Towards less hazardous chemicals : identifying chemical bioactivity through fish behavioral profiles.


Because most chemicals in commerce lack empirical toxicology information, innovative approaches are needed to identify substances presenting elevated hazards and risks to public health and the environment. When larval fish models are employed with automated tracking technologies, behavioral studies can be used to perform rapid, diagnostic toxicity screens for large volumes of chemicals. Beyond utility in chemical safety screening applications, behaviors are integrated processes that are critical for organism survival and reproduction. This dissertation developed novel approaches to diagnostically examine chemicals for toxicity using larval fish models, and further extended these efforts beyond lab raised models to examine effects of neuroactive substances on wild fish populations. In Chapter two, methods used in the biomedical sciences to study therapeutic attributes of novel molecules were adapted for environmental screening applications. Using automated tracking software, a protocol was developed to quantify locomotor and photomotor responses (PMRs) of two common larval fish models, the zebrafish and fathead minnow. These developed methods were applied to study the behavioral effects of a common aquatic contaminant and neuro-stimulant, caffeine, which exerted photomotor and locomotor responses at environmentally relevant levels. In Chapter three, these methods were broadly applied to develop larval fish behavioral response profiles for a variety of different chemicals from diverse mode of action (MOA) categories. Both fish models demonstrated unique behavioral responses upon exposure to each chemical indicating that behavioral response may be informative of compound specific MOAs. Chapter four demonstrated that in the two most common larval fish models, refractory PMR and locomotor patterns appear informative of electrophilic properties associated with oxidative stress for SN2 chemicals. Property-based quantum mechanical modeling of electrophile reaction energies were predictive of experimental in vivo acute and sublethal toxicity, which provide important implications for identifying and designing less hazardous industrial chemicals. Because lab fish models cannot be expected to be representative of wild fish populations, Chapter five examined behavioral effects of two commonly prescribed psychiatric medications, oxazepam and sertraline, on perch collected from natural waters. Results from this study identified time related effects on fish boldness and neuroactive pharmaceutical related effects on fish activity levels.

Behavior. High throughput screening. Alternative toxicity testing. Chemical bioactivity. Comparative toxicology.