Testing the “Read-across hypothesis” by investigating the effects of ibuprofen on fish.

Human
pharmaceuticals present in the environment have the potential to cause adverse
effects on non-target organisms. The “read-across hypothesis” stipulates that
pharmaceuticals will exhibit similar biological effects across species (e.g. human
and fish) if the molecular target has been conserved and the effective drug
concentrations are reached (Cmax). We tested this hypothesis by evaluating if ibuprofen,
a non-selective inhibitor of prostaglandins and the cyclooxygenase (COX) enzyme,
can mimic its primary effect in humans, on fish, at comparable plasma
concentrations. The endpoints, “prostaglandin E metabolite”
(PGEM) levels and the mRNA expression of COX (ptgs) gene, were measured in the gills of control and exposed fathead
minnows (Pimephales promelas), using enzyme-immunoassay and quantitative
real-time PCR (qPCR). Fish were exposed, for 24-72 h, to measured water
concentrations of 9 (n= 12), 370 (n= 40) and 470 µg ibuprofen/L (n= 12). Water and blood plasma
concentrations were determined using LC-MS/MS. Results showed that PGEM levels in
fish exposed to 370 and 470 µg ibuprofen/L were significantly decreased
compared to control fish, when mean plasma ibuprofen concentrations were 1.8 to
5.6-fold below the Cmax. The plasma ibuprofen concentrations and PGEM levels varied
greatly between individuals. In fish exposed to 9 µg
ibuprofen/L, when the mean plasma ibuprofen concentration was 224-fold below Cmax, no change in PGEM levels was observed. These data
provide evidence for the read-across hypothesis, but suggest establishing a
direct dose-response between internal plasma and PGEM is difficult, and would
require significantly larger numbers of fish to overcome the inter-individual
variation.