A Systems Toxicology Approach to Elucidate the Mechanisms
Involved in RDX Species-Specific Sensitivity
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Abstract
Interspecies uncertainty factors in ecological risk assessment
provide conservative estimates of risk where limited or no toxicity
data is available. We quantitatively examined the validity of interspecies
uncertainty factors by comparing the responses of zebrafish (<i>Danio rerio</i>) and fathead minnow (<i>Pimephales promelas</i>) to the energetic compound 1,3,5-trinitroperhydro-1,3,5-triazine
(RDX), a known neurotoxicant. Relative toxicity was measured through
transcriptional, morphological, and behavioral end points in zebrafish
and fathead minnow fry exposed for 96 h to RDX concentrations ranging
from 0.9 to 27.7 mg/L. Spinal deformities and lethality occurred at
1.8 and 3.5 mg/L RDX respectively for fathead minnow and at 13.8 and
27.7 mg/L for zebrafish, indicating that zebrafish have an 8-fold
greater tolerance for RDX than fathead minnow fry. The number and
magnitude of differentially expressed transcripts increased with increasing
RDX concentration for both species. Differentially expressed genes
were enriched in functions related to neurological disease, oxidative-stress,
acute-phase response, vitamin/mineral metabolism and skeletal/muscular
disorders. Decreased expression of collagen-coding transcripts were
associated with spinal deformity and likely involved in sensitivity
to RDX. Our work provides a mechanistic explanation for species-specific
sensitivity to RDX where zebrafish responded at lower concentrations
with greater numbers of functions related to RDX tolerance than fathead
minnow. While the 10-fold interspecies uncertainty factor does provide
a reasonable cross-species estimate of toxicity in the present study,
the observation that the responses between ZF and FHM are markedly
different does initiate a call for concern regarding establishment
of broad ecotoxicological conclusions based on model species such
as zebrafish