The transgenerational effects of maternal low-protein diet during lactation on offspring

Lin-Jian Gu; Li Li; Qian-Nan Li; Ke Xu; Wei Yue; Jing-Yi Qiao; Tie-Gang Meng; Ming-Zhe Dong; Wen-Long Lei; Jia-Ni Guo; Zhen-Bo Wang; Qing-Yuan Sun

doi:10.1016/j.jgg.2024.04.008

Volume 51 Issue 8

Aug. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(8): 824-835

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The transgenerational effects of maternal low-protein diet during lactation on offspring

doi: 10.1016/j.jgg.2024.04.008

a. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
b. University of Chinese Academy of Sciences, Beijing 100049, China;
c. Institute of Laboratory Animal Sciences, CAMS & PUMC, Beijing 100021, China;
d. Guangzhou Key Laboratory of Metabolic Diseases and Reproductive Health, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, China

Funds:

This work was supported by the National R&D program of China (2022YFC2703500), the Science and Technology Program of Guangzhou, China (202201020292 and 2023A03J0258), the Natural Science Foundation of Shandong Province (ZR2021ZD33), and the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and Chinese Academy of Sciences (FIRMC181101).

Received Date: 2024-01-07
Accepted Date: 2024-04-11
Rev Recd Date: 2024-04-10

Available Online: 2025-06-06

Publish Date: 2024-04-23

Abstract

Abstract

Environmental factors such as diet and lifestyle can influence the health of both mothers and offspring. However, its transgenerational transmission and underlying mechanisms remain largely unknown. Here, using a maternal lactation-period low-protein diet (LPD) mouse model, we show that maternal LPD during lactation causes decreased survival and stunted growth, significantly reduces ovulation and litter size, and alters the gut microbiome in the female LPD-F1 offspring. The transcriptome of LPD-F1 metaphase II (MII) oocytes shows that differentially expressed genes are enriched in female pregnancy and multiple metabolic processes. Moreover, maternal LPD causes early stunted growth and impairs metabolic health, which is transmitted over two generations. The methylome alteration of LPD-F1 oocytes can be partly transmitted to the F2 oocytes. Together, our results reveal that LPD during lactation transgenerationally affects offspring health, probably via oocyte epigenetic changes.
- Lactation diet,
- Maternal low-protein diet,
- DNA methylation,
- Transgenerational effect,
- Oocyte

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References(62)

References

Baker, J.M., Al-Nakkash, L., Herbst-Kralovetz, M.M., 2017. Estrogen gut microbiome axis: physiological and clinical implications. Maturitas 103, 45-53.

Barker, D.J.P., Osmond, C., 1986. Infant-mortality, childhood nutrition, and ischemic-heart-disease in england and wales. Lancet 1, 1077-1081.

Benjamin-Chung, J., Mertens, A., Colford, J.M., Jr., Hubbard, A.E., van der Laan, M.J., Coyle, J., Sofrygin, O., Cai, W., Nguyen, A., Pokpongkiat, N.N., et al., 2023. Early-childhood linear growth faltering in low- and middle-income countries. Nature 621, 550-557.

Berger, P.K., Plows, J.F., Jones, R.B., Alderete, T.L., Rios, C., Pickering, T.A., Fields, D.A., Bode, L., Peterson, B.S., Goran, M.I., 2020. Associations of maternal fructose and sugar-sweetened beverage and juice intake during lactation with infant neurodevelopmental outcomes at 24 months. Am. J. Clin. Nutr. 112, 1516-1522.

Carone, B.R., Fauquier, L., Habib, N., Shea, J.M., Hart, C.E., Li, R., Bock, C., Li, C., Gu, H., Zamore, P.D.,et al., 2010. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084-1096.

Chen, B., Du, Y.-R., Zhu, H., Sun, M.-L., Wang, C., Cheng, Y., Pang, H., Ding, G., Gao, J., Tan, Y., et al., 2022. Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. Nature 605, 761-776.

Chen, Q., Yan, M., Cao, Z., Li, X., Zhang, Y., Shi, J., Feng, G.-H., Peng, H., Zhang, X., Zhang, Y., et al., 2016. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397-400.

