Paternal environmental exposure-induced spermatozoal small noncoding RNA alteration meditates the intergenerational epigenetic inheritance of multiple diseases

Abstract

Studies of human and mammalian have revealed that environmental exposure can affect paternal health conditions as well as those of the offspring. However, studies that explore the mechanisms that meditate this transmission are rare. Recently, small noncoding RNAs (sncRNAs) in sperm have seemed crucial to this transmission due to their alteration in sperm in response to environmental exposure, and the methodology of microinjection of isolated total RNA or sncRNAs or synthetically identified sncRNAs gradually lifted the veil of sncRNA regulation during intergenerational inheritance along the male line. Hence, by reviewing relevant literature, this study intends to answer the following research concepts: (1) paternal environmental factors that can be passed on to offspring and are attributed to spermatozoal sncRNAs, (2) potential role of paternal spermatozoal sncRNAs during the intergenerational inheritance process, and (3) the potential mechanism by which spermatozoal sncRNAs meditate intergenerational inheritance. In summary, increased attention highlights the hidden wonder of spermatozoal sncRNAs during intergenerational inheritance. Therefore, in the future, more studies should focus on the origin of RNA alteration, the target of RNA regulation, and how sncRNA regulation during embryonic development can be sustained even in adult offspring.

Keywords

small noncoding RNAs / epigenetic inheritance / paternal intergenerational inherence / extracellular vesicles

References

[1] Zhang Y, Shi J, Rassoulzadegan M, Tuorto F, Chen Q. Sperm RNA code programmes the metabolic health of offspring. Nat Rev Endocrinol 2019; 15(8): 489–498

[2] Rando OJ. Intergenerational transfer of epigenetic information in sperm. Cold Spring Harb Perspect Med 2016; 6(5): a022988

[3] Weigmann K. Lifestyle in the sperm: there is growing evidence that epigenetic marks can be inherited. But what is the nature of the information they store and over how many generations do they prevail? EMBO Rep 2014; 15(12): 1233–1237

[4] Sales VM, Ferguson-Smith AC, Patti ME. Epigenetic mechanisms of transmission of metabolic disease across generations. Cell Metab 2017; 25(3): 559–571

[5] Klastrup LK, Bak ST, Nielsen AL. The influence of paternal diet on sncRNA-mediated epigenetic inheritance. Mol Genet Genomics 2019; 294(1): 1–11

[6] Rodgers AB, Morgan CP, Leu NA, Bale TL. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA 2015; 112(44): 13699–13704

[7] Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014; 17(5): 667–669

[8] Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, Feng GH, Peng H, Zhang X, Zhang Y, Qian J, Duan E, Zhai Q, Zhou Q. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 2016; 351(6271): 397–400

[9] Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG, Bing XY, Belleannee C, Kucukural A, Serra RW, Sun F, Song L, Carone BR, Ricci EP, Li XZ, Fauquier L, Moore MJ, Sullivan R, Mello CC, Garber M, Rando OJ. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 2016; 351(6271): 391–396

[10] Grandjean V, Fourré S, De Abreu DA, Derieppe MA, Remy JJ, Rassoulzadegan M. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep 2016; 5: 18193

[11] Vågerö D, Pinger PR, Aronsson V, van den Berg GJ. Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons. Nat Commun 2018; 9(1): 5124

[12] Lumey LH, Stein AD, Kahn HS, van der Pal-de Bruin KM, Blauw GJ, Zybert PA, Susser ES. Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol 2007; 36(6): 1196–1204

[13] Bygren LO, Kaati G, Edvinsson S. Longevity determined by paternal ancestors’ nutrition during their slow growth period. Acta Biotheor 2001; 49(1): 53–59

[14] Pembrey ME. Male-line transgenerational responses in humans. Hum Fertil (Camb) 2010; 13(4): 268–271

[15] Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet 2002; 10(11): 682–688

