Abstract
Transgenerational effects of maternal nutrition or other environmental ‘exposures’ are well recognised, but the possibility of exposure in the male influencing development and health in the next generation(s) is rarely considered. However, historical associations of longevity with paternal ancestors' food supply in the slow growth period (SGP) in mid childhood have been reported. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified 166 fathers who reported starting smoking before age 11 years and compared the growth of their offspring with those with a later paternal onset of smoking, after correcting for confounders. We analysed food supply effects on offspring and grandchild mortality risk ratios (RR) using 303 probands and their 1818 parents and grandparents from the 1890, 1905 and 1920 Överkalix cohorts, northern Sweden. After appropriate adjustment, early paternal smoking is associated with greater body mass index (BMI) at 9 years in sons, but not daughters. Sex-specific effects were also shown in the Överkalix data; paternal grandfather's food supply was only linked to the mortality RR of grandsons, while paternal grandmother's food supply was only associated with the granddaughters' mortality RR. These transgenerational effects were observed with exposure during the SGP (both grandparents) or fetal/infant life (grandmothers) but not during either grandparent's puberty. We conclude that sex-specific, male-line transgenerational responses exist in humans and hypothesise that these transmissions are mediated by the sex chromosomes, X and Y. Such responses add an entirely new dimension to the study of gene–environment interactions in development and health.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Drake AJ, Walker BR : The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J Endocrinol 2004; 180: 1–16.
Shorter J, Lindquist S : Prions as adaptive conduits of memory and inheritance. Nature Rev Genet 2005; 6: 435–450.
Ostermeier GC, Miller D, Huntriss JD, Diamond MP, Krawetz S : Delivering spermatozoan RNA to the oocyte. Nature 2004; 429: 154.
Yasui K, Mihara S, Zhao C et al: Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res 2004; 64: 1403–1410.
Epel ES, Blackburn EH, Lin J et al: Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci 2004; 101: 17312–17315.
Bird A : DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16: 6–21.
Rakyan VK, Chong S, Champ ME et al: Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs following maternal and paternal transmission. Proc Natl Acad Sci 2003; 100: 2538–2543.
Anway MD, Cupp AS, Uzumcu M, Skinner MK : Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005; 308: 1466–1469.
Bygren LO, Kaati G, Edvinsson S : Longevity determined by ancestors' overnutrition during their slow growth period. Acta Biotheoretica 2001; 49: 53–59.
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: 682–688.
Golding J, Pembrey M, Jones R, ALSPAC Study Team: ALSPAC – the avon longitudinal study of parents and children. I. Study methodology. Paediatr Perinat Epidemiol 2001; 15: 74–87.
Ness AR : The avon longitudinal study of parents and children (ALSPAC) –a resource for the study of the environmental determinants of childhood obesity. Eur J Endocrinol 2004; 151: U141–U149.
Prader A, Largo RH, Molinari L, Issler C : Physical growth of Swiss children from birth to 20 years of age. First Zurich Study of Growth and Development. Helv Paediatr Acta 1989; 43 (Suppl 52): 1–125.
Tanner JM : A history of the study of human growth. Cambridge: Cambridge University Press, 1981.
SAS/STAT software, Version 8.2 of SAS System for Windows. Copyright 1999–2001 Cary, NC, USA: SAS Institute Inc.
Campbell JH, Perkins P : Transgenerational effects of drug and hormonal treatments in mammals: a review of observations and ideas. Prog Brain Res 1988; 73: 535–553.
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: 49–55.
Barber R, Plumb MA, Boulton E, Roux I, Dubrova Y : Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice. Proc Natl Acad Sci 2002; 99: 6877–6882.
Drake AJ, Walker BR, Seckl JR : Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 2005; 288: R34–R38.
Robaire B, Hales BF (eds): Advances in Male Mediated Developmental Toxicity. New York: Kluwer Academic/Plenum Publishers, 2003.
Weismann A : The Germ-Plasm: A Theory of Heredity, (translated from the 1892 German edn by W Newton and H Ronnfeldt). London: Walter Scott, 1893.
Graham H, Power C : Childhood disadvantage and health inequalities: a framework for policy based on lifecourse research. Child Care Health Dev 2004; 30: 671–678.
Pembrey ME : Time to take epigenetic inheritance seriously. Eur J Hum Genet 2002; 10: 669–671.
Johnson J, Canning J, KanekoT et al.: Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428: 145–150.
Zubenko GS, Stiffler JS, Hughes, Fatigati MJ, Zubenko WN : Genome survey for loci that influence successful aging: sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry 2002; 10: 619–630.
Acknowledgements
We are extremely grateful to all the mothers and their partners who took part and to the midwives for their cooperation and help in recruitment into ALSPAC. The whole ALSPAC study team comprises interviewers, computer technicians, laboratory technicians, clerical workers, research scientists, volunteers and managers who continue to make the study possible. ALSPAC is supported by the Wellcome Trust, the Medical Research Council (MRC), the Department of Health, the Department of the Environment and many others. We acknowledge Lennart Backman, MD, for his contribution to the Swedish study that was supported by the Swedish Councils for Planning and Coordination of Research (FRN 940020:4) and Working Life and Social Research (FAS 2001-1061). We thank Marilyn Monk and Tim Cole for comments on earlier manuscripts.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
Pembrey, M., Bygren, L., Kaati, G. et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14, 159–166 (2006). https://doi.org/10.1038/sj.ejhg.5201538
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201538
Keywords
This article is cited by
-
Inheritance of perturbed methylation and metabolism caused by uterine malnutrition via oocytes
BMC Biology (2023)
-
Inheritance of paternal lifestyles and exposures through sperm DNA methylation
Nature Reviews Urology (2023)
-
Missing Causality and Heritability of Autoimmune Hepatitis
Digestive Diseases and Sciences (2023)
-
Epigenetics and the role of nutraceuticals in health and disease
Environmental Science and Pollution Research (2023)
-
Effects of paternal exposure to cigarette smoke on sperm DNA methylation and long-term metabolic syndrome in offspring
Epigenetics & Chromatin (2022)
