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Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

ABSTRACT: Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid dexamethasone, affects the RNA payload of mature sperm as soon as 3 hr after exposure. It further impacts early embryonic transcriptional trajectories, as determined by single-embryo sequencing, and metabolism in the offspring. We show persistent regulation of tRNA fragments in sperm and descendant 2-cell embryos, suggesting transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in sperm circRNAs and their targets in the early embryo, highlighting this class as an additional candidate in RNA-mediated inheritance of disease risk.

SUBMITTER: Gapp K

PROVIDER: S-EPMC8346661 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

Gapp Katharina K Parada Guillermo E GE Gross Fridolin F Corcoba Alberto A Kaur Jasmine J Grau Evelyn E Hemberg Martin M Bohacek Johannes J Miska Eric A EA

iScience 20210716 8

Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid ...[more]

PMID: 34386731

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Project description:BackgroundWhile many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.MethodsMale mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.ResultsWe found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.ConclusionsOur study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.

Project description:BackgroundThe trend of postponing childbearing age is prevalent worldwide. Advanced paternal age (APA) is associated with adverse pregnancy outcomes and offspring health. However, the underlying mechanism by which paternal aging affects the risk of offspring neuropsychiatric disorders is unclear. Our study aims to explore the behavioral phenotypes and the pathologic epigenetic alterations of APA offspring inherited from aging sperm.MethodsBehavioral tests, ELISA assay, immunofluorescence and western blotting were performed on offspring mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) were used to investigate the modified N6-methyladenosine (m6A) profiles of paternal sperm and offspring hippocampus. Intervention of gene expression by lentivirus and adeno-associated virus in both vivo and vitro examined the potential therapeutic targets of intergenerational inherited neuroinflammation.ResultsIn our study, APA offspring exhibit cognitive impairment and autism-like behavior. An increase in neuroinflammation in APA offspring is associated with microglial overactivation, which manifests as abnormal morphology and augmented engulfment. MeRIP-seq of F0 sperm and F1 hippocampus reveal that Nr4a2 is hypermethylated with decreased expression in APA offspring involving in synaptic plasticity and microglial function. In addition, Ythdc1, an m6A reader protein, is markedly elevated in aging sperm and remains elevated in adult hippocampus of APA group. Enhanced Ythdc1 recognizes and suppresses the hypermethylated Nr4a2, thereby contributing to the abnormal phenotype in offspring. The overexpression of Ythdc1 triggers microglial activation in vitro and its suppression in the hippocampus of APA progeny alleviates behavioral aberrations and attenuates neuroinflammation.ConclusionOur study provides additional evidence of the abnormal behavioral phenotypes of APA offspring and reveals potential epigenetic inheritance signatures and targeted genes for future research.

Dataset Information

Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

Publications

Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

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