[16] Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjöström M, Golding JA; LSPAC Study Team. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14(2): 159–166

[17] Chen TH, Chiu YH, Boucher BJ. Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program. Am J Clin Nutr 2006; 83(3): 688–692

[18] Northstone K, Golding J, Davey Smith G, Miller LL, Pembrey M. Prepubertal start of father’s smoking and increased body fat in his sons: further characterisation of paternal transgenerational responses. Eur J Hum Genet 2014; 22(12): 1382–1386

[19] Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, Flory JD, Bierer LM, Meaney MJ. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 2014; 171(8): 872–880

[20] Marczylo EL, Amoako AA, Konje JC, Gant TW, Marczylo TH. Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 2012; 7(5): 432–439

[21] Delbès G, Hales BF, Robaire B. Toxicants and human sperm chromatin integrity. Mol Hum Reprod 2010; 16(1): 14–22

[22] Ruden DM, Garfinkel MD, Sollars VE, Lu X. Waddington’s widget: Hsp90 and the inheritance of acquired characters. Semin Cell Dev Biol 2003; 14(5): 301–310

[23] Ptashne M. Epigenetics: core misconcept. Proc Natl Acad Sci USA 2013; 110(18): 7101–7103

[24] Boucher BJ, Ewen SW, Stowers JM. Betel nut (Areca catechu) consumption and the induction of glucose intolerance in adult CD1 mice and in their F1 and F2 offspring. Diabetologia 1994; 37(1): 49–55

[25] Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 2006; 441(7092): 469–474

[26] Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 2010; 466(7304): 383–387

[27] Berger SL. Transgenerational inheritance of longevity: epigenetic mysteries abound. Cell Metab 2012; 15(1): 6–7

[28] Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014; 17(1): 89–96

[29] Benito E, Kerimoglu C, Ramachandran B, Pena-Centeno T, Jain G, Stilling RM, Islam MR, Capece V, Zhou Q, Edbauer D, Dean C, Fischer A. RNA-dependent intergenerational inheritance of enhanced synaptic plasticity after environmental enrichment. Cell Rep 2018; 23(2): 546–554

[30] Gapp K, Soldado-Magraner S, Alvarez-Sánchez M, Bohacek J, Vernaz G, Shu H, Franklin TB, Wolfer D, Mansuy IM. Early life stress in fathers improves behavioural flexibility in their offspring. Nat Commun 2014; 5(1): 5466

[31] Wu L, Lu Y, Jiao Y, Liu B, Li S, Li Y, Xing F, Chen D, Liu X, Zhao J, Xiong X, Gu Y, Lu J, Chen X, Li X. Paternal psychological stress reprograms hepatic gluconeogenesis in offspring. Cell Metab 2016; 23(4): 735–743

[32] Schuster A, Skinner MK, Yan W. Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environ Epigenet 2016; 2(1): dvw001

[33] Rompala GR, Mounier A, Wolfe CM, Lin Q, Lefterov I, Homanics GE. Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Front Genet 2018; 9: 32

[34] Wagner KD, Wagner N, Ghanbarian H, Grandjean V, Gounon P, Cuzin F, Rassoulzadegan M. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev Cell 2008; 14(6): 962–969

[35] Grandjean V, Gounon P, Wagner N, Martin L, Wagner KD, Bernex F, Cuzin F, Rassoulzadegan M. The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development 2009; 136(21): 3647–3655

[36] Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 2015; 16(2): 71–84

[37] Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010; 143(7): 1084–1096

[38] Fullston T, Ohlsson Teague EM, Palmer NO, DeBlasio MJ, Mitchell M, Corbett M, Print CG, Owens JA, Lane M. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 2013; 27(10): 4226–4243

[39] Peng H, Shi J, Zhang Y, Zhang H, Liao S, Li W, Lei L, Han C, Ning L, Cao Y, Zhou Q, Chen Q, Duan E. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res 2012; 22(11): 1609–1612

