As global change alters multiple environmental conditions, predicting species’ responses can be challenging without understanding how each environmental factor influences organismal performance. Approaches quantifying mechanistic relationships can greatly complement correlative field data, strengthening our abilities to forecast global change impacts. Substantial salinity increases are projected in the San Francisco Estuary, California, due to anthropogenic water diversion and climatic changes, where the critically endangered delta smelt (Hypomesus transpacificus) largely occurs in a low‐salinity zone (LSZ), despite their ability to tolerate a much broader salinity range. In this study, we combined molecular and organismal measures to quantify the physiological mechanisms and sublethal responses involved in coping with salinity changes. Delta smelt utilize a suite of conserved molecular mechanisms to rapidly adjust their osmoregulatory physiology in response to salinity changes in estuarine environments. However, these responses can be energetically expensive, and delta smelt body condition was reduced at high salinities. Thus, acclimating to salinities outside the LSZ could impose energetic costs that constrain delta smelt's ability to exploit these habitats. By integrating data across biological levels, we provide key insight into the mechanistic relationships contributing to phenotypic plasticity and distribution limitations and advance the understanding of the molecular osmoregulatory responses in nonmodel estuarine fishes.
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