Fermat's Library | Persistent epigenetic differences associated with prenatal exposure to famine in humans annotated/explained version.

"The Dutch Hunger Winter has proved unique in unexpected ways. Beca...

Important: "These data are the ﬁrst to contribute empirical support...

'The Dutch famine of 1944–45 was a famine that took place in the Ge...

This is the truly groundbreaking finding: epigenetic effects that w...

Important: "Our study provides the first evidence that transient en...

We know so much less about epigenetics than genetics, yet the forme...

Persistent epigenetic differences associated with

prenatal exposure to famine in humans

Bastiaan T. Heijmans

a,1,2

, Elmar W. Tobi

a,2

, Aryeh D. Stein

, Hein Putter

, Gerard J. Blauw

, Ezra S. Susser

e,f

P. Eline Slagboom

, and L. H. Lumey

e,1

Departments of

Molecular Epidemiology,

Medical Statistics, and

Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands;

Hubert Department of Global Health, Rollins School of Public Health, Emory University Atlanta, GA 30322;

Department of Epidemiology, Mailman School

of Public Health, Columbia University, New York, NY 10032; and

New York State Psychiatric Institute, New York, NY 10032

Edited by Charles R. Cantor, Sequenom Inc., San Diego, CA, and approved September 17, 2008 (received for review July 7, 2008)

Extensive epidemiologic studies have suggested that adult disease

risk is associated with adverse environmental conditions early in

development. Although the mechanisms behind these relation-

ships are unclear, an involvement of epigenetic dysregulation has

been hypothesized. Here we show that individuals who were

prenatally exposed to famine during the Dutch Hunger Winter in

1944–45 had, 6 decades later, less DNA methylation of the im-

printed IGF2 gene compared with their unexposed, same-sex

siblings. The association was speciﬁc for periconceptional expo-

sure, reinforcing that very early mammalian development is a

crucial period for establishing and maintaining epigenetic marks.

These data are the ﬁrst to contribute empirical support for the

hypothesis that early-life environmental conditions can cause epi-

genetic changes in humans that persist throughout life.

developmental origins 兩 DNA methylation 兩 insulin-like growth factor II 兩

nutrition 兩 periconception

uperimposed on the DNA sequence is a layer of epigenetic

infor mation that is herit able, particularly during mitosis, and

c ontrols the potential of a genomic region to be transcribed (1).

Methyl groups coupled to cy tosines in cy tosine-guanine (CpG)

dinucleotides and modifications of histones that package the

DNA are the t wo main molecular marks that compose this

infor mation and regulate chromatin str ucture and DNA acces-

sibilit y (2).

A nimal studies have indicated that certain transient environ-

ment al influences can produce persistent changes in epigenetic

marks that have life-long phenotypic consequences (3, 4). Early

embryonic development is of special interest in this respect,

because this is a crucial period for establishing and maintaining

epigenetic marks (5). Indeed, culturing of preimplantation mice

embryos found that epigenetic marks are susceptible to nutri-

tional conditions in the very early st ages of mammalian devel-

opment (6, 7).

One of the rare opportunities for studying the relevance of

such findings to humans is presented by indiv iduals who were

prenat ally exposed to famine during the Dutch Hunger Winter

(8). This period of famine was the c onsequence of a German-

imposed food embargo in the western part of The Netherlands

toward the end of World War II in the winter of 1944–45. During

this period, registries and health care remained intact, so that

individuals who were prenatally exposed to this famine can be

traced. Moreover, the period of famine was clearly defined, and

of ficial food rations were documented. These unique features

allow us to assess whether prenatal exposure to famine is

associated with persistent epigenetic differences in humans.

One of the best-characterized epigenetically regulated loci is

insulin-like growth factor II (IGF2). IGF2 is a key factor in

human growth and development and is maternally imprinted (9).

Imprinting is maint ained through the IGF2 dif ferentially meth-

ylated region (DMR), the hypomethylation of which leads to

bi-allelic expression of IGF2 (10). We recently studied IGF2

DMR methylation in 372 twins (11). IGF2 DMR methylation is

a normally distributed quantitative trait that is largely deter-

mined by genetic factors in both adolescence and middle age,

indicating that the methylation mark is stable up to middle age.

Thus, if affected by environmental conditions early in human

development, altered IGF2 DMR methylation may be detected

many years later.

Here we used our ongoing Hunger Winter Families Study (8)

to investigate whether prenatal exposure to famine is associated

with persistent differences in methylation of the IGF2 DMR.