[40] Reilly JN, McLaughlin EA, Stanger SJ, Anderson AL, Hutcheon K, Church K, Mihalas BP, Tyagi S, Holt JE, Eamens AL, Nixon B. Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome. Sci Rep 2016; 6(1): 31794

[41] Hutcheon K, McLaughlin EA, Stanger SJ, Bernstein IR, Dun MD, Eamens AL, Nixon B. Analysis of the small non-protein-coding RNA profile of mouse spermatozoa reveals specific enrichment of piRNAs within mature spermatozoa. RNA Biol 2017; 14(12): 1776–1790

[42] Sullivan R. Epididymosomes: role of extracellular microvesicles in sperm maturation. Front Biosci (Schol Ed) 2016; 8(1): 106–114

[43] Hua M, Liu W, Chen Y, Zhang F, Xu B, Liu S, Chen G, Shi H, Wu L. Identification of small non-coding RNAs as sperm quality biomarkers for in vitro fertilization. Cell Discov 2019; 5(1): 20

[44] Zhang Y, Zhang X, Shi J, Tuorto F, Li X, Liu Y, Liebers R, Zhang L, Qu Y, Qian J, Pahima M, Liu Y, Yan M, Cao Z, Lei X, Cao Y, Peng H, Liu S, Wang Y, Zheng H, Woolsey R, Quilici D, Zhai Q, Li L, Zhou T, Yan W, Lyko F, Zhang Y, Zhou Q, Duan E, Chen Q. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat Cell Biol 2018; 20(5): 535–540

[45] Nätt D, Kugelberg U, Casas E, Nedstrand E, Zalavary S, Henriksson P, Nijm C, Jäderquist J, Sandborg J, Flinke E, Ramesh R, Örkenby L, Appelkvist F, Lingg T, Guzzi N, Bellodi C, Löf M, Vavouri T, Öst A. Human sperm displays rapid responses to diet. PLoS Biol 2019; 17(12): e3000559

[46] Shi J, Zhang Y, Tan D, Zhang X, Yan M, Zhang Y, Franklin R, Shahbazi M, Mackinlay K, Liu S, Kuhle B, James ER, Zhang L, Qu Y, Zhai Q, Zhao W, Zhao L, Zhou C, Gu W, Murn J, Guo J, Carrell DT, Wang Y, Chen X, Cairns BR, Yang XL, Schimmel P, Zernicka-Goetz M, Cheloufi S, Zhang Y, Zhou T, Chen Q. PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications. Nat Cell Biol 2021; 23(4): 424–436

[47] Kiani J, Grandjean V, Liebers R, Tuorto F, Ghanbarian H, Lyko F, Cuzin F, Rassoulzadegan M. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet 2013; 9(5): e1003498

[48] Sarker G, Sun W, Rosenkranz D, Pelczar P, Opitz L, Efthymiou V, Wolfrum C, Peleg-Raibstein D. Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc Natl Acad Sci USA 2019; 116(21): 10547–10556

[49] Peleg-Raibstein D, Sarker G, Litwan K, Krämer SD, Ametamey SM, Schibli R, Wolfrum C. Enhanced sensitivity to drugs of abuse and palatable foods following maternal overnutrition. Transl Psychiatry 2016; 6(10): e911

[50] Sarker G, Berrens R, von Arx J, Pelczar P, Reik W, Wolfrum C, Peleg-Raibstein D. Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition. Transl Psychiatry 2018; 8(1): 195

[51] Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, Peters AHFM, Patti ME, Ferguson-Smith AC. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 2014; 345(6198): 1255903

[52] Shea JM, Serra RW, Carone BR, Shulha HP, Kucukural A, Ziller MJ, Vallaster MP, Gu H, Tapper AR, Gardner PD, Meissner A, Garber M, Rando OJ. Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev Cell 2015; 35(6): 750–758

