Degradation of aquatic ecosystems is an unfortunate consequence of industrialization, urbanization and general societial activity. The health of biological communities in these systems is subject to chemical stressors including emerging contaminants and legacy compounds that inevitably transit from land-based ecosystems into aquatic habitats. Fish have been utilized as preferred vertebrate sentinels of these systems for decdes; however, base-line data regarding disease, immune responses, endocrine function and other physiological responses is often not experimentally qualified prior to field application. Here, the presence of estrogen receptors (ERs) in channel catfish ( Ictalurus punctatus ) leukocytes is demonstrated. Estrogens affect the responsiveness of channel catfish peripheral blood leukocytes (PBLs) to mitogens in vitro. The ERs, ERα and ERβ2, are differentially expressed depending on leukocyte lineage, phenotype, and state of activation. Estrogens are likely involved in the regulation of immune responses in vivo, and estrogenic endocrine disrupting chemicals may directly impact leukocyte function. Additionally, laboratory studies established a better understanding of immune and endocrine responses to polychlorinated biphenyl (PCB) exposure in brown bullheads (Amieurus nebulosus ) and Atlantic salmon (Salmo salar ). This legacy compound clearly modulated the immune response in both species, and likely predisposes these animals to disease. Interestingly, short-term short-duration exposures to environmentally relevant concentrations during early development can have long-term effects on T-cell populations of the immune system in salmon. These laboratory studies facilitated the interpretation of data collected from a multi season field study in the Ashtabula River where PCB contamination is thought to have negative impacts on resident biota. This applied field study utilized brown bullheads and largemouth bass ( Micropterus salmoides ) collected from the Ashtabula River and a reference site, Conneaut Creek. Histological, immunological, allometric and endocrine biomarker endpoints provided strong evidence that fish from the Ashtabula River are biologically different than those from the reference site. Data also emphasized the advantage of a multi-tier, multi-species, multi-season sampling approach. The biological data were supported by body burden chemical analysis. Lastly, two diseases of bullheads resulting from Edwardsiella ictaluri and Henneguya gurlei were descrbed, and further the understanding of infectious diseases of this sentinel fish.