Multiomics Point of Departure (moPOD) Modeling Supports an Adverse Outcome Pathway Network for Ionizing Radiation

While adverse biological effects of acute high-dose ionizing
radiation
have been extensively investigated, knowledge on chronic low-dose
effects is scarce. The aims of the present study were to identify
hazards of low-dose ionizing radiation to Daphnia magna using multiomics dose–response modeling and to demonstrate
the use of omics data to support an adverse outcome pathway (AOP)
network development for ionizing radiation. Neonatal D. magna were exposed to γ radiation for 8 days. Transcriptomic analysis
was performed after 4 and 8 days of exposure, whereas metabolomics
and confirmative bioassays to support the omics analyses were conducted
after 8 days of exposure. Benchmark doses (BMDs, 10% benchmark response)
as points of departure (PODs) were estimated for both dose-responsive
genes/metabolites and the enriched KEGG pathways. Relevant pathways
derived using the BMD modeling and additional functional end points
measured by the bioassays were overlaid with a previously published
AOP network. The results showed that several molecular pathways were
highly relevant to the known modes of action of γ radiation,
including oxidative stress, DNA damage, mitochondrial dysfunction,
protein degradation, and apoptosis. The functional assays showed increased
oxidative stress and decreased mitochondrial membrane potential and
ATP pool. Ranking of PODs at the pathway and functional levels showed
that oxidative damage related functions had relatively low PODs, followed
by DNA damage, energy metabolism, and apoptosis. These were supportive
of causal events in the proposed AOP network. This approach yielded
promising results and can potentially provide additional empirical
evidence to support further AOP development for ionizing radiation.