Acetaminophen-induced developmental neurobehavioral and sensory organ toxicity in zebrafish

Acetaminophen (APAP) also known as paracetamol, is the only antipyretic and analgesic agent that can be administered to pregnant women. In addition to hepatotoxicity in cases of an overdose, the developmental neurotoxicity of APAP has been reported in model organisms. In this study, developing zebrafish were used to assess the neurotoxic effects of waterborne APAP exposure (0.039-2.5 mM). At 120 hpf, the spontaneous swimming distance was significantly reduced at all tested APAP concentrations under alternating light-dark conditions. Touch-evoked escape velocity, which assesses the motor function, was not significantly affected at any concentration and it increased at moderate APAP doses. The optokinetic response was only reduced at 2.5 mM APAP concentrations, suggesting that the decrease in spontaneous swimming at low APAP doses is unlikely to be due to motor or visual impairments. Vibration-evoked responses, indicative of the sensory function, were slightly but significantly diminished at 0.625 and 2.5 mM APAP concentrations. At 72 h post-fertilization (hpf), acridine orange and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining showed that exposure to 2.5 mM APAP resulted in regulated cell death in the cerebellum, retina, and dorsal trunk. Some APAP-induced cell death in the dorsal trunk was confirmed to be of neuronal origin using Tg(eno2:Cerulean) transgenic zebrafish. N-acetylcysteine, a well-known antioxidant and antidote for APAP toxicosis in humans, partially attenuated APAP-induced cell death. These results suggest that APAP induces developmental neurobehavioral and sensory organ toxicity in the absence of detectable regulated cell death under the present experimental conditions.