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Sins of the Fathers, and Their Fathers European Journal of Human Genetics (2006) 14, 131–132 & 2006 Nature Publishing Group All rights reserved 1018-4813/06 $30.00 www.nature.com/ejhg the establishment of the epigenetic state NEWS AND COMMENTARY at these loci can be modified by environ- ment. For example, the epigenetic state of Epigenetics the agouti viable yellow locus, containing a ...................................... gene contributing to coat colour in mice, can be manipulated by altering the diet of Sins of the fathers, and their the pregnant female.12,13 At this stage, these effects have only been studied in F1 fathers offspring. However, epigenetics does pro- Emma Whitelaw vide a possible mechanism for the trans- generational effects reported by Pembrey ......................................................................... and co-workers. European Journal of Human Genetics (2006) 14, 131–132. Their intriguing finding of transgenera- tional effects that are sex-specific, is also doi:10.1038/sj.ejhg.5201567 not without precedent in animal systems. It has been known for some time that transient exposure of pregnant female rats fascinating article by Marcus genetic and environmental factors in this to vinclozolin, a fungicide used in the Pembrey and co-workers,1 pub- phenomenon remains unclear, most in- wine industry, can cause reproductive 14 lished in this issue of the Eur- terpret it as an example of the effects of abnormalities in male offspring. A re- 15 Aopean Journal of Human Genetics, maternal undernutrition. cent study has shown that the repro- suggests that the behaviour (or environ- In animal models, these types of effects, ductive abnormalities, including reduced ment) of prepubescent boys could influ- termed fetal programming, can be pro- sperm count and sperm motility, are ence the phenotype of their sons and duced by exposing offspring in utero to detected in nearly all male offspring for grandsons. a manipulation such as dietary restric- at least four generations. The effect could Using data collected in the Avon Long- tion of the pregnant female.5 Although not be passed through female subjects; itudinal Study of Parents and Children most studies of fetal programming only female siblings of affected males in the F2 (ALSPAC), they showed that early paternal address effects in the first-generation generation, when mated with untreated smoking was associated with greater body offspring, there is strong evidence that, controls, produced male offspring with mass index at 9 years of age in sons, but not at least in some cases, these programmed normal fertility. in daughters. This prompted them to phenotypes are maintained for several The authors favour the idea that the return to the records of the 1890, 1905 generations.6 For example, prenatal pro- toxin causes epigenetic changes to the DNA and 1920 cohorts from Overkalix, an gramming of birth weight by maternal in the developing germ line of the male isolated community in Northern Sweden. food restriction or maternal exercise have embryos, and that this change is main- Previously, they reported an association of been shown to last for more than one tained and carried along with the sperm to ancestral food supply with longevity2 and generation.7,8 the next generation. However a role for the with cardiovascular and diabetic mortality.3 The molecular basis for these apparently Y chromosome, similar to that postulated Reanalysis showed that the paternal nongenetic transgeneration effects is not by Pembrey, remains a possibility. grandfathers’ food supply during mid known. One hypothesis is that it involves There are many intriguing parallels childhood was linked to the mortality risk epigenetics. Epigenetics is the process by between the rat study from the Skinner ratio of grandsons, but not granddaugh- which patterns of gene expression are lab and the Pembrey study in humans. ters. The study suggested that in humans, modified in a mitotically heritable man- Geneticists, epigeneticists and environ- a one-off environmental event could ner by mechanisms that do not involve mental biologists are still grappling with influence phenotype for more than one DNA mutation. Epigenetic modifications these surprising results. Whether