Skip to main content
SpringerLink
Log in

Female offspring sired by diet induced obese male mice display impaired blastocyst development with molecular alterations to their ovaries, oocytes and cumulus cells

  • Epigenetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To investigate the impacts that a paternal high fat diet (HFD) has on embryology, ovarian/cumulus cell gene expression and COC metabolism from female offspring, using a mouse model.

Methods

Founder male mice were either fed a control diet (CD) or a HFD for 12 weeks. The HFD induced obesity but not diabetes, and founder males were then mated to normal weight CD fed female mice. Female offspring were maintained on a CD, super-ovulated, mated and the resultant zygotes were cultured to the blastocyst stage for embryo morphology, blastocyst cell number and apoptosis assessment. Ovaries and cumulus cells from offspring were collected for gene expression analysis of selected genes that maintain chromatin remodeling and endoplasmic reticulum (ER), metabolic and inflammatory homeostasis. Cumulus/oocyte complexes were also investigated for glucose uptake and lipid accumulation.

Results

Female offspring sired by obese fathers produced embryos with delayed development and impaired quality, displayed increases in ovarian expression of Glut1, Glut3 and Glut4, and an increase in cumulus cell expression of Glut4. Interestingly their COCs did take up more glucose, but did accumulate more lipid.

Conclusions

A paternal HFD is associated with subfertility in female offspring despite the offspring being fed a CD and this subfertility is concomitant with ovarian/cumulus cell molecular alterations and increased lipid accumulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ogden CLC, Margaret D; Kit, Brian K.; Flegal, Katherine M. Prevalence of Obesity in the United States, 2009–2010: Centers for Diease Control and Prevention, Statistics NCfH. 2012.

  2. Fejes I, Koloszar S, Szollosi J, Zavaczki Z, Pal A. Is semen quality affected by male body fat distribution? Andrologia. 2005;37(5):155–9.

    Article  CAS  PubMed  Google Scholar 

  3. Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, Meikle AW. Male obesity and alteration in sperm parameters. Fertil Steril. 2008;90(6):2222–5.

    Article  PubMed  Google Scholar 

  4. Aggerholm AS, Thulstrup AM, Toft G, Ramlau-Hansen CH, Bonde JP. Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Fertil Steril. 2008;90(3):619–26.

    Article  CAS  PubMed  Google Scholar 

  5. Chavarro JE, Toth TL, Wright DL, Meeker JD, Hauser R. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil Steril. 2010;93(7):2222–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Jensen TK, Andersson AM, Jorgensen N, Andersen AG, Carlsen E, Petersen JH, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril. 2004;82(4):863–70.

    Article  CAS  PubMed  Google Scholar 

  7. Kort HI, Massey JB, Elsner CW, Mitchell-Leef D, Shapiro DB, Witt MA, et al. Impact of body mass index values on sperm quantity and quality. J Androl. 2006;27(3):450–2.

    Article  PubMed  Google Scholar 

  8. Bakos HW, Henshaw RC, Mitchell M, Lane M. Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology. Fertil Steril. 2011;95(5):1700–4.

    Article  PubMed  Google Scholar 

  9. Mitchell M, Bakos HW, Lane M. Paternal diet-induced obesity impairs embryo development and implantation in the mouse. Fertil Steril. 2011;95(4):1349–53.

    Article  PubMed  Google Scholar 

  10. Keltz J, Zapantis A, Jindal SK, Lieman HJ, Santoro N, Polotsky AJ. Overweight men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles. J Assist Reprod Genet. 2010;27(9–10):539–44.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Binder NK, Mitchell M, Gardner DK. Parental diet-induced obesity leads to retarded early mouse embryo development and altered carbohydrate utilisation by the blastocyst. Reprod Fertil Dev. 2012;24(6):804–12.

    Article  CAS  PubMed  Google Scholar 

  12. Binder NK, Hannan NJ, Gardner DK. Paternal diet-induced obesity retards early mouse embryo development, mitochondrial activity and pregnancy health. PLoS One. 2012;7(12):e52304.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab. 2006;91(4):1275–83.

