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A deleterious impact on the C. elegans fertility over generation after a chronic exposure to ionizing irradiation: A multigenerational transcriptomic evidence

ABSTRACT: Parental exposure to environmental stress factors during gestation as well as embryonal developmental may lead to deleterious consequences onto the offspring. In the present study, we assessed the adverse effects and mode of toxic action of chronic exposure to ionizing radiation over 4 generations in Caenorhabditis elegans (C. elegans). Our data show a decrease of 23% in the number of offspring on the first generation F0 and a decrease of more than 40% in subsequent generations F1, F2 and F3 from parental exposure.Transcriptomic analysis revealed modulation of a common set of genes functions betweenthrough generations that included transcription factors, as well as genes involved in stress response, unfolded protein response, lipid metabolism and reproduction. Furthermore, a drastic increase in the number of differentially expressed genes involved in defense response was measured in the last two generations, suggesting a cumulative stress effect of ionizing radiation exposure. Integration of these multi-scale data demonstrates that chronic gamma exposure can impact the germline and induce an increase in defense mechanisms, including apoptosis, antioxidant enzymes, and a modulation of lipid metabolism to improve resistance to stress. Harmful effects intensify over generations, after F0 at the phenotypic level F0 and F1 at the transcriptomic level , emphasizing the importance of studying effects of chronic exposure to pollutants over several generations.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE175918 | GEO | 2022/05/01

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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A deleterious impact on the C. elegans fertility over generation after a chronic exposure to ionizing irradiation: A multigenerational transcriptomic evidence

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