this is a generation in a sex-specific way. If true, include, among others, the methylation new kind of genetic event, which is Y- these findings implied a novel kind of state of the DNA and the proteins that specific, or an epigenetic event that is transgenerational inheritance, an idea package the DNA into chromosomes. The sperm-specific, or something else alto- strengthened by recent studies in animal epigenetic state of the genome is estab- gether, remains unclear. However, the systems. lished in early development and is gen- implications of the finding are profound. The effects of maternal nutrition or erally thought to be cleared between From a public health point of view, other environmental ‘exposures’ are well generations. what makes the Pembrey study particu- recognised in mammals, including hu- However, there is increasing evidence larly interesting is that it argues that mans. Epidemiological studies from the that some parts of the genome are not exposure in the male can affect the UK have demonstrated an association cleared leading to transgenerational in- development and health of males for between low birth weight and adult onset heritance of epigenetic state in these at least two generations, and this is disease, including heart disease and dia- specific parts, termed transgenerational rarely, if ever, considered. This paper betes.4 While the relative importance of epigenetic inheritance.9–11 Furthermore, should stimulate both epidemiologists News and Commentary 132 and experimental biologists to look for 3 Kaati G, Bygren LO, Edvinsson S: Cardio- agouti locus in the mouse. Nat Genet 1999; transgenerational effects in other situa- vascular and diabetes mortality deter- 23: 314 – 318. tions. Furthermore, these findings may go mined by nutrition during parents’ and 11 Rakyan VK, Chong S, Champ ME et al: grandparents’ slow growth period. Eur J Transgenerational inheritance of epige- some way toward shifting the balance of Hum Genet 2002; 10: 682 – 688. netic states at the murine Axin(Fu) allele responsibility for the unborn, away from 4 Barker D: In utero programming of chronic occurs after maternal and paternal trans- the mother. Fathers-to-be take note! disease. Clin Sci 1998; 95: 115 – 128. mission. Proc Natl Acad Sci USA 2003; 100: 5 Nathanielsz PW, Thornburg KL: Fetal 2538 –2543. programming: from gene to functional 12 Cooney CA, Dave AA, Wolff GL: Maternal Dr E Whitelaw is at the Queensland systems – an overview. J Physiol 2003; methyl supplements in mice affect epi- Institute of Medical Research, 300 Herston 547:3–4. genetic variation and DNA methylation 6 Drake AJ, Walker BR: The intergenerational Road, Herston, Queensland 4006, of offspring. J Nutr 2002; 132: 2393S – effects of fetal programming: non-genomic 2400S. Australia. mechanisms for the inheritance of low 13 Waterland RA, Jirtle RL: Transposable ele- E-mail: [email protected] birth weight and cardiovascular risk. ments: targets for early nutritional effects J Endocrinol 2004; 180: 1 –16. on epigenetic gene regulation. Mol Cell Biol 7 Stewart RJ, Preece RF, Sheppard HG: Twelve 2003; 23: 5293 –5300. generations of marginal protein deficiency. 14 Kelce WR, Monosson E, Gamcsik MP et al: Br J Nutr 1975; 33: 233 – 253. References Environmental hormone disruptors: evi- 8 Pinto M, Shetty P: Influence of exercise- dence that vinclozolin developmental 1 Pembrey M, Bygren LO, Kaati GP et al: Sex- induced maternal stress on fetal outcome toxicity is mediated by antiandrogenic specific, sperm-mediated transgenerational in Wistar rats: intergenerational effects. Br metabolites. Toxicol Appl Pharmacol 1994; responses in humans. Eur J Hum Genet J Nutr 1995; 73: 645 – 653. 126: 276 –285. 2005; 14: 159 – 166. 9 Roemer I, Reik W, Dean W, Klose J: 15 Anway MD, Cupp AS, Uzumcu M 2 Bygren LO, Kaati G, Edvinsson S: Longevity Epigenetic inheritance in the mouse. Curr et al: Epigenetic transgenerational determined by ancestors’ overnutrition Biol 1997; 7: 277 – 280. actions of endocrine disruptors and during their slow growth period. Acta 10 Morgan HD, Sutherland HG, Martin DI, male fertility. Science 2005; 308: 1466 – Biotheoret 2001; 49: 53 –59. Whitelaw E: Epigenetic inheritance at the 1469. European Journal of Human Genetics.
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