The effect of environmental factors in cellular processes has been an area of
interest for decades. Within this research field, emerging research niches appear
concominantly with advances in molecular biology and genetics. One such field is the
one of molecular toxicology, which investigates the molecular and cellular events that
certain chemicals trigger. Chemicals that present genotoxic properties are of particular
interest based on the potential contribution to the aetiology of cancer that the
discoveries of their effects might provide. A group of chemicals that belong to this
category are heterocyclic amines, organic compounds that are formed during the
cooking of red meat from the pyrolysis of aminoacids. Research into heterocyclic
amines has created a well established description for their ability to create DNA
adducts that lead to mutations. Recent reports from our laboratory however, indicated
that certain heterocyclic amines, and in particular 2-amino-1-methyl-6-phenylimidazo
[4,5-b] pyridine (PhIP), present with molecular effects that are non genotoxic but
nevertheless carcinogenic and are very similar to those induce by the natural hormone
estradiol in breast cancer cells. Based on these findings this thesis set out to
investigate whether these non-genotoxic effects of PhIP also extend to epigenetic
mechanisms of gene expression control, and more specifically microRNA expression
regulation. MicroRNAs are a class of small non-coding RNA molecules that posttrasncriptionally
regulate gene expression and are involved in an array of process
including carcinogenesis. Our results showed that PhIP, as well as estradiol, drive
differential regulation of microRNAs and that these effects are very similar amongst
the two compounds. This deregulation of microRNAs could be an attributing factor to
the cancer promoting characteristics of both estradiol and PhIP and they extend the
estrogenic character of this heterocyclic amine to the area of epigenetic regulation,
and microRNAs in particular.