Abstract
Toxicometabolomics and biotransformation product (bioTP) elucidation were carried out in single zebrafish (ZF) embryos exposed to carbamazepine (CBZ). Exposures were conducted in 96-well plates containing six CBZ concentrations ranging from 0.5 μg/L to 50 mg/L (n = 12 embryos per dose). In the 50 mg/L dose group, 33% of embryos developed edema during the exposure (120 hpf), while hatching was significantly delayed in three of the lower-dose groups (0.46, 3.85, and 445 μg/L) compared to the control at 48 hpf. Toxicometabolomic analysis together with random forest modeling revealed a total of 80 significantly affected metabolites (22 identified via targeted lipidomics and 58 via nontarget analysis). The wide range of doses enabled the observation of both monotonic and nonmonotonic dose responses in the metabolome, which ultimately produced a unique and comprehensive biochemical picture that aligns with existing knowledge on the mode of action of CBZ. The combination of high dose exposures and apical endpoint assessment in single embryos also enabled hypothesis generation regarding the target organ for the morphologically altering insult. In addition, two CBZ bioTPs were identified without additional exposure experiments. Overall, this work showcases the potential of toxicometabolomics and bioTP determination in single ZF embryos for rapid and comprehensive chemical hazard assessment.
Highlights
The pharmaceutical carbamazepine (CBZ) was first marketed in 1962 and is primarily used to treat neurological disorders such as epilepsy, schizophrenia, and bipolar disorder
Further information on the MoA of CBZ is needed, at environmentally relevant concentrations. To address this knowledge gap, we report here on metabolomic perturbations of single zebrafish (ZF) embryos exposed to six different concentrations of CBZ, spanning both environmentally relevant and apical endpoint-inducing con
The determination of biotransformation products and toxicometabolomics was carried out in single ZF embryos exposed to CBZ at doses ranging from environmentally relevant to morphologically altering
Summary
The pharmaceutical carbamazepine (CBZ) was first marketed in 1962 and is primarily used to treat neurological disorders such as epilepsy, schizophrenia, and bipolar disorder. High LC50s for CBZ (i.e., 1.5 to ≥245 mg/L) determined across several species have led some researchers to conclude that CBZ poses minimal risk to the aquatic environment.[6,7] its ubiquitous occurrence and sublethal effects at low doses have led to renewed concerns that CBZ exposure in fish could lead to adverse effects on the population level.[6,7] For example, chronic exposure to 0.5 and 10 μg/L CBZ decreased reproductive output in adult ZF, while similar levels (0.01−100 μg/L) perturbed behavior and reproduction in both ZF embryos and Daphnia magna.[8,9] These data point to the need for further information on biochemical perturbations underlying the MoA of CBZ, at environmentally relevant concentrations. Further information on the MoA of CBZ is needed, at environmentally relevant concentrations
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