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      Paternal Effects in Mammalian Reproduction: Functional, Environmental, and Clinical Relevance of Sperm Components in Early Embryos and Beyond

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          ABSTRACT

          In addition to widely recognized contributions of the paternal genome, centriole, and oocyte‐activation factors, sperm deliver a wide range of macromolecules to the fertilized embryo. The impacts of these factors on the embryo, progeny, and even subsequent generations have become increasingly apparent, along with an understanding of an extensive potential for male health and environmental exposures to exert both immediate and long‐term impacts on mammalian reproduction. Available data reveal that sperm factors interact with and regulate the actions of oocyte factors as well as exerting additional direct effects on the early embryo. This review provides a summary of the nature and mechanisms of paternal effects in early mammalian embryos, long‐term effects in progeny, susceptibility of sperm components to diverse environmental factors, and potential approaches to mitigate adverse effects of such exposures.

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          Most cited references190

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          Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder.

          Increasing evidence indicates that metabolic disorders in offspring can result from the father's diet, but the mechanism remains unclear. In a paternal mouse model given a high-fat diet (HFD), we showed that a subset of sperm transfer RNA-derived small RNAs (tsRNAs), mainly from 5' transfer RNA halves and ranging in size from 30 to 34 nucleotides, exhibited changes in expression profiles and RNA modifications. Injection of sperm tsRNA fractions from HFD males into normal zygotes generated metabolic disorders in the F1 offspring and altered gene expression of metabolic pathways in early embryos and islets of F1 offspring, which was unrelated to DNA methylation at CpG-enriched regions. Hence, sperm tsRNAs represent a paternal epigenetic factor that may mediate intergenerational inheritance of diet-induced metabolic disorders.
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            Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.

            Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary-adrenal (HPA) stress axis reactivity in offspring. In the current study, we rigorously examine the hypothesis that these sperm miRs function postfertilization to alter offspring stress responsivity and, using zygote microinjection of the nine specific miRs, demonstrated a remarkable recapitulation of the offspring stress dysregulation phenotype. Further, we associated long-term reprogramming of the hypothalamic transcriptome with HPA axis dysfunction, noting a marked decreased in the expression of extracellular matrix and collagen gene sets that may reflect an underlying change in blood-brain barrier permeability. We conclude by investigating the developmental impact of sperm miRs in early zygotes with single-cell amplification technology, identifying the targeted degradation of stored maternal mRNA transcripts including sirtuin 1 and ubiquitin protein ligase E3a, two genes with established function in chromatin remodeling, and this potent regulatory function of miRs postfertilization likely initiates a cascade of molecular events that eventually alters stress reactivity. Overall, these findings demonstrate a clear mechanistic role for sperm miRs in the transgenerational transmission of paternal lifetime experiences.
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              Dynamic reprogramming of DNA methylation in the early mouse embryo.

              Dynamic epigenetic modification of the genome occurs during early development of the mouse. Active demethylation of the paternal genome occurs in the zygote, followed by passive demethylation during cleavage stages, and de novo methylation, which is thought to happen after implantation. We have investigated these processes by using indirect immunofluorescence with an antibody to 5-methyl cytosine. In contrast to previous work, we show that demethylation of the male pronucleus is completed within 4 h of fertilisation. This activity is intricately linked with and not separable from pronucleus formation. In conditions permissive for polyspermy, up to five male pronuclei underwent demethylation in the same oocyte. Paternal demethylation in fertilised oocytes deficient for MBD2, the only candidate demethylase, occurred normally. Passive loss of methylation occurred in a stepwise fashion up to the morulae stage without any evidence of spatial compartmentalisation. De novo methylation was observed specifically in the inner cell mass (ICM) but not in the trophectoderm of the blastocyst and hence may have an important role in early lineage specification. This is the first complete and detailed analysis of the epigenetic reprogramming cycle during preimplantation development. The three phases of methylation reprogramming may have roles in imprinting, the control of gene expression, and the establishment of nuclear totipotency.
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                Author and article information

                Contributors
                lathamk1@msu.edu
                Journal
                Mol Reprod Dev
                Mol Reprod Dev
                10.1002/(ISSN)1098-2795
                MRD
                Molecular Reproduction and Development
                John Wiley and Sons Inc. (Hoboken )
                1040-452X
                1098-2795
                23 March 2025
                March 2025
                : 92
                : 3 ( doiID: 10.1002/mrd.v92.3 )
                : e70020
                Affiliations
                [ 1 ] Department of Animal Science Michigan State University East Lansing Michigan USA
                [ 2 ] Department of Obstetrics, Gynecology and Reproductive Biology Michigan State University East Lansing Michigan USA
                Author notes
                [*] [* ] Correspondence: Keith E. Latham ( lathamk1@ 123456msu.edu )

                Author information
                http://orcid.org/0000-0003-1206-9059
                Article
                MRD70020
                10.1002/mrd.70020
                11931271
                9d06600e-9ccc-44d3-b191-14db6b0cd802
                © 2025 The Author(s). Molecular Reproduction and Development published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 February 2025
                : 23 January 2025
                : 05 March 2025
                Page count
                Figures: 2, Tables: 0, Pages: 17, Words: 14496
                Funding
                Funded by: The author supported by Michigan State University AgBioResearch and Michigan State University.
                Categories
                Review Article
                Review Article
                Custom metadata
                2.0
                March 2025
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.5.4 mode:remove_FC converted:24.03.2025

                Developmental biology
                epigenetic,microrna,paternal factor,semen,sperm quality,sperm transcriptome,transgenerational effects

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