Chen, T.T., Chen, X., Zhang, S.S., Zhu, J.W., Tang, B.X., Wang, A.K., Dong, L.L., Zhang, Z.W., Yu, C.X., Sun, Y.L., et al., 2021. The genome sequence archive family: toward explosive data growth and diverse data types. Genomics Proteomics & Bioinformatics 19, 578-583.

Cox, L.M., Yamanishi, S., Sohn, J., Alekseyenko, A.V., Leung, J.M., Cho, I., Kim, S.G., Li, H., Gao, Z., Mahana, D., et al., 2014. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705-721.

Daxinger, L., Whitelaw, E., 2012. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153-162.

De-Regil, L.M., Fernandez-Gaxiola, A.C., Dowswell, T., Pena-Rosas, J.P., 2010. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database of Syst. Rev. 2015, CD007950.

de Waard, M., Brands, B., Kouwenhoven, S.M.P., Calvo Lerma, J., Crespo-Escobar, P., Koletzko, B., Zalewski, B.M., van Goudoever, J.B., 2017. Optimal nutrition in lactating women and its effect on later health of offspring: a systematic review of current evidence and recommendations (EarlyNutrition project). Crit. Rev. Food Sci. Nutr. 57, 4003-4016.

Elgart, M., Stern, S., Salton, O., Gnainsky, Y., Heifetz, Y., Soen, Y., 2016. Impact of gut microbiota on the fly's germ line. Nat. Commun. 7, 11280.

Fehr, K., Moossavi, S., Sbihi, H., Boutin, R.C.T., Bode, L., Robertson, B., Yonemitsu, C., Field, C.J., Becker, A.B., Mandhane, P.J., et al., 2020. Breastmilk feeding practices are associated with the co-occurrence of bacteria in mothers' milk and the infant gut: the child cohort study. Cell Host & Microbe 28, 285-297.

Fleming, T.P., 2018. The remarkable legacy of a father's diet on the health of his offspring. Proc. Natl. Acad. Sci. U. S. A. 115, 9827-9829.

Francis, E.C., Dabelea, D., Shankar, K., Perng, W., 2021. Maternal diet quality during pregnancy is associated with biomarkers of metabolic risk among male offspring. Diabetologia 64, 2478-2490.

Gahurova, L., Tomizawa, S.I., Smallwood, S.A., Stewart-Morgan, K.R., Saadeh, H., Kim, J., Andrews, S.R., Chen, T., Kelsey, G., 2017. Transcription and chromatin determinants of de novo DNA methylation timing in oocytes. Epigenetics & Chromatin 10. https://doi.org/10.1186/s13072-017-0133-5.

Ge, Z.J., Luo, S.M., Lin, F., Liang, Q.X., Huang, L., Wei, Y.C., Hou, Y., Han, Z.M., Schatten, H., Sun, Q.Y., 2014. DNA methylation in oocytes and liver of female mice and their offspring: effects of high-fat-diet-induced obesity. Environ. Health Perspect. 122, 159-164.

Gluckman, P.D., Hanson, M.A., Cooper, C., Thornburg, K.L., 2008. Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61-73.

Gould, J.M., Smith, P.J., Airey, C.J., Mort, E.J., Airey, L.E., Warricker, F.D.M., Pearson-Farr, J.E., Weston, E.C., Gould, P.J.W., Semmence, O.G., et al., 2018. Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory. Proc. Natl. Acad. Sci. U. S. A. 115, E7398-E7407.

Granger, C.L., Embleton, N.D., Palmer, J.M., Lamb, C.A., Berrington, J.E., Stewart, C.J., 2021. Maternal breastmilk, infant gut microbiome and the impact on preterm infant health. Acta Paediatr. 110, 450-457.

Guo, H., Zhu, P., Guo, F., Li, X., Wu, X., Fan, X., Wen, L., Tang, F., 2015. Profiling DNA methylome landscapes of mammalian cells with single-cell reduced-representation bisulfite sequencing. Nat. Protoc. 10, 645-659.

Guo, Y., Qi, Y., Yang, X., Zhao, L., Wen, S., Liu, Y., Tang, L., 2016. Association between polycystic ovary syndrome and gut microbiota. PLoS ONE 11, e0153196.

Herzl, E., Schmitt, E.E., Shearrer, G., Keith, J.F., 2023. The effects of a western diet vs. a high-fiber unprocessed diet on health outcomes in mice offspring. Nutrients 15, 2858.