Our primary focus was exposure during periconception, thus

ensuring that the exposure was present during the very early

st ages of development that are critical in epigenetic program-

ming. To further investigate the role of timing, we also studied

individuals who were exposed late in gest ation.

Results

Periconceptional Exposure. Our primary goal was to test whether

peric onceptional exposure to famine was associated with differ-

ences in IGF2 DMR methylation in adulthood. Toward this end,

we selected the 60 individuals from the Hunger Winter Families

Study who were conceived during the famine 6 decades ago. The

ex posure period thus included the very early stages of develop-

ment. The exposed individuals were compared with their same-

sex sibling to achieve partial genetic matching. Using a quanti-

t ative mass spectrometry– based method (12, 13), the

methylation of five CpG dinucleotides within the IGF2 DMR

was measured (11). Three CpG sites were measured individually,

and two were measured simultaneously, because they could not

be resolved due to their close proximity. All CpG sites but one

were significantly less methylated among periconceptionally

ex posed individuals compared with their siblings (1.5 ⫻ 10

⫺4

ⱕ

P ⱕ 8.1 ⫻ 10

⫺3

; see Table 1). The average methylation fraction

of the IGF2 DMR based on all five CpG sites was 0.488 among

ex posed siblings and 0.515 among unexposed siblings. Thus,

peric onceptional exposure was associated with a 5.2% lower

methylation (P ⫽ 5.9 ⫻ 10

⫺5

), corresponding to 0.48 standard

deviations (SDs) of the c ontrols. The association was indepen-

dent of sex (P

interaction

⫽ 0.20).

Fig. 1A displays the difference in IGF2 DMR methylation

within sibships according to the estimated conception date of the

famine-ex posed individual. IGF2 DMR methylation was lowest

in the famine-exposed individual among 72% (43/60) of sibships;

this lower methylation was observed in conceptions across the

famine period. Official daily rations were set weekly during the

Author contributions: B.T.H., A.D.S., E.S.S., P.E.S., and L.H.L. designed research; E.W.T. and

G.J.B. performed research; B.T.H., E.W.T., H.P., and L.H.L. analyzed data; and B.T.H., E.W.T.,

P.E.S., and L.H.L. wrote the paper.

The authors declare no conﬂict of interest.

This article is a PNAS Direct Submission.

To whom correspondence may be addressed. E-mail: b.t.heijmans@lumc.nl or lumey@

columbia.edu.

B.T.H. and E.W.T. contributed equally to this work.

17046–17049

兩

PNAS

兩

November 4, 2008

兩

vol. 105

兩

no. 44 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0806560105

famine period and were the same for every individual. The

average daily rations were 667 kcal (SD, 151) (Fig. 1 A), and there

was little variation in the percentage of calories from proteins

(⬇12%, of which 4% of animal origin), fat (19%), and carbo-

hydrates (69%) (14).

As a technical validation, IGF2 DMR methylation was remea-

sured in 46 of 60 periconceptionally exposed individuals and

their same-sex siblings, repeating the whole procedure from

bisulfite treatment to quantification. A similarly lower 5.6%

IGF2 DMR methylation was observed (P ⫽ 2.1 ⫻ 10

⫺3

c onfirming our initial findings.

Late Gestational Exposure. To further investigate the influence of

timing, we selected the 62 individuals who were exposed to

famine late in gestation for at least 10 weeks, so that they were

born in or shortly after the famine. We found no difference in

IGF2 DMR methylation between the exposed individuals and

their unexposed siblings (Table 2; Fig. 1B).

To formally test whether the association with lower IGF2

DMR methylation depended on the timing of exposure, we

analyzed the peric onceptional and late exposure groups together

with all 122 controls in a single model (Table 3). Periconcep-

tional exposure was associated with lower methylation (P ⫽

1.5 ⫻ 10

⫺5

), whereas late exposure was not (P ⫽ 0.69). Further-

more, there was statistically significant evidence for an interac-

tion between timing and exposure (P

interaction

⫽ 4.7 ⫻ 10

⫺3

indicating that the association was timing-specific.

