Steroid biosynthesis

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

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

Abstract: Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.

Molecular Markers of Endocrine Disruption in Aquatic Organisms

Abstract: A wide range of organic contaminant compounds prevalent in the aquatic environment has been shown to exhibit hormone-disrupting activity. The actual potency of such compounds are low compared with endogenous hormones, such as 17beta-estradiol, but may still produce detrimental biological effects. Induced hormone levels are routinely measured using commercial testing kits, though these fail to relate to actual effects. Field and laboratory studies on the biological effects of environmental estrogens have, in the past, largely relied on assays of vitellogenin (vtg) induction in male fish, reduced growth in testes formation, and intersex incidence. Here, we critically review the current and potential application of molecular techniques in assessing the adverse biological reproductive effects of endocrine-disrupting chemicals in aquatic organisms. The role of fish (estrogen, androgen, and progestogen) hormone receptors and invertebrate (ecdysone) hormone receptor, egg production (vtg and chorion) proteins, steroid biosynthesis enzymes (aromatase, sulfotransferase, and hydroxysteroid dehydrogenase), DNA damage, apoptosis, and their potential development as biomarkers are discussed in turn. In each case, the sequences characterized are presented and homologies across species are highlighted. Molecular methods of gauging vtg and zona radiata (ZR) expression and protein concentrations have included immunoassay and reverse transcription polymerase chain reaction (RT-PCR). Suggestions for the isolation for key gene expression products (aromatase, ZR, and vtg, for instance), from a wider range of fish species using degenerate primers, are given. Endocrine disruption in invertebrates has received less attention compared with fish, partly because the knowledge regarding invertebrate endocrinology is limited. Here we review and suggest alternate isolation strategies for key players in the imposex induction process: vitellin (Vn), aromatase, and Ala-Pro-Gly-Trp (APGW) amide neurohormone. Current molecular-level techniques rely on ligand-binding assays, enzyme-linked immunosorbent assay (ELISA), and, more recently, gene expression. In the future, more reliance will be placed on the development of gene expression assays using reporter systems combined with cross-species PCR-based or polyclonal antibody-based assays. We discuss the use of recombinant receptors as a means of primary screening of environmental samples for estrogenicity and antiestrogenicity, which avoids species and seasonal variation in receptor response to ligand binding, a recognized problem of earlier bioassays. Most exciting is the potential that microarray and proteomics approaches have to offer. Such techniques are now used routinely in medical research to identify specific genes and proteins affected by treatment with endocrine disruptors, including estradiol. The technique has yet to be used to screen aquatic organisms, but it has the potential to implicate previously unsuspected estradiol-sensitive genes that may later become molecular markers of endocrine disruption.

Zebrafish sex determination and differentiation: involvement of FTZ-F1 genes.

Abstract: Sex determination is the process deciding the sex of a developing embryo. This is usually determined genetically; however it is a delicate process, which in many cases can be influenced by environmental factors. The mechanisms controlling zebrafish sex determination and differentiation are not known. To date no sex linked genes have been identified in zebrafish and no sex chromosomes have been identified. However, a number of genes, as presented here, have been linked to the process of sex determination or differentiation in zebrafish. The zebrafish FTZ-F1 genes are of central interest as they are involved in regulating interrenal development and thereby steroid biosynthesis, as well as that they show expression patterns congruent with reproductive tissue differentiation and function. Zebrafish can be sex reversed by exposure to estrogens, suggesting that the estrogen levels are crucial during sex differentiation. The Cyp19 gene product aromatase converts testosterone into 17 beta-estradiol, and when inhibited leads to male to female sex reversal. FTZ-F1 genes are strongly linked to steroid biosynthesis and the regulatory region of Cyp19 contains binding sites for FTZ-F1 genes, further linking FTZ-F1 to this process. The role of FTZ-F1 and other candidates for zebrafish sex determination and differentiation is in focus of this review.

Regulation of Endothelial Function by Mitochondrial Reactive Oxygen Species

Abstract: Mitochondria are well known for their central roles in ATP production, calcium homeostasis, and heme and steroid biosynthesis. However, mitochondrial reactive oxygen species (ROS), including superoxide and hydrogen peroxide, once thought to be toxic byproducts of mitochondrial physiologic activities, have recently been recognized as important cell-signaling molecules in the vascular endothelium, where their production, conversion, and destruction are highly regulated. Mitochondrial reactive oxygen species appear to regulate important vascular homeostatic functions under basal conditions in a variety of vascular beds, where, in particular, they contribute to endothelium-dependent vasodilation. On exposure to cardiovascular risk factors, endothelial mitochondria produce excessive ROS in concert with other cellular ROS sources. Mitochondrial ROS, in this setting, act as important signaling molecules activating prothrombotic and proinflammatory pathways in the vascular endothelium, a process that initially manifests itself as endothelial dysfunction and, if persistent, may lead to the development of atherosclerotic plaques. This review concentrates on emerging appreciation of the importance of mitochondrial ROS as cell-signaling molecules in the vascular endothelium under both physiologic and pathophysiologic conditions. Future potential avenues of research in this field also are discussed.