    Article  CAS  PubMed  Google Scholar 

  14. Ng S-F, Lin RCY, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs [bgr]-cell dysfunction in female rat offspring. Nature. 2010;467(7318):963–6. doi:10.1038/nature09491.

    Article  CAS  PubMed  Google Scholar 

  15. Fullston T, Ohlsson Teague EM, Palmer NO, DeBlasio MJ, Mitchell M, Corbett M, et al. 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 : Off Publ Fed Am Soc Exp Biol. 2013;27(10):4226–43 [Research Support, Non-U.S. Gov’t].

    Article  CAS  Google Scholar 

  16. Fullston T, Palmer NO, Owens JA, Mitchell M, Bakos HW, Lane M. Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice. Hum Reprod. 2012;27(5):1391–400 [Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  17. Minge CE, Bennett BD, Norman RJ, Robker RL. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality. Endocrinology. 2008;149(5):2646–56.

    Article  CAS  PubMed  Google Scholar 

  18. Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, et al. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology. 2010;151(11):5438–45.

    Article  CAS  PubMed  Google Scholar 

  19. Alexander J, Chang GQ, Dourmashkin JT, Leibowitz SF. Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6J mice compared to control strains. Int J Obes (Lond). 2006;30(1):50–9.

    Article  CAS  Google Scholar 

  20. Council NHaMR. Australian Code for the Care and Use of Animals for Scientific Purposes. 2013;8th Edition.

  21. WHO. WHO laboratory manual for the examination and processing of human semen. Fifth Edition ed. 2010.

  22. Nasr-Esfahani MH, Aitken JR, Johnson MH. Hydrogen peroxide levels in mouse oocytes and early cleavage stage embryos developed in vitro or in vivo. Development. 1990;109(2):501–7.

    CAS  PubMed  Google Scholar 

  23. Lane M, Maybach JM, Gardner DK. Addition of ascorbate during cryopreservation stimulates subsequent embryo development. Hum Reprod. 2002;17(10):2686–93.

    Article  CAS  PubMed  Google Scholar 

  24. Gardner DK, Lane M, Watson AJ. In: Gardner DK, Lane M, Watson AJ, editors. A laboratory guide to the mammalian embryo. New York: Oxford University Press; 2004.

    Google Scholar 

  25. Lane M, Gardner DK. Effect of incubation volume and embryo density on the development and viability of mouse embryos in vitro. Hum Reprod. 1992;7(4):558–62 [Research Support, Non-U.S. Gov’t].

    CAS  PubMed  Google Scholar 

  26. Gardner DK, Lane MW, Lane M. EDTA stimulates cleavage stage bovine embryo development in culture but inhibits blastocyst development and differentiation. Mol Reprod Dev. 2000;57(3):256–61.

    Article  CAS  PubMed  Google Scholar 

  27. Zander DL, Thompson JG, Lane M. Perturbations in mouse embryo development and viability caused by ammonium are more severe after exposure at the cleavage stages. Biol Reprod. 2006;74(2):288–94.

    Article  CAS  PubMed  Google Scholar 

  28. Kamjoo M, Brison DR, Kimber SJ. Apoptosis in the preimplantation mouse embryo: effect of strain difference and in vitro culture. Mol Reprod Dev. 2002;61(1):67–77.

    Article  CAS  PubMed  Google Scholar 

  29. Goossens K, van Poucke M, van Soom A, Vandesompele J, van Zeveren A, Peelman LJ. Selection of reference genes for quantitative real-time PCR in bovine preimplantation embryos. BMC Dev Biol. 2005;5:27.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Robert C, McGraw S, Massicotte L, Pravetoni M, Gandolfi F, Sirard MA. Quantification of housekeeping transcript levels during the development of bovine preimplantation embryos. Biol Reprod. 2002;67(5):1465–72 [Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  31. Lane M, Gardner DK. Ammonium induces aberrant blastocyst differentiation, metabolism, pH regulation, gene expression and subsequently alters fetal development in the mouse. Biol Reprod. 2003;69(4):1109–17 [Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  32. McPherson NO, Bakos HW, Owens JA, Setchell BP, Lane M. Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth. PLoS One. 2013;8(8):e71459 [Research Support, Non-U.S. Gov’t].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. van den Berg SW, Dolle ME, Imholz S, van der AD, van ’t Slot R, Wijmenga C, et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study. Int J Obes (Lond). [Research Support, Non-U.S. Gov’t]. 2009 Oct;33(10):1143–52.