Birth Weight. The mean birth weight of the 62 individuals exposed

late in gestation was 3126 g (SD, 408), which is 296 g lower (95%

c onfidence interval [CI], ⫺420 to ⫺170 g) than the mean (3422

g; SD, 464) of 324 reference births in 1943 at the same institu-

tions (P ⫽ 4 ⫻ 10

⫺6

) (15). The lower birth weight underscores

the impact of the famine during the Hunger Winter notwith-

st anding the absence of an association with IGF2 DMR methyl-

ation. The mean birth weight of the 60 individuals who were

ex posed periconceptionally was 3612 g (SD, 648), not lower that

that of the reference births (95% CI, ⫹15 to ⫹ 365 g; P ⫽ 0.03).

IGF2 DMR methylation was not associated with birth weight

(P ⫽ 0.39).

Age Association. To put the association of periconceptional

famine ex posure with a 5.2% lower IGF2 DMR methylation into

perspective, we assessed the relationship between age and IGF2

DMR methylation in the 122 control individuals. Within the age

range studied (43–70 years), a 10-year-older age was associated

with a 3.6% lower methylation (P ⫽ .015).

Discussion

Here we report that periconceptional exposure to famine during

the Dutch Hunger Winter is associated with lower methylation

of the IGF2 DMR 6 decades later. The hypomethylation that we

observed is highly comparable to that found for the Nr3c1 and

Ppara genes in offspring of female rats fed an isocaloric protein-

deficient diet starting before pregnancy (⫺8.2% and ⫺10.2% vs

⫺5.2% in our human study) (16), although greater effects for the

Agtr1b gene have been found in a similar rat model (17). These

dat a from animal models are consistent with the interpretation

that famine underlies the IGF2 hypomethylation that we ob-

served and may be related to a deficiency in methyl donors, such

as the amino acid methionine (3). An additional contribution of

other stressors, such as cold and emotional stress (8), cannot be

Fig. 1. Difference in IGF2 DMR methylation between individuals prenatally exposed to famine and their same-sex sibling. (A) Periconceptional exposure:

Difference in methylation according to the mother’s last menstrual period (a common estimate of conception) before conception of the famine-exposed

individual. ( B) Exposure late in gestation: Difference in methylation according to the date of birth of the famine-exposed individual. To describe the difference

in methylation according to estimated conception and birth dates, a lowess curve (red or blue) is drawn. The average distributed rations (in kcal/day) between

December 1944 and June 1945 are depicted in green.

Table 1. IGF2 DMR methylation among individuals periconceptionally exposed to famine and their unexposed,

same-sex siblings

IGF2 DMR

methylation

Mean methylation fraction (SD)

Relative change

exposed

Difference

in SDs PExposed (n ⫽ 60) Controls (n ⫽ 60)

Average 0.488 (0.047) 0.515 (0.055) ⫺5.2% ⫺0.48 5.9 ⫻ 10

⫺5

CpG 1 0.436 (0.037) 0.470 (0.041) ⫺6.9% ⫺0.78 1.5 ⫻ 10

⫺4

CpG 2 and 3 0.451 (0.033) 0.473 (0.055) ⫺4.7% ⫺0.41 8.1 ⫻ 10

⫺3

CpG 4 0.577 (0.114) 0.591 (0.112) ⫺2.3% ⫺0.12 .41

CpG 5 0.491 (0.061) 0.529 (0.068) ⫺7.2% ⫺0.56 1.4 ⫻ 10

⫺3

P values were obtained using a linear mixed model and adjusted for age.

Heijmans et al. PNAS

兩

November 4, 2008

兩

vol. 105

兩

no. 44

兩

17047

GENETICS

r uled out, however. Our study provides the first evidence that

transient environment al conditions early in human gestation can

be recorded as persistent changes in epigenetic information.

In contrast to periconceptional ex posure to famine, exposure

late in gestation was not associated with IGF2 DMR methyl-

ation. Epigenetic marks may be particularly vulnerable during

the very early stage of mammalian development, which is a

cr ucial period for establishing and maintain ing epigenetic marks

(5). Experiments in which mouse zygotes were cultured to

blastoc ysts favor this hypothesis (6, 7). The timing dependence

of the association that we observed also may relate to the timing

of tissue development, however (18). We studied blood and adult

blood cells stem from the hematopoietic system, which is est ab-

lished relatively early in mammalian development (eg, day 10.5

in the mouse embryo [cf. weeks 4–6 in human gest ation] (19)).

Det ailed future studies are needed to establish whether the

susceptibilit y of epigenetic marks is an intrinsic property of early

mammalian development or a general feature of newly devel-

oping tissues throughout gestation. Our results do not exclude

the occurrence of epigenetic changes later in development (20)

or during aging (21).

