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Paternal hypoxia exposure primes offspring for increased hypoxia resistance

ABSTRACT: Environmental challenges experienced by an organism can have multiple effects at an individual level, with recent work also suggesting these challenges may affect their unexposed offspring. In a time of rapid environmental change, understanding whether environmental challenges experienced by organisms could increase the fitness of future generations to survive these same stressors, is critically needed. Low dissolved oxygen is a common environmental challenge that aquatic organisms encounter, resulting in numerous physiological, phenotypic, and epigenetic changes. In this study, we use zebrafish (Danio rerio) as a model to investigate how paternal hypoxia experience impacts subsequent progeny. Males were exposed to moderate hypoxia (11-13 kPA) for 2 weeks, bred to create an F1 generation, and progeny underwent an acute hypoxia (0-1 kPA) tolerance assay. Using time to loss of equilibrium and loss of equilibrium frequency as measured of hypoxia resistance, we show that paternal exposure to hypoxia endow offspring with a greater tolerance to acute hypoxia, compared to offspring of unexposed males, though there are strong family x treatment effects. In addition to phenotypic alternations, we also investigated changes in gene expression in offspring. We conducted RNA-Seq on whole fry and detected 91 differentially expressed genes, including two hemoglobin genes that are significantly upregulated by more than 4-fold in the offspring of hypoxia exposed males. Moreover, the offspring which maintained equilibrium the longest showed the greatest upregulation in hemoglobin expression. Paternal exposures to physiological challenges are thus able to impact the phenotype and gene expression of their unexposed progeny. We conducted whole genome bisulfite sequencing (WGBS) on the sperm of parental males to assess whether changes in progeny phenotype and gene expression are underpinned by changes in DNA methylation. While we observed coupling of methylation levels in the parental sperm and gene expression in progeny overall, we did not detect differential methylation at any of the differentially expressed genes, suggesting that another epigenetic mechanism is responsible for the observed changes in gene expression. Overall, our findings suggest that a ‘memory’ of past hypoxia exposure is maintained and that this environmentally induced information is transferred to subsequent generations, pre-acclimating progeny to cope with hypoxic conditions.

ORGANISM(S): Danio rerio

PROVIDER: GSE160662 | GEO | 2022/01/01

REPOSITORIES: GEO

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Project description:Parental exposure to environmental stress can result in an increased diseases risk in the offspring. Although literature on maternal contribution to hereditary diseases are growing, the paternal contribution is frequently underrecognized. Since human studies reported that 80% of transmitted mutations arise in the paternal germline, it is crucial to understand the mechanism underlying the paternally inherited genome instability. Ionizing radiation (IR) is a major source of mutagenesis through inducing DNA double-strand breaks (DSBs). Here, we used sex-separated C. elegans mutants to investigate the paternal contribution to IR-induced transgenerational effects. Specifically, we found that paternal exposure to IR leads to a transgenerational embryonic lethality, and this effect is only observed when the radiation exposure occurred close to the time of fertilization. In the offspring of the irradiated males (F1 generation), we detected various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. These phenotypes are attributed to the usage of two error-prone repair machinery, the polymerase-theta mediated end joining (TMEJ) and the non-homologous End Joining (NHEJ). Surprisingly, depletion of a human histone H1.0 ortholog, HIS-24, can significantly rescue this transgenerational embryonic lethality. Moreover, this rescue effect is associated with the downregulation of heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2), and the knocking-down of heterochromatin protein, HPL-1, could mimic the rescue effect of HIS-24 depletion. We also noticed that removal of the histone H1 and heterochromatin marker could activate the error-free repair machinery, Homologous Recombination repair (HR), thus improving the viability of the offspring carrying paternally inherited DNA damage. Altogether, our work sheds light on the importance of paternal radiation exposure on the health of offspring. In addition, our work establishes a previously unknown mechanism underlying the transgenerational genome instability and provides a potential therapeutic target for preventing the hereditary diseases caused by paternal radiation exposure.

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Paternal hypoxia exposure primes offspring for increased hypoxia resistance

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