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

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BACKGROUND: Society is increasing concerned that chemicals in their environment may disrupt endocrine processes, potentially resulting in reproductive problems, certain cancers and other toxicities related to sexual differentiation, growth and development in humans and wildlife. My NSERC programme aims to identify 'emerging' pesticides, medications and natural compounds that interfere with steroid synthesis. Aromatase (CYP19) and steroid 5-alpha-reductase (SRD5A) are of particular interest as they are key to producing the most potent estrogens and androgens, 17-estradiol and dihydrotestosterone, and are involved in various endocrine pathologies. In humans, aromatase is expressed in numerous tissues under the control of at least 10 alternate promoters; this unlike non-primates where aromatase is expressed in gonads and brain only. Thus, the promoter-specific disruption of aromatase by environmental chemicals can have widely differing effects in humans that would be missed in laboratory animals. In wildlife, steroidogenesis is difficult to study because experimental animals are rarely available. However, we are developing innovative cell-based systems designed to mimic in vitro, a physiological environment, that is relevant for humans and wildlife in vivo. THEMES: My NSERC programme has 3 main themes: (1) identify the structural requirements of natural or synthetic chemicals that enable them to interfere with the function of steroidogenic enzymes; (2) elucidate cellular mechanisms involved in inhibition/induction of steroidogenesis and determine effects on estrogen and androgen receptor-mediated signalling in cell-based bioassays; (3) develop physiologically relevant cell-based models to study chemical endocrine disruption in humans and wildlife, focusing on 2-D and 3-D co-culture systems. SIGNIFICANCE: My NSERC programme is expected to have several impacts. Theme 1 will focus on emerging contaminants to which humans and wildlife are increasingly exposed and will identify those of concern as endocrine disrupters and in need of further study. A mechanism-based structure-activity analysis will help identify novel endocrine disrupters to be prioritized for testing based on molecular structure. Theme 2 will help us better understand how chemicals alter cell signalling pathways to disrupt the gene expression of steroidogenic enzymes. The interaction of emerging pesticides and natural compounds with the tissue-specific regulation of aromatase in humans will provide fundamental knowledge on sex-differences in how our endocrine system reacts to chemical exposures in our environment. Theme 3 will provide physiologically and toxicologically relevant test systems for the mechanistic study of (novel) endocrine disrupting chemicals and which will refine, reduce or may replace the need for animal experiments.