Intergenerational Dynamics of Epigenetically Inherited Hypoxia Tolerance in Zebrafish

Epigenetic inheritance, the transfer of phenotypes from parental generation (P 0 ) to subsequent generations without altering their DNA sequence, has important functions in biological processes including development, disease susceptibility, and evolutionary adaptations. In the context of development and evolution we studied epigenetic inheritance of hypoxia tolerance in low heterozygosity NHGRI-1 zebrafish from a P 0 to multiple clutches of a subsequent generation (F 1 ). We hypothesized that hypoxia tolerance in the P 0 would ‘wash out’ after multiple clutches within an F 1 , observed as loss of hypoxia tolerance in the F 1 . To test our hypothesis, the P 0 was exposed to control oxygen conditions (PO 2 ~21 kPa), mild hypoxia (PO 2 ~15 kPa), moderate hypoxia (PO 2 ~12 kPa), and severe hypoxia (PO 2 ~9 kPa) for three weeks. After recovery periods of 2-, 4-, 6-, and 8-weeks fish were bred. Their offspring were tested for morphological alterations (body mass, fork length), hypoxia tolerance, oxygen consumption, and cardiac function (heart rate, stroke volume, cardiac output) at 7 days post-fertilization. Hypoxia tolerance indicated by time to loss of equilibrium (TLoE) increased with decreased oxygen and was higher in females (males TLoE from 1.3 to 2.3 min, females TLoE from ~2 to 5.5 min). The offspring of hypoxia-exposed parents had increased body mass (~290 µg vs ~240 µg in controls) and fork length (~4.3 mm vs ~3.9 mm), especially in the first clutch. Importantly, offspring hypoxia tolerance, assessed as TLoE ‘washed out’ after the second clutch (4 weeks of recovery), where values form TLoE decreased from ~5 to ~1.5 min. Additionally, oxygen consumption (ṀO 2 ) increased from ~11 to ~25 µM O 2 g -1 h -1 . The effect of hypoxia on cardiac function washed after one clutch (2 weeks of recovery) for heart rate (increased form ~120 to ~160 beats min -1 ) but continued until the fourth clutch (8 weeks of recovery) on stroke volume (~0.4 nL beat -1 in hypoxic offspring compared to ~0.2 nL beat -1 in controls) and cardiac output (~50-60 nL min -1 in hypoxic fish compared to ~30-40 nL min -1 ). Collectively, these data showed the dynamic effect of hypoxia on morphological and physiological variables, which ‘washed out’ differently across multiple clutches of an F 1 (as a function of time) and depending on the employed oxygen level (stressor dose). Unexpectedly, we also demonstrated how morphological and physiological responses to hypoxia differ significantly between sexes in the P 0 . Future studies will continue to investigate the effect of hypoxia tolerance in subsequent generations (F 2 to F n ) and its associated mechanisms. National Science Foundation IOB#2103499 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.