  34. Robker RL, Akison LK, Bennett BD, Thrupp PN, Chura LR, Russell DL, et al. Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. J Clin Endocrinol Metab. 2009;94(5):1533–40.

    Article  CAS  PubMed  Google Scholar 

  35. Boyle KE, Newsom SA, Janssen RC, Lappas M, Friedman JE. Skeletal muscle MnSOD, mitochondrial complex II, and SIRT3 enzyme activities are decreased in maternal obesity during human pregnancy and gestational diabetes mellitus. J Clin Endocrinol Metab. 2013;98(10):E1601–9 [Research Support, N.I.H., Extramural].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Bakos HW, Mitchell M, Setchell BP, Lane M. The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model. Int J Androl. 2010 Jul 23.

  37. Palmer NO, Bakos HW, Owens JA, Setchell BP, Lane M. Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function. Am J Physiol Endocrinol Metab. 2012;302(7):E768–80 [In Vitro Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  38. Palmer NO, Fullston T, Mitchell M, Setchell BP, Lane M. SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod Fertil Dev. 2011;23(7):929–39 [Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  39. Mitchell M, Cashman KS, Gardner DK, Thompson JG, Lane M. Disruption of mitochondrial malate-aspartate shuttle activity in mouse blastocysts impairs viability and fetal growth. Biol Reprod. 2009;80(2):295–301 [Research Support, Non-U.S. Gov’t].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Lane M, Gardner DK. Differential regulation of mouse embryo development and viability by amino acids. J Reprod Fertil. 1997;109(1):153–64.

    Article  CAS  PubMed  Google Scholar 

  41. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127(19):4195–202 [Research Support, Non-U.S. Gov’t].

    CAS  PubMed  Google Scholar 

  42. Ghanayem BI, Bai R, Kissling GE, Travlos G, Hoffler U. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol Reprod. 2010;82(1):96–104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003;89(1):3–9 [Review].

    Article  CAS  PubMed  Google Scholar 

  44. Garvey WT, Maianu L, Huecksteadt TP, Birnbaum MJ, Molina JM, Ciaraldi TP. Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. J Clin Invest. 1991;87(3):1072–81 [Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Sivitz WI, DeSautel SL, Kayano T, Bell GI, Pessin JE. Regulation of glucose transporter messenger RNA in insulin-deficient states. Nature. 1989;340(6228):72–4 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.].

    Article  CAS  PubMed  Google Scholar 

  46. Berger J, Biswas C, Vicario PP, Strout HV, Saperstein R, Pilch PF. Decreased expression of the insulin-responsive glucose transporter in diabetes and fasting. Nature. 1989;340(6228):70–2 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.].

    Article  CAS  PubMed  Google Scholar 

  47. Colton SA, Pieper GM, Downs SM. Altered meiotic regulation in oocytes from diabetic mice. Biol Reprod. 2002;67(1):220–31 [Research Support, U.S. Gov’t, P.H.S.].

    Article  CAS  PubMed  Google Scholar 

  48. Wang Q, Ratchford AM, Chi MM, Schoeller E, Frolova A, Schedl T, et al. Maternal diabetes causes mitochondrial dysfunction and meiotic defects in murine oocytes. Mol Endocrinol. 2009;23(10):1603–12 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Purcell SH, Moley KH. The impact of obesity on egg quality. J Assist Reprod Genet. 2011;28(6):517–24 [Review].

    Article  PubMed Central  PubMed  Google Scholar 

  50. Adastra KL, Chi MM, Riley JK, Moley KH. A differential autophagic response to hyperglycemia in the developing murine embryo. Reproduction. 2011;141(5):607–15 [Research Support, N.I.H., Extramural].

    Article  CAS  PubMed  Google Scholar 

  51. Wang Q, Chi MM, Schedl T, Moley KH. An intercellular pathway for glucose transport into mouse oocytes. Am J Physiol Endocrinol Metab. 2012;302(12):E1511–8 [Research Support, N.I.H., Extramural].