The developmental origins hypothesis states that adverse

c onditions during development contribute to adult disease risk

(22). Although the mechanisms behind these relationships are

unclear, the involvement of epigenetic dysregulation has been

proposed (22–24). Our findings are a key element in elaborating

this hypothesis. Human studies on the developmental origins of

health and disease often use low birth weight as a proxy for a

c ompromised prenat al development (22). Our data indicate that

such studies are not necessarily sufficient for testing the involve-

ment of epigenetics and thus extend our prev ious finding that

birth weight is a poor surrogate for nutritional status during

gestation (15). Epigenetic differences were found among indi-

viduals who were exposed to famine early in gestation and had

a normal birth weight. Exposure to famine late in gest ation was

associated with low birth weight, as ex pected, but not with

epigenetic changes. To monitor the crucial stages of early

development, assessing maternal lifestyle, especially regarding

nutrition (25), and embryo growth using three-dimensional

ultrasonography (26) may be more appropriate than assessing

birth weight.

The current study presents a first example of an association

bet ween a periconceptional exposure and DNA methylation in

humans. It will be of prime interest to investigate whether other

ex posures during early development that are more common in

modern societies, including overnutrition (3) and assisted repro-

ductive technologies (27), give rise to similar associations. In

addition, the extent to which epigenetic marks at other genomic

regions are vulnerable to such exposures remains to be estab-

lished. A key area to ex plore in future studies will be to assess

the phenotypic consequences of changes in epigenetic marks.

Diseases that have been associated with early gestational expo-

sure to famine, such as schizophrenia (28) and coronary heart

disease (29), are of particular interest in this respect. Analogous

to current studies in genetic epidemiology (30), such epigenetic

epidemiologic studies may need to be large and to include

replication. Understanding how epigenetic control depends on

early exposure may shed light on the link between development

and health over the lifespan and ultimately suggest new ways to

prevent human disease.

Methods

Study Population. The design of and recruitment for the Hunger Winter

Families Study were described previously (8). Individuals exposed to famine

prenatally were recruited by identiﬁcation and follow-up of live singleton

births in 1945 and early 1946 at three institutions in famine-exposed cities (the

midwifery training schools in Amsterdam and Rotterdam and the Leiden

University hospital). As controls, same-sex siblings and unrelated individuals

from the same institutions who were born before or conceived after the

famine period were recruited. Clinical examination, including blood sam-

pling, was completed for 311 exposed individuals, 311 same-sex siblings, and

349 unrelated controls. Birth weight was abstracted from birth records from

the three institutions. No birth weight data are available for the same-sex

siblings who were not born at these institutions.

For the current epigenetic study, we focused on exposed individuals and

their siblings as controls to achieve partial genetic matching in view of the

Table 2. IGF2 DMR methylation among individuals exposed to famine late in gestation and their unexposed,

same-sex siblings

IGF2 DMR

methylation

Mean methylation fraction (SD)

Relative change

exposed

Difference

in SDs PExposed (n ⫽ 62) Controls (n ⫽ 62)

Average 0.514 0.045 0.519 0.036 ⫺0.9% ⫺0.12 .64

CpG 1 0.460 0.044 0.464 0.048 ⫺0.9% ⫺0.09 .68

CpG 2 and 3 0.462 0.039 0.471 0.039 ⫺1.7% ⫺0.21 .46

CpG 4 0.602 0.085 0.612 0.073 ⫺1.5% ⫺0.12 .30

CpG 5 0.529 0.060 0.531 0.060 ⫺0.3% ⫺0.02 .77

P values were obtained using a linear mixed model and adjusted for age.

Table 3. Timing of famine exposure during gestation, IGF2 DMR methylation, and

birth weight

Periconceptional

exposure

Late gestational

exposure All controls

n 60 62 122

Males, % 46.7 45.2 45.9

Mean age, years 58.1 (SD, 0.35) 58.8 (SD, 0.4) 57.1 (SD, 5.5)

Birth weight, g 3612 (SD, 648) 3126 (SD, 408) —

IGF2 DMR methylation

Average 0.488 (SD, 0.047) 0.514 (SD, 0.045) 0.517 (SD, 0.047)

vs all controls

1.5 ⫻ 10

⫺5

.69

interaction

4.7 ⫻ 10

⫺3

P values were obtained using a linear mixed model and adjusted for age.