Iwamori, T., Lin, Y.-N., Ma, L., Iwamori, N., Matzuk, M.M., 2011. Identification and characterization of RBM44 as a novel intercellular bridge protein. PLoS ONE 6, e17066.

Jones, P.A., 2012. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484-492.

Kinyoki, D.K., Osgood-Zimmerman, A.E., Pickering, B.V., Schaeffer, L.E., Marczak, L.B., Lazzar-Atwood, A., Collison, M.L., Henry, N.J., Abebe, Z., Adamu, A.A., et al., 2010. Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. Cancer Res. 70, 2829-2839.

Kong, Z., Xie, D., Boike, T., Raghavan, P., Burma, S., Chen, D.J., Habib, A.A., Chakraborty, A., Hsieh, J.T., Saha, D., 2010. Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. Cancer Res 70, 2829–2839.

Lismer, A., Dumeaux, V., Lafleur, C., Lambrot, R., Brind'Amour, J., Lorincz, M.C., Kimmins, S., 2021. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev. Cell 56, 671-686.

Love, M.I., Huber, W., Anders, S., 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Bio. 15, 550.

Lowe, W.L., Jr., Scholtens, D.M., Kuang, A., Linder, B., Lawrence, J.M., Lebenthal, Y., McCance, D., Hamilton, J., Nodzenski, M., Talbot, O., et al., 2019. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care 42, 372-380.

Lyons, K.E., Ryan, C.A., Dempsey, E.M., Ross, R.P., Stanton, C., 2020. Breast milk, a source of beneficial microbes and associated benefits for infant health. Nutrients 12, 1039.

Markle, J.G.M., Frank, D.N., Mortin-Toth, S., Robertson, C.E., Feazel, L.M., Rolle-Kampczyk, U., von Bergen, M., McCoy, K.D., Macpherson, A.J., Danska, J.S., 2013. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084-1088.

Marshall, N.E., Abrams, B., Barbour, L.A., Catalano, P., Christian, P., Friedman, J.E., Hay, W.W., Jr., Hernandez, T.L., Krebs, N.F., Oken, E., et al., 2022. The importance of nutrition in pregnancy and lactation: lifelong consequences. Am. J. Obstet. Gynecol. 226, 607-632.

Painter, R.C., Roseboom, T.J., Bleker, O.P., 2005. Prenatal exposure to the Dutch famine and disease in later life: An overview. Reprod. Toxicol. 20, 345-352.

Patro, R., Duggal, G., Love, M.I., Irizarry, R.A., Kingsford, C., 2017. Salmon provides fast and bias-aware quantification of transcript expression. Nature Methods 14, 417-419.

Peters, J., 2014. The role of genomic imprinting in biology and disease: an expanding view. Nat. Rev. Genet. 15, 517-530.

Picelli, S., Bjorklund, A.K., Faridani, O.R., Sagasser, S., Winberg, G., Sandberg, R., 2013. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. Nat. Methods 10, 1096-1098.

Radford, E.J., Ito, M., Shi, H., Corish, J.A., Yamazawa, K., Isganaitis, E., Seisenberger, S., Hore, T.A., Reik, W., Erkek, S., Peters, A.H.F.M., et al., 2014. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903.

Rodgers, A.B., Morgan, C.P., Leu, N.A., Bale, T.L., 2015. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl. Acad. Sci. U. S. A. 112, 13699-13704.

Saben, J.L., Boudoures, A.L., Asghar, Z., Thompson, A., Drury, A., Zhang, W., Chi, M., Cusumano, A., Scheaffer, S., Moley, K.H., 2016. Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Rep. 16, 1-8.

Sales, V.M., Ferguson-Smith, A.C., Patti, M.E., 2017. Epigenetic mechanisms of transmission of metabolic disease across generations. Cell Metab. 25, 559-571.

Schwarzer, M., Gautam, U.K., Makki, K., Lambert, A., Brabec, T., Joly, A., Srutkova, D., Poinsot, P., Novotna, T., Geoffroy, S., et al., 2023. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science 379, 826-833.

Skoracka, K., Ratajczak, A.E., Rychter, A.M., Dobrowolska, A., Krela-Kazmierczak, I., 2021. Female Fertility and the Nutritional Approach: The Most Essential Aspects. Adv. Nutr. 12, 2372-2386.