[53] Sendler E, Johnson GD, Mao S, Goodrich RJ, Diamond MP, Hauser R, Krawetz SA. Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res 2013; 41(7): 4104–4117

[54] Kawano M, Kawaji H, Grandjean V, Kiani J, Rassoulzadegan M. Novel small noncoding RNAs in mouse spermatozoa, zygotes and early embryos. PLoS One 2012; 7(9): e44542

[55] Krawetz SA, Kruger A, Lalancette C, Tagett R, Anton E, Draghici S, Diamond MP. A survey of small RNAs in human sperm. Hum Reprod 2011; 26(12): 3401–3412

[56] Dietz DM, Laplant Q, Watts EL, Hodes GE, Russo SJ, Feng J, Oosting RS, Vialou V, Nestler EJ. Paternal transmission of stress-induced pathologies. Biol Psychiatry 2011; 70(5): 408–414

[57] Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci 2013; 33(21): 9003–9012

[58] Bohacek J, Farinelli M, Mirante O, Steiner G, Gapp K, Coiret G, Ebeling M, Durán-Pacheco G, Iniguez AL, Manuella F, Moreau JL, Mansuy IM. Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress. Mol Psychiatry 2015; 20(5): 621–631

[59] Gapp K, Bohacek J, Grossmann J, Brunner AM, Manuella F, Nanni P, Mansuy IM. Potential of environmental enrichment to prevent transgenerational effects of paternal trauma. Neuropsychopharmacology 2016; 41(11): 2749–2758

[60] McGreevy KR, Tezanos P, Ferreiro-Villar I, Pallé A, Moreno-Serrano M, Esteve-Codina A, Lamas-Toranzo I, Bermejo-Álvarez P, Fernández-Punzano J, Martín-Montalvo A, Montalbán R, Ferrón SR, Radford EJ, Fontán-Lozano Á, Trejo JL. Intergenerational transmission of the positive effects of physical exercise on brain and cognition. Proc Natl Acad Sci USA 2019; 116(20): 10103–10112

[61] Wang Y, Chen ZP, Hu H, Lei J, Zhou Z, Yao B, Chen L, Liang G, Zhan S, Zhu X, Jin F, Ma R, Zhang J, Liang H, Xing M, Chen XR, Zhang CY, Zhu JN, Chen X. Sperm microRNAs confer depression susceptibility to offspring. Sci Adv 2021; 7(7): eabd7605

[62] Gapp K, van Steenwyk G, Germain PL, Matsushima W, Rudolph KLM, Manuella F, Roszkowski M, Vernaz G, Ghosh T, Pelczar P, Mansuy IM, Miska EA. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol Psychiatry 2020; 25(9): 2162–2174

[63] Chan JC, Morgan CP, Adrian Leu N, Shetty A, Cisse YM, Nugent BM, Morrison KE, Jašarević E, Huang W, Kanyuch N, Rodgers AB, Bhanu NV, Berger DS, Garcia BA, Ament S, Kane M, Neill Epperson C, Bale TL. Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment. Nat Commun 2020; 11(1): 1499

[64] Liu WM, Pang RT, Chiu PC, Wong BP, Lao K, Lee KF, Yeung WS. Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc Natl Acad Sci USA 2012; 109(2): 490–494

[65] Hong Y, Wang C, Fu Z, Liang H, Zhang S, Lu M, Sun W, Ye C, Zhang CY, Zen K, Shi L, Zhang C, Chen X. Systematic characterization of seminal plasma piRNAs as molecular biomarkers for male infertility. Sci Rep 2016; 6(1): 24229

[66] Roberts TC. The microRNA Biology of the mammalian nucleus. Mol Ther Nucleic Acids 2014; 3: e188

[67] Sinkkonen L, Hugenschmidt T, Berninger P, Gaidatzis D, Mohn F, Artus-Revel CG, Zavolan M, Svoboda P, Filipowicz W. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 2008; 15(3): 259–267

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