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Involvement of circulating factors in the transmission of paternal experiences through the germline.

ABSTRACT: Environmental factors can change phenotypes in exposed individuals and offspring and involve the germline, likely via biological signals in the periphery that communicate with germ cells. Here, using a mouse model of paternal exposure to traumatic stress, we identify circulating factors involving peroxisome proliferator-activated receptor (PPAR) pathways in the effects of exposure to the germline. We show that exposure alters metabolic functions and pathways, particularly lipid-derived metabolites, in exposed fathers and their offspring. We collected data in a human cohort exposed to childhood trauma and observed similar metabolic alterations in circulation, suggesting conserved effects. Chronic injection of serum from trauma-exposed males into controls recapitulates metabolic phenotypes in the offspring. We identify lipid-activated nuclear receptors PPARs as potential mediators of the effects from father to offspring. Pharmacological PPAR activation in vivo reproduces metabolic dysfunctions in the offspring and grand-offspring of injected males and affects the sperm transcriptome in fathers and sons. In germ-like cells in vitro, both serum and PPAR agonist induce PPAR activation. Together, these results highlight the role of circulating factors as potential communication vectors between the periphery and the germline.

SUBMITTER: van Steenwyk G

PROVIDER: S-EPMC7705452 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Involvement of circulating factors in the transmission of paternal experiences through the germline.

van Steenwyk Gretchen G Gapp Katharina K Jawaid Ali A Germain Pierre-Luc PL Manuella Francesca F Tanwar Deepak K DK Zamboni Nicola N Gaur Niharika N Efimova Anastasiia A Thumfart Kristina M KM Miska Eric A EA Mansuy Isabelle M IM

The EMBO journal 20201009 23

Environmental factors can change phenotypes in exposed individuals and offspring and involve the germline, likely via biological signals in the periphery that communicate with germ cells. Here, using a mouse model of paternal exposure to traumatic stress, we identify circulating factors involving peroxisome proliferator-activated receptor (PPAR) pathways in the effects of exposure to the germline. We show that exposure alters metabolic functions and pathways, particularly lipid-derived metabolit ...[more]

PMID: 33034389

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Project description:Study questionWhat are the long-term developmental, reproductive and genetic consequences of mitochondrial replacement therapy (MRT) in primates?Summary answerLongitudinal investigation of MRT rhesus macaques (Macaca mulatta) generated with donor mtDNA that is exceedingly distant from the original maternal counterpart suggest that their growth, general health and fertility is unremarkable and similar to controls.What is known alreadyMitochondrial gene mutations contribute to a diverse range of incurable human disorders. MRT via spindle transfer in oocytes was developed and proposed to prevent transmission of pathogenic mtDNA mutations from mothers to children.Study design, size, durationThe study provides longitudinal studies on general health, fertility as well as transmission and segregation of parental mtDNA haplotypes to various tissues and organs in five adult MRT rhesus macaques and their offspring.Participants/materials, setting, methodsMRT was achieved by spindle transfer between metaphase II oocytes from genetically divergent rhesus macaque populations. After fertilization of oocytes with sperm, heteroplasmic zygotes contained an unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mitochondrial (mt)DNA. MRT monkeys were grown to adulthood and their development and general health was regularly monitored. Reproductive fitness of male and female MRT macaques was evaluated by time-mated breeding and production of live offspring. The relative contribution of donor, maternal, and paternal mtDNA was measured by whole mitochondrial genome sequencing in all organs and tissues of MRT animals and their offspring.Main results and the role of chanceBoth male and female MRT rhesus macaques containing unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mtDNA reached healthy adulthood, were fertile and most animals stably maintained the initial ratio of parental mtDNA heteroplasmy and donor mtDNA was transmitted from females to offspring. However, in one monkey out of four analyzed, initially negligible maternal mtDNA heteroplasmy levels increased substantially up to 17% in selected internal tissues and organs. In addition, two monkeys showed paternal mtDNA contribution up to 33% in selected internal tissues and organs.Large scale dataN/A.Limitations, reasons for cautionConclusions in this study were made on a relatively low number of MRT monkeys, and on only one F1 (first generation) female. In addition, monkey MRT involved two wildtype mtDNA haplotypes, but not disease-relevant variants. Clinical trials on children born after MRT will be required to fully determine safety and efficacy of MRT for humans.Wider implications of the findingsOur data show that MRT is compatible with normal postnatal development including overall health and reproductive fitness in nonhuman primates without any detected adverse effects. 'Mismatched' donor mtDNA in MRT animals even from the genetically distant mtDNA haplotypes did not cause secondary mitochondrial dysfunction. However, carry-over maternal or paternal mtDNA contributions increased substantially in selected internal tissues / organs of some MRT animals implying the possibility of mtDNA mutation recurrence.Study funding/competing interest(s)This work has been funded by the grants from the Burroughs Wellcome Fund, the National Institutes of Health (RO1AG062459 and P51 OD011092), National Research Foundation of Korea (2018R1D1A1B07043216) and Oregon Health & Science University institutional funds. The authors declare no competing interests.

Project description:OBJECTIVES:Fatherhood has evolved in recent decades from 'a moral teacher' to 'an involved father'. However, fatherhood experiences have not been examined in detail. This meta-synthesis aimed to examine fathers' experiences, needs, and perceptions of their involvement with their infants during the first 12 months of birth. METHOD:Six electronic databases were systematically searched: PubMed, CINAHL, Embase, Scopus, PsycINFO, ProQuest (grey literature). The search resulted in 13 studies that met the inclusion criteria. Quality appraisal was conducted using the Critical Appraisal Skills Programme Checklist. All 13 studies met the appraisal criteria and were included in the meta-synthesis. The findings of the 13 studies were synthesized using the steps of Sandelowski and Barroso in conducting meta-synthesis. RESULTS:The 13 included studies comprised studies conducted in the West, Africa, and Asia. Fatherhood experiences differed according to different sociocultural contexts. Three themes were identified: (1) trajectory of the father-infant relationship, (2) reinforcements and hindrances to involvement, and (3) change from self-oriented to family-oriented behavior. Changes in a father's relationship with his infant were influenced by relationships with his spouse and family members after the birth of the infant. Reinforcements, hindrances, and needs to fathers' involvement were identified. Fathering responsibility and parenting satisfaction that developed overtime influenced a father's behavior, changing from self-oriented to family-oriented. SIGNIFICANCE:This is the first meta-synthesis that examined fathers' experiences, needs, and perceptions of their involvement with their infants during the first 12 months of birth. Multiple factors were found to influence the socially-defined fathering ideology. Cultural practices of fatherhood and fathers' own perceptions shaped their actual fathering behaviors. The findings of this study may guide healthcare professionals as frontline personnel to understand fathers' needs and experiences in order to promote fathers' involvement in the early days after their infants' birth.

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Involvement of circulating factors in the transmission of paternal experiences through the germline.

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Involvement of circulating factors in the transmission of paternal experiences through the germline.

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