis of E2 to potentially offset the effect of FAD on aromatase. In another study, Ankley et al. (2007) exposed fathead minnows to the steroidogenesis inhibitor ketoconazole for 21 days. Testosterone production by testis or ovary tissue collected from ketoconazole-exposed fish was significantly reduced compared with control fish. However, there was significant up-regulation of genes coding for cytochrome P450 cholesterol side-chain cleavage (P450scc, CYP11A) and cytochrome P450 c17αhydroxylase, 17,20-lyase, and concentration-dependent proliferation of steroid-producing interstitial cells in the testis of exposed males. As a result, plasma T and E2 concentrations in exposed fish were similar to those of controls, despite the decreased rate of steroid production per unit mass of tissue, suggesting a compensatory response to ketoconazole (Ankley et al. 2007). Both the FAD and ketocona zole studies suggest that fish have the capacity to adapt to and potentially recover from the direct effects of steroidogenesis inhibitors. Aromatase is a key steroidogenic enzyme shown to be subject to inhibition, at least in vitro, by a variety of chemicals present in the environment, including certain pesticides, organochlorines, and organotins (Sanderson 2006). The aim of this study was to develop a more comprehensive understanding of molecular and biochemical responses of fathead minnows to aromatase inhibition, including direct effects, compensation, and/or recovery. We examined a time course of selected gene expression and biochemical responses over the course of an 8-day waterborne exposure to two concentrations of FAD, followed by an 8-day recovery period in control water. The experiment was designed to test several hypotheses: FAD would elicit direct effects consistent with its presumptive mode of action Over time, there would be compensatory molecular responses in females, consistent with an attempt to increase E2 synthesis Compensatory effects at the molecular level would correspond to changes in circulating E2 and/or rates of ex vivo E2 production Effects would be time and concentration dependent There would be recovery after cessation of FAD exposure. Although FAD is a drug with no direct environmental relevance, its specificity makes it a useful model chemical for studying this mode of action. Results of this study provide an improved understanding of the dynamics of biological response to this chemical, and its removal. This knowledge will contribute to formulation of a robust, biologically based toxicity pathway model for the effects of estradiol synthesis inhibitors.

99 citations

Journal ArticleDOI
TL;DR: It is shown that in mice with a unique hypomorphic androgen mutation, which disrupts the feedback loop governing T synthesis, that genes involved in cholesterol biosynthesis/uptake and steroid biosynthesis are up-regulated and accumulation of active sterol response element-binding protein 2 is not required for up-regulation of genes involved with cholesterol bios synthesis and uptake in Leydig cells.
Abstract: The male sex steroid, testosterone (T), is synthesized from cholesterol in the testicular Leydig cell under control of the pituitary gonadotropin LH. Unlike most cells that use cholesterol primarily for membrane synthesis, steroidogenic cells have additional requirements for cholesterol, because it is the essential precursor for all steroid hormones. Little is known about how Leydig cells satisfy their specialized cholesterol requirements for steroid synthesis. We show that in mice with a unique hypomorphic androgen mutation, which disrupts the feedback loop governing T synthesis, that genes involved in cholesterol biosynthesis/uptake and steroid biosynthesis are up-regulated. We identify LH as the central regulatory molecule that controls both steroidogenesis and Leydig cell cholesterol homeostasis in vivo. In addition to the primary defect caused by high levels of LH, absence of T signaling exacerbates the lipid homeostasis defect in Leydig cells by eliminating a short feedback loop. We show that T signaling can affect the synthesis of steroids and modulates the expression of genes involved in de novo cholesterol synthesis. Surprisingly, accumulation of active sterol response element-binding protein 2 is not required for up-regulation of genes involved in cholesterol biosynthesis and uptake in Leydig cells.

99 citations

Journal ArticleDOI
TL;DR: Cadmium‐induced alterations in the cellular morphology and in the production of progesterone by the cells was determined after exposure to concentrations of 8, 16, 32 and 64 μM CdCl2 for 2, 4, 8, 24 and 48 h.
Abstract: Cadmium (Cd) is able to decrease preovulatory luteinizing hormone (LH) levels in blood and inhibit ovulation in rats. In this study the direct effects of Cd on steroidogenesis in granulosa cells were investigated. The cells obtained from ovarian follicular aspirates of 41 women undergoing in vitro fertilization (IVF) were cultured. Cadmium-induced alterations in the cellular morphology and in the production of progesterone by the cells was determined after exposure to concentrations of 8, 16, 32 and 64 microM CdCl2 for 2, 4, 8, 24 and 48 h. Progesterone secretion by granulosa cells could be stimulated with increasing concentrations of follicle-stimulating hormone (FSH). Combined effects of Cd and FSH were also studied. Cadmium diminished progesterone production in unstimulated and FSH-supported cells depending on its concentration and the exposure time. Follicle-stimulating hormone (100 ng ml[-1]) protected against Cd-induced suppression of progesterone production. Cadmium interfered with cell-cell junctions and the adherence of cells. No protective effect of FSH on Cd-induced alteration in cell morphology could be observed. Retraction of cytoplasmic extensions occurred at a lower dose and within a shorter exposure than a decrease in progesterone production. In conclusion, Cd exerted a direct effect on both granulosa cell morphology and on steroid biosynthesis. The lowest Cd concentration (16 microM) that was able to reduce progesterone production was about 3.5 times higher than levels reported in the ovary of a female smoker. The presented data can help to define environmental, occupational and life-style (smoking) risk factors in gonadal function during the preconception period of the female reproductive lifespan.

99 citations

Journal ArticleDOI
TL;DR: Evidence is presented to show that in the case of CYP17 the attack of Fe(III)-O-O(-) on the target carbon is promoted by cytochrome b(5), which acts as a conformational regulator of CYp17 that provides a safety mechanism which ensures that during corticoid biosynthesis, which involves 17α-hydroxylation by CYP19, androgen formation is avoided.

98 citations


Network Information
Related Topics (5)
Amino acid
124.9K papers, 4M citations
78% related
Gene expression
113.3K papers, 5.5M citations
78% related
Protein kinase A
68.4K papers, 3.9M citations
78% related
Receptor
159.3K papers, 8.2M citations
78% related
Insulin
124.2K papers, 5.1M citations
76% related
Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202315
202221
2021117
2020109
201975
201860