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A n n u a l C o n g r e s s o n
Medicinal Chemistry,
Pharmacology and toxicology
Journal of Organic & Inorganic Chemistry
ISSN: 2472-1123
J u l y 3 0 - 3 1 , 2 0 1 8
Am s t e r d a m , N e t h e r l a n d s
Medchem & Toxicology 2018
Page 19
H
umans are exposed to thousands of environmental chemicals with poorly understood toxicological properties. In vivo toxicity
testing is time-consuming, costly and ethically questionable because of the large numbers of laboratory animal required. Although
current in vitro models have considerably improved our understanding of chemical mechanisms of toxicity, these systems mostly
determine single endpoints in single cell types, which poorly reflect the intact organism. The goal of my laboratory is to better reproduce
in vivo interactions by developing co-culture models that incorporate physiologically relevant intercellular communications. Our focus
is on steroidogenesis, an important but poorly studied target for endocrine disrupting chemicals. In humans, sex steroid hormones
are essential for healthy reproduction and pregnancy, but are also involved in diseases such as hormone-dependent breast cancer.
Aromatase (
CYP19
) converts androgens to estrogens and, unlike in non-primates (e.g. rodents), where it is expressedonly ingonads and
brain, human aromatase is expressed in numerous tissues includingmammary gland (where it is overexpressed in hormone-dependent
breast cancer) and placenta using tissue-specific promoters. As rodent models are inadequate, we developed several physiologically
relevant human in vitro models to evaluate the effects of neonicotinoid insecticides, a poorly studied class of emerging pesticides, on
sex hormone biosynthesis. Cellular co-culture models of the feto-placental unit and human breast tumor microenvironment were used
to determine effects of neonicotinoids on steroid production and promoter-specific regulation of
CYP19
. Neonicotinoids increased
CYP19
gene expression promoter-specifically in our human co-culture models. In the feto-placental co-culture model, neonicotinoids
increasedestradiol andestrone, but strongly inhibitedestriol production. Inour breast cancermodel, neonicotinoids inducedapromoter-
switch in
CYP19
expression, with silencing of normal mammary promoter 1.4 and activation of pro-cancerous promoters PII, 1.3 and
1.7, resulting in aromatase overexpression, similar to that observed clinically in patients. These are the first studies to document in vitro,
disruptive effects of neonicotinoids on human steroidogenesis in physiologically relevant multi-cell systems.
Biography
Thomas Sanderson has obtained his PhD from the University of British Columbia, Vancouver, Canada and did Postdoctoral studies at Michigan State University, USA. He is an
Associate Professor at the INRS-Institut Armand-Frappier, Laval (Québec), Canada and has publishedmore than 70 papers in reputed journals. His toxicology laboratory is focused
on studying interactions of chemicals with steroidogenic enzymes in humans and wildlife and is currently funded by the Natural Sciences and Engineering Council (NSERC) of
Canada and the Alternatives Research and Development Foundation (USA). He is Editorial Board Member of
Toxicological Sciences and Peer J.
thomas.sanderson@iaf.inrs.caDevelopment and application of
physiologically relevant in vitro models
of human steroidogenesis in toxicology:
the endocrine disrupting potential of
neonicotinoid pesticides in humans
J Thomas Sanderson, Elyse Caron-Beaudoin,
Rachel Viau
INRS - Institut Armand-Frappier, Laval, QC, Canada
J Thomas Sanderson et al., J Org Inorg Chem 2018, Volume 4
DOI: 10.21767/2472-1123-C3-007