ToxSci Advance Access originally published online on June 28, 2006
Toxicological Sciences 2006 94(1):3-21; doi:10.1093/toxsci/kfl051
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The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals
INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus Boulevard (Pointe-Claire), Montréal, Québec, Canada H9R 1G6
Received March 7, 2006; accepted April 21, 2006
Various chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms. Increasingly, the enzymes involved in the steroid biosynthesis pathway are being recognized as important targets for the actions of various endocrine-disrupting chemicals. Interferences with steroid biosynthesis may result in impaired reproduction, alterations in (sexual) differentiation, growth, and development and the development of certain cancers. Steroid hormone synthesis is controlled by the activity of several highly substrate-selective cytochrome P450 enzymes and a number of steroid dehydrogenases and reductases. Particularly aromatase (CYP19), the enzyme that converts androgens to estrogens, has been the subject of studies into the mechanisms by which chemicals interfere with sex steroid hormone homeostasis and function, often related to (de)feminization and (de)masculinazation processes. Studies in vivo and in vitro have focussed on ovarian and testicular function, with less attention given to other steroidogenic organs, such as the adrenal cortex. This review aims to provide a comprehensive overview of the state of knowledge regarding the mechanisms by which chemicals interfere with the function of steroidogenic enzymes in various tissues and organisms. The endocrine toxicities and mechanisms of action related to steroidogenesis of a number of classes of drugs and environmental contaminants are discussed. In addition, several potential in vitro bioassays are reviewed for their usefulness as screening tools for the detection of chemicals that can interfere with steroidogenesis. 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. Considerably more detailed and systematic research in this area of (endocrine) toxicology is required for a better understanding of risks to humans and wildlife.
Key Words: aromatase; steroidogenesis; H295R cells; cytochrome P450; endocrine disrupters; pesticides.
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