Fish are widely used for monitoring aquatic ecosystem health and water contamination by organic toxicants from natural and anthropogenic sources. However, most of these studies only focused on the measurement of specific toxicants and did not examine the impact of chemical mixtures. In this study, we examined whether the tissue exposome captured in vivo with solid-phase microextraction (SPME) without lethal sampling and analyzed by liquid chromatography-high resolution mass spectrometry can detect differences between Catostomus commersonii exhibiting a significant induction of CYP1A1, through case/control comparisons, controlling for false discovery rates. We observed the presence of environmental toxicants in induced case fish known as potential inducers of CYP1A1. We also found significant changes in the levels of anti-oxidants, short-lived oxysterols and other lipids associated with CYP1A1 induction, possibly due to oxidative stress, lipid peroxidation and free fatty acids mobilization to maintain homeostatic state. In vivo SPME opens the way to perform repeated sampling on the same animal over the time and explore the individual internal exposome trajectory for better characterization of the links between toxicant load and health effects, at the individual scale.