Smallwood, S.A., Kelsey, G., 2012. De novo DNA methylation: a germ cell perspective. Trends Genet. 28, 33-42.

Smith, Z.D., Meissner, A., 2013. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204-220.

Stewart, K.R., Veselovska, L., Kelsey, G., 2016. Establishment and functions of DNA methylation in the germline. Epigenomics 8, 1399-1413.

Takahashi, Y., Valencia, M.M., Yu, Y., Ouchi, Y., Takahashi, K., Shokhirev, M.N., Lande, K., Williams, A.E., Fresia, C., Kurita, M., et al., 2023. Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice. Cell 186, 715-731.

Tang, S.-B., Zhang, T.-T., Yin, S., Shen, W., Luo, S.-M., Zhao, Y., Zhang, C.-L., Klinger, F.G., Sun, Q.-Y., Ge, Z.-J., 2023. Inheritance of perturbed methylation and metabolism caused by uterine malnutrition via oocytes. BMC Biol. 21, 43.

Tobi, E.W., Lumey, L.H., Talens, R.P., Kremer, D., Putter, H., Stein, A.D., Slagboom, P.E., Heijmans, B.T., 2009. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Mol. Genet. 18, 4046-4053.

Watkins, A.J., Dias, I., Tsuro, H., Allen, D., Emes, R.D., Moreton, J., Wilson, R., Ingram, R.J.M., Sinclair, K.D., 2018. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc. Natl. Acad. Sci. U. S. A. 115, 10064-10069.

Wei, Y., Yang, C.R., Wei, Y.P., Zhao, Z.A., Hou, Y., Schatten, H., Sun, Q.Y., 2014. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc. Natl. Acad. Sci. U. S. A. 111, 1873-1878.

Winship, A.L., Gazzard, S.E., Cullen-McEwen, L.A., Bertram, J.F., Hutt, K.J., 2018. Maternal low-protein diet programmes low ovarian reserve in offspring. Reproduction 156, 299-311.

Xu, B., Qin, W., Chen, Y., Tang, Y., Zhou, S., Huang, J., Ma, L., Yan, X., 2023. Multi-omics analysis reveals gut microbiota-ovary axis contributed to the follicular development difference between Meishan and Landrace x Yorkshire sows. J. Anim. Sci. Biotechnol. 14, 68.

Xue, Y.B., Bao, Y.M., Zhang, Z., Zhao, W.M., Xiao, J.F., He, S.M., Zhang, G.Q., Li, Y.X., Zhao, G.P., Chen, R.S., et al., 2022. Database resources of the national genomics data center, china national center for bioinformation in 2022. Nucleic Acids Res. 50, D27-D38.

Yelverton, C.A., Killeen, S.L., Feehily, C., Moore, R.L., Callaghan, S.L., Geraghty, A.A., Byrne, D.F., Walsh, C.J., Lawton, E.M., Murphy, E.F., et al., 2023. Maternal breastfeeding is associated with offspring microbiome diversity; a secondary analysis of the MicrobeMom randomized control trial. Front. Microbiol. 14, 1154114.

Yu, G., Wang, L.-G., Han, Y., He, Q.-Y., 2012. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284-287.

Yuan, X., Tan, Y., Bajinka, O., Jammeh, M.L., Dukureh, A., Obiegbusi, C.N., Abdelhalim, K.A., Mohanad, M., 2024. The connection between epigenetics and gut microbiota-current perspective. Cell Biochem. Funct. 42, e3941.

Zambrano, E., Rodriguez-Gonzalez, G.L., Guzman, C., Garcia-Becerra, R., Boeck, L., Diaz, L., Menjivar, M., Larrea, F., Nathanielsz, P.W., 2005. A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development. J. Physiol. 563, 275-284.

Zenk, F., Loeser, E., Schiavo, R., Kilpert, F., Bogdanovic, O., Iovino, N., 2017. Germ line-inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition. Science 357, 212-216.

Zhu, Y., Bond, J., Thomas, P., 2003. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl. Acad. Sci. U. S. A. 100, 2237-2242.

Zou, J., Ngo, V.L., Wang, Y., Wang, Y., Gewirtz, A.T., 2022. Maternal fiber deprivation alters microbiota in offspring, resulting in low-grade inflammation and predisposition to obesity. Cell Host Microbe 31, 45-57.

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