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Roberts R, Stark J, Iatropoulou A, Becker DL, Franks S, Hardy K. Energy substrate metabolism of mouse cumulus-oocyte complexes: response to follicle-stimulating hormone is mediated by the phosphatidylinositol 3-kinase pathway and is associated with oocyte maturation. Biol Reprod. 2004;71(1):199–209 [Research Support, Non-U.S. Gov’t].

    Article  CAS  PubMed  Google Scholar 

  53. Phy JL, Conover CA, Abbott DH, Zschunke MA, Walker DL, Session DR, et al. Insulin and messenger ribonucleic acid expression of insulin receptor isoforms in ovarian follicles from nonhirsute ovulatory women and polycystic ovary syndrome patients. J Clin Endocrinol Metab. 2004;89(7):3561–6 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.].

    Article  CAS  PubMed  Google Scholar 

  54. Pantasri T, Norman RJ. The effects of being overweight and obese on female reproduction: a review. Gynecol Endocrinol. 2013 Nov 4.

  55. Ekart J, McNatty K, Hutton J, Pitman J. Ranking and selection of MII oocytes in human ICSI cycles using gene expression levels from associated cumulus cells. Hum Reprod. 2013;28(11):2930–42.

    Article  CAS  PubMed  Google Scholar 

  56. Youngson NA, Whitelaw E. The effects of acquired paternal obesity on the next generation. Asian J Androl. 2011;13(2):195–6.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Soubry A, Murphy SK, Wang F, Huang Z, Vidal AC, Fuemmeler BF, et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond). 2013 Oct 25.

  58. Palmer NO, Bakos HW, Fullston T, Lane M. Impact of obesity on male fertility, sperm function and molecular composition. Spermatogenesis. 2012;2(4):253–63.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Sutton-McDowall ML, Gilchrist RB, Thompson JG. The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction. 2010;139(4):685–95.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Vitrolife for their donation of all culture media used in this study.

This work was supported by the Australian National Health and Medical Research Council project grant awarded to ML. ML is a recipient of a NHMRC SRF and TF/NOM are recipients of NHMRC ECFs.

Conflict of interest

T.F., H.S., L.Y.S., W.X.K., L.L.W., R.L.R., N.O.M. and M.L. declare that they have nothing to disclose.

Author information

Author notes

    Authors and Affiliations

    1. Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Robinson Research Institute, Level 3 Medical School South, The University of Adelaide, Adelaide, South Australia, 5005, Australia

      Tod Fullston, Helana Shehadeh, Lauren Y. Sandeman, Wan Xian Kang, Linda L. Wu, Rebecca L. Robker, Nicole O. McPherson & Michelle Lane

    2. The Freemasons Foundation Centre for Men’s Health, The University of Adelaide, Adelaide, SA, 5005, Australia

      Nicole O. McPherson

    3. Monash IVF Group, Melbourne, Victoria, 3168, Australia

      Michelle Lane

    Authors
    1. Tod Fullston
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Helana Shehadeh
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lauren Y. Sandeman
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wan Xian Kang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Linda L. Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rebecca L. Robker
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Nicole O. McPherson
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Michelle Lane
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Tod Fullston.

    Additional information

    Capsule Although is has been previously demonstrated that paternal obesity can impede the fertility of female offspring, the development of embryos and the molecular charecterisation of reproductive material had not been investigated. Here we show that as a result of paternal obesity female offspring produce embryos with impaired development/quality, have alterations to the epxression of glucose tranpsorter genes in ovaries/cumulus cells and increased lipid uptake into cumulus-oocyte complexes.

    Tod Fullston and Helana Shehadeh contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplemental Fig. 1

    (DOC 160 kb)

    Supplemental Table 1

    (DOCX 42 kb)

    Supplemental Table 2

    (DOCX 39 kb)

    Supplemental Table 3

    (DOCX 39 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Fullston, T., Shehadeh, H., Sandeman, L.Y. et al. Female offspring sired by diet induced obese male mice display impaired blastocyst development with molecular alterations to their ovaries, oocytes and cumulus cells. J Assist Reprod Genet 32, 725–735 (2015). https://doi.org/10.1007/s10815-015-0470-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10815-015-0470-x

    Keywords

    Search

    Navigation