Interactions of natural and synthetic compounds with steroidogenic enzymes and sex hormone receptor signalling

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There is increasing societal concern regarding chemicals that may disrupt endocrine processes, potentially resulting in reproductive problems, certain cancers and other toxicities related to (sexual) differentiation, growth and development. Various compounds have been identified as inhibitors of steroidogenesis, including pesticides, drugs and natural compounds. Most of these are in vitro studies, few in vivo studies exist. Aromatase (CYP19) and steroid 5alpha-reductase (SRD5A) are of particular interest as they are the key steroidogenic enzymes producing the most potent estrogens and androgens, 17ß-estradiol and DHT, respectively, and are involved in various endocrine pathologies. We hypothesize that natural or synthetic compounds with structures resembling the endogenous androgens (androstenedione, testosterone) act as inhibitors of CYP19 and SRD5A activity (which utilize androgens as natural substrates) and as antagonists of the androgen receptor (AR). The objectives of my research programme are to 1) identify the structural requirements of natural or synthetic chemicals enabling them to interfere with the catalytic activity or gene expression of the CYP19 and SRD5A, as well as with AR signalling; 2) elucidate mechanisms (signalling pathways involved) of enzyme inhibition/induction or AR ant(agonism) in vitro in cell-based assays; 3) evaluate the biological activity of these compounds in vivo in bioluminescent mouse models. Applying nanotechnology, compounds with potent and possibly beneficial effects in vitro, but poorly effective in vivo, will be encapsulated in nanoparticles with properties that will improve in vivo delivery and biological efficacy. This research programme will provide a better understanding of the mechanisms (signalling pathways) involved in CYP19, SRD5A and AR regulation. It will identify novel structures that may lead to the development of novel CYP19 and SRD5A inhibitors or AR antagonist which could be used to treat various diseases. It will evaluate or improve the effectiveness in vivo of compounds shown to be active in vitro providing important information on the conditions under which it is valid to extrapolate in vitro effects to an in vivo situation.