While the field of epigenetics is increasingly recognized to contribute to the emergence of phenotypes in mammalian research models across different developmental and generational timescales, the comparative biology of epigenetics in the large and physiologically diverse vertebrate infraclass of teleost fish remains comparatively understudied. The cypriniform zebrafish and the salmoniform rainbow trout and Atlantic salmon represent two especially important teleost orders, because they offer the unique possibility to comparatively investigate the role of epigenetic regulation in 3R and 4R duplicated genomes. In addition to their sequenced genomes, these teleost species are well-characterized model species for development and physiology, and therefore allow for an investigation of the role of epigenetic modifications in the emergence of physiological phenotypes during an organism's lifespan and in subsequent generations. This review aims firstly to describe the evolution of the repertoire of genes involved in key molecular epigenetic pathways including histone modifications, DNA methylation and microRNAs in zebrafish, rainbow trout, and Atlantic salmon, and secondly, to discuss recent advances in research highlighting a role for molecular epigenetics in shaping physiological phenotypes in these and other teleost models. Finally, by discussing themes and current limitations of the emerging field of teleost epigenetics from both theoretical and technical points of view, we will highlight future research needs and discuss how epigenetics will not only help address basic research questions in comparative teleost physiology, but also inform translational research including aquaculture, aquatic toxicology, and human disease.

Excess glucocorticoid transferred from stressed mother to the embryo affects developing vertebrate offspring, but the underlying programming events are unclear. In this study, we tested the hypothesis that increased zygotic glucocorticoid deposition, mimicking a maternal stress scenario, modifies early brain development and larval behaviour in zebrafish (Danio rerio). Cortisol was microinjected into the yolk at one cell-stage, to mimic maternal transfer, and the larvae [96 hours post-fertilization (hpf)] displayed increased activity in light and a reduction in thigmotaxis, a behavioural model for anxiety, suggesting an increased propensity for boldness. This cortisol-mediated behavioural phenotype corresponded with an increase in primary neurogenesis, as measured by incorporation of EdU at 24 hpf, in a region-specific manner in the preoptic region and the pallium, the teleostean homolog of the hippocampus. Also, cortisol increased the expression of the proneural gene neurod4, a marker of neurogenesis, in a region- and development-specific manner in the embryos. Altogether, excess zygotic cortisol, mimicking maternal stress, affects early brain development and behavioural phenotype in larval zebrafish. We propose a key role for cortisol in altering brain development leading to enhanced boldness, which may be beneficial in preparing the offspring to a stressful environment and enhancing fitness.

Abnormal embryo cortisol level causes developmental defects and poor survival in zebrafish (Danio rerio). However, no study has demonstrated that maternal stress leads to higher embryo cortisol content in zebrafish. We tested the hypothesis that maternal stress-associated elevation in cortisol levels increases embryo cortisol content in this asynchronous breeder. Zebrafish mothers were fed cortisol-spiked food for 5 days, to mimic maternal stress, followed by daily breeding for 10 days to monitor temporal embryo cortisol content. Cortisol treatment increased mean embryo yield, but the daily fecundity was variable among the groups. Embryo cortisol content was variable in both groups over a 10-day period. A transient elevation in cortisol levels was observed in the embryos from cortisol-fed mothers only on day 3, but not on subsequent days. We tested whether excess cortisol stimulates 11βHSD2 expression in ovarian follicles as a means to regulate embryo cortisol deposition. Cortisol treatment in vitro increased 11β HSD2 levels sevenfold, and this expression was regulated by actinomycin D and cycloheximide suggesting tight regulation of cortisol levels in the ovarian follicles. We hypothesize that cortisol-induced upregulation of 11βHSD2 activity in the ovarian follicles is a mechanism restricting excess cortisol incorporation into the eggs during maternal stress.

The coordination of the hypoxic response is attributed, in part, to hypoxia-inducible factor 1α (Hif-1α), a regulator of hypoxia-induced transcription. After the teleost-specific genome duplication, most teleost fishes lost the duplicate copy of Hif-1α, except species in the cyprinid lineage that retained both paralogues of Hif-1α (Hif1aa and Hif1ab). Little is known about the contribution of Hif-1α, and specifically of each paralogue, to hypoxia tolerance. Here, we examined hypoxia tolerance in wild-type (Hif1aa +/+ ab +/+ ) and Hif-1α knockout lines (Hif1aa −/− ; Hif1ab −/− ; Hif1aa −/− ab −/− ) of zebrafish ( Danio rerio ). Critical O 2 tension ( P crit ; the partial pressure of oxygen (PO 2 ) at which O 2 consumption can no longer be maintained) and time to loss of equilibrium (LOE), two indices of hypoxia tolerance, were assessed in larvae and adults. Knockout of both paralogues significantly increased P crit (decreased hypoxia tolerance) in larval fish. Prior exposure of larvae to hypoxia decreased P crit in wild-type fish, an effect mediated by the Hif1aa paralogue. In adults, individuals with a knockout of either paralogue exhibited significantly decreased time to LOE but no difference in P crit . Together, these results demonstrate that in zebrafish, tolerance to hypoxia and improved hypoxia tolerance after pre-exposure to hypoxia (pre-conditioning) are mediated, at least in part, by Hif-1α.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is a widely prescribed antidepressant drug routinely detected in the aquatic environment. However, little is known about its impact on the physiology of nontarget organisms. We tested the hypothesis that venlafaxine perturbs brain monoamine levels and disrupts molecular responses essential for stress coping and feeding activity in fish. Rainbow trout (Oncorhynchus mykiss) were exposed to waterborne venlafaxine (0.2 and 1.0 μg/L) for 7 days. This treatment elevated norepinephrine, serotonin, and dopamine levels in the brain in a region-specific manner. Venlafaxine also increased the transcript levels of genes involved in stress and appetite regulation, including corticotropin releasing factor, pro-opiomelanocortin B, and glucose transporter type 2 in distinct brain regions of trout. The drug treatment reduced the total feed consumed per day, but did not affect the feeding behavior of the dominant and subordinate fish. However, the subordinate fish from the venlafaxine-exposed group had significantly higher plasma cortisol levels compared to the subordinate fish in the control group. Collectively, our results demonstrate that venlafaxine, at environmentally realistic levels, is a neuroendocrine disruptor, impacting the stress and feeding responses in rainbow trout. We propose the midbrain region as a key target for venlafaxine impact and the mode of action involves abnormal monoamine content in trout.