The spectrum of circulating RNA: A window into systems toxicology

Adverse effects caused by therapeutic drugs are a serious and
costly health concern. Despite the body’s systemic responses to
therapeutics, the liver is often the focus of damage and is usually
the focus of studies of toxic effects due to its active roles in
the metabolism of xenobiotics. It is extremely difficult, however,
to assess systemic responses with currently available methods.
Comprehensive cataloging of cell-free circulating RNAs using
next-generation sequencing technology may open a window to
assess drug-associated adverse effects at the systems level. To
explore this potential, we conducted an RNA profiling study using
the well-characterized acetaminophen overdose mouse model on
liver and plasma with microarray and next-generation sequencing
platforms, respectively. After drug treatment, the levels of a number
of transcripts, both endogenous and exogenous RNAs, showed
significant changes in plasma, reflecting not only the classical
liver injury induced by acetaminophen overdose but also damage
in tissues other than the liver. The changes in exogenous RNAs
also reflect alteration on dieting behavior after acetaminophen
overdose. Besides reporting an extensive list of circulating RNAbased
biomarker candidates, this study illustrates the possibility
of using circulating RNAs to assess global effects of therapeutics.
This could also lead to a new approach for a more comprehensive
assessment of the efficacy and safety of therapeutics.