Chronic exposure to diclofenac induces delayed mandibular defects in medaka (Oryzias latipes) in a sex-dependent manner

Abstract Diclofenac is widely distributed in freshwater environments. To support a robust aquatic risk assessment, medaka ( Oryzias latipes ) were exposed to diclofenac at sublethal concentrations of 0.608, 2.15, 7.29, 26.5, and 94.8 μg/L (as mean measured concentrations) from fertilized eggs to 90-day posthatch. Except for the induction of mandibular defects, no deleterious effects were observed on hatching success and time to hatching at the embryonic stage, or on posthatch mortality, growth in hatched larvae and juveniles, and no abnormal behavior was observed. After 40-day posthatch, mandibular defects in the fish were observed at a concentration of 7.29 μg/L and above. Cumulatively, a morphological examination showed that 4% of the fish in the 7.29 μg/L treatment, 20% in the 26.5 μg/L treatment, and 38% in the 94.8 μg/L treatment exhibited mandibular defects, and the sex ratio of fish with mandibular defects was skewed toward males. These results suggest that diclofenac affects bone remodeling in the lower jaw of medaka after puberty in a sex-dependent manner. The lowest observed-effect concentration and no observed-effect concentration of diclofenac for mandibular dysmorphism through the partial life cycle exposure of the medaka were 26.5 and 7.29 μg/L, respectively.