Crtain pesticides, environmental contaminants, (veterinary and human) drugs and compounds of natural origin can interfere with steroid biosynthesis and metabolism in humans and wildlife. The mechanisms of deregulation of steroidogenesis by chemicals and the toxicological consequences thereof are relatively unexplored fields of research, yet are currently of great interest given the concern regarding hormone-disrupting chemicals, the rise in hormone-dependent cancers and the increased incidence of reproductive problems in humans and wildlife.
My current research is focused on the synthesis and metabolism of estrogens and androgens by various cytochrome P450 and reductase enzymes that are present in steroidogenic tissues and hormone-dependent tumors. Enzymes such as CYP19 (aromatase), CYP17 and 5α-reductase, among others are of particular interest because their elevated expression is associated with an increased risk of some cancers.
My emphasisis on how chemicals disrupt the expression or catalytic activity of steroidogenic enzymes in vitro in various mammalian cell lines, and in vivo in transgenic mice. Induction by xenobiotics appears to be mediated by the cAMP-activated protein kinase A pathway in gonads and adrenocortical cells (Sanderson et al. 2004). However, in other target tissues other second messenger systems (PKC, Jak/Stat, glucocorticoids) are involved (Heneweer et al. 2004). This work will be expanded to study primary cells from human and wildlife tissues.
Various plant products are known to interfere with steroidogenesis and/or metabolism and to act as agonists or antagonists for estrogen and androgen receptors. However, for many of these compounds, the specific target enzymes or hormone receptors are unknown. As part of a long-term project funded by NSERC, the (steroidogenic) enzyme inhibiting or inducing properties of various naturally occurring polyphenolic compounds and synthetic analogues of these compounds will be examined and structure-activity relationships will be delineated.
Effects of chemicals on in vitro steroid synthesis are highly cell-type dependent and do not take into account biokinetics factors such as absorption, distribution and metabolism. Limited numbers of in vivo studies will be performed to confirm in vitro findings and to validate cell-based bioassays as useful and predictive models for effects in vivo.
J. Thomas Sanderson obtained his B.Sc. (Faculty of Chemistry and Pharmacochemistry, 1989) from the Free University of Amsterdam, The Netherlands, followed by a Ph.D. (Faculty of Pharmaceutical Sciences, 1994) from the University of British Columbia in Vancouver, Canada. After a postdoctoral research position at Michigan State University (National Food Safety and Toxicology Center, 1994-1997), he held an Assistant Professorship at Utrecht University, The Netherlands (Institute for Risk Assessment Sciences, 1997-2005) where he was tenured since 2003. Since 2005, Thomas Sanderson holds a position of Associate Professor at the INRS-Institute Armand-Frappier
His research interests concern the interactions of chemicals with the expression and function of enzymes involved in steroid biosynthesis, and their relation to the development of hormone-dependent cancers and endocrine disruption. Current research activities, funded by the Natural Sciences and Engineering Research Council of Canada (NSERC) aim to elucidate the mechanism by which a wide variety of chemicals, including environmental contaminants, drugs and compounds of natural origin interfere with androgen and estrogen biosynthesis in human and animal models.
// 26 avril 2018
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