17048

兩

www.pnas.org兾cgi兾doi兾10.1073兾pnas.0806560105 Heijmans et al.

high heritability of IGF2 DMR methylation (11). From these, we selected the

sibships with an individual exposed to famine periconceptionally and those

with an individual exposed to famine late in gestation. Periconceptional

exposure was deﬁned as the mother’s last menstrual period before conceiving

the exposed individual between November 28, 1944 and May 15, 1945. This

yielded 60 sibships. Exposure late in gestation was deﬁned as a birth between

January 28 and May 30, 1945, so that the duration of the famine exposure was

at least 10 weeks. This yielded 62 sibships.

DNA Methylation. Methylation of the IGF2 DMR was measured using genomic

DNA from whole blood extracted using the salting-out method. One micro-

gram of genomic DNA was bisulﬁte-treated using the EZ 96-DNA methylation

kit (Zymo Research). Sibships were bisulﬁte-treated on the same plate. Three

plates were used to process the 244 samples, each with an equal number of

samples and a similar distribution in periconceptionally and late-exposed

subjects. The region harboring the IGF2 DMR (chr11:2,126,035–2,126,372 in

NCBI build 36.1) was ampliﬁed using primers described elsewhere (11). DNA

methylation was measured using a mass spectrometry–based method (Epi-

typer, Sequenom) (12), the quantitative accuracy (R

duplicate measure-

ments ⱖ 0.98) and concordance with clonal polymerase chain reaction bisul-

ﬁte sequencing of which has been reported previously (13, 31). All

measurements were done in triplicate. CpG dinucleotides whose measure-

ment was confounded by single nucleotide polymorphisms, as we discussed in

a previous report (11), were discarded as part of quality control. The CpG

dinucleotides reported in the current study were located at positions 41, 57

and 60, 202, and 251 bp in the amplicon targeting the IGF2 DMR. Methylation

data were 93% complete. DNA methylation of ﬁve CpG dinucleotides could be

measured, three individually and two as a pair because they were directly

adjacent and could not be resolved individually.

Statistical Analysis. The mean methylation fractions of individual CpGs and

their SDs presented in the tables and ﬁgures are based on raw data. To obtain

the average methylation of the whole IGF2 DMR presented in the tables and

ﬁgures, missing methylation data were ﬁrst imputed using estimates from

linear mixed models, thereby exploiting the correlations among CpG sites (11).

To test for differences between exposed individuals and their unexposed

siblings, age-adjusted linear mixed models were applied to the raw data

without imputation of missing values. These analyses accounted for age at

examination, family relations, correlated methylation of CpG dinucleotides,

and methylation data missing at random. Exposure status, CpG dinucleotide,

and age were entered as ﬁxed effects, and sibship was entered as a random

effect. The model including both the periconceptional and the late-exposure

groups was extended with a variable indicating timing of the exposure and an

interaction term of exposure status times exposure time. To test for the

association between IGF2 DMR methylation and birth weight, birth weight

was added as a ﬁxed effect. The linear mixed model may be viewed as an

extension of the paired t-test; the model reduces to a paired t-test with

identical outcomes if within-family methylation differences are assessed for a

single CpG nucleotide and if data are complete and age adjustment is omitted.

All P values are two-sided, and all statistical analyses were performed using

SPSS 14.0.

ACKNOWLEDGMENTS. We thank the participants of the Hunger Winter

Families Study, TNO Quality of Life for contact tracing, the staff of the

Gerontology and Geriatrics Study Center at the Leiden University Medical

Center for performing the clinical examinations, Marja Kersbergen and Mar-

got van Schie for extracting genomic DNA, and Dennis Kremer for technical

assistance. This work was supported by grants from the Netherlands Heart

Foundation (2006B083 to B.T.H.), the U.S. National Institutes of Health (RO1-

HL067914 to L.H.L.), the Netherlands Organization for Scientiﬁc Research

NWO (911– 03-016 to P.E.S.), and the European Union–funded Network of

Excellence LifeSpan (FP6 036894).

1. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: How the genome

integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254.

2. Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669 –

681.

3. Waterland RA, Jirtle RL (2003) Transposable elements: Targets for early nutritional

effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300.

4. Sinclair KD, et al. (2007) DNA methylation, insulin resistance, and blood pressure in

offspring determined by maternal periconceptional B vitamin and methionine status.

Proc Natl Acad SciUSA104:19351–19356.

5. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian develop-

ment. Science 293:1089 –1093.

6. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM (2000) Differential

effects of culture on imprinted H19 expression in the preimplantation mouse embryo.

Biol Reprod 62:1526 –1535.

7. Morgan HD, Jin XL, Li A, Whitelaw E, O’Neill C (2008) The culture of zygotes to the

blastocyst stage changes the postnatal expression of an epigentically labile allele,

agouti viable yellow, in mice. Biol Reprod 79:618 – 623.

8. Lumey LH, et al. (2007) Cohort proﬁle: The Dutch Hunger Winter Families Study. Int J

Epidemiol 36:1196 –1204.

9. Smith FM, Garﬁeld AS, Ward A (2006) Regulation of growth and metabolism by

imprinted genes. Cytogenet Genome Res 113:279–291.

10. Cui H, et al. (2003) Loss of IGF2 imprinting: A potential marker of colorectal cancer risk.

Science 299:1753–1755.

11. Heijmans BT, Kremer D, Tobi EW, Boomsma DI, Slagboom PE (2007) Heritable rather

than age-related environmental and stochastic factors dominate variation in DNA

methylation of the human IGF2/H19 locus. Hum Mol Genet 16:547–554.

12. Ehrich M, et al. (2005) Quantitative high-throughput analysis of DNA methylation

patterns by base-speciﬁc cleavage and mass spectrometry. Proc Natl Acad Sci USA

102:15785–15790.

13. Coolen MW, Statham AL, Gardiner-Garden M, Clark SJ (2007) Genomic proﬁling of CpG

methylation and allelic speciﬁcity using quantitative high-throughput mass spectrom-

etry: Critical evaluation and improvements. Nucleic Acids Res 35:e119.

14. Burger GCE, Drummond JC, Sandstead HR (1948) Malnutrition and Starvation in

Western Netherlands, September 1944–July 1945, Part 1 (General State Printing Ofﬁce,

The Hague).

15. Stein AD, Zybert PA, van de Bor M, Lumey LH (2004) Intrauterine famine exposure and

body proportions at birth: The Dutch Hunger Winter. Int J Epidemiol 33:831– 836.

16. Burdge GC, et al. (2007) Dietary protein restriction of pregnant rats in the F0 gener-

ation induces altered methylation of hepatic gene promoters in the adult male

offspring in the F1 and F2 generations. Br J Nutr 97:435–439.

17. Bogdarina I, Welham S, King PJ, Burns SP, Clark AJ (2007) Epigenetic modiﬁcation of

the renin-angiotensin system in the fetal programming of hypertension. Circ Res

100:520–526.

18. Waterland RA, Lin JR, Smith CA, Jirtle RL (2006) Post-weaning diet affects genomic

imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15:705–716.

19. Dzierzak E, Speck NA (2008) Of lineage and legacy: The development of mammalian

hematopoietic stem cells. Nat Immunol 9:129–136.

20. Weaver IC, et al. (2004) Epigenetic programming by maternal behavior. Nat Neurosci

7:847–854.

21. Bjornsson HT, et al. (2008) Intra-individual change over time in DNA methylation with

familial clustering. JAMA 299:2877–2883.

22. Waterland RA, Michels KB (2007) Epigenetic epidemiology of the developmental

origins hypothesis. Annu Rev Nutr 27:363–388.

23. Cutﬁeld WS, Hofman PL, Mitchell M, Morison IM (2007) Could epigenetics play a role

in the developmental origins of health and disease? Pediatr Res 61:68R–75R.

24. McClellan JM, Susser E, King MC (2006) Maternal famine, de novo mutations, and

schizophrenia. JAMA 296:582–584.

25. Verkleij-Hagoort AC, et al. (2007) Validation of the assessment of folate and vitamin

B12 intake in women of reproductive age: The method of triads. Eur J Clin Nutr

61:610– 615.

26. Verwoerd-Dikkeboom CM, Koning AH, van der Spek PJ, Exalto N, Steegers EA (2008)

Embryonic staging using a 3D virtual reality system. Hum Reprod 23:1479–1484.

27. DeBaun MR, Niemitz EL, Feinberg AP (2003) Association of in vitro fertilization with

Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum

Genet 72:156 –160.

28. Susser E, et al. (1996) Schizophrenia after prenatal famine: Further evidence. Arch Gen

Psychiatry 53:25–31.

29. Painter RC, et al. (2006) Early onset of coronary artery disease after prenatal exposure

to the Dutch famine. Am J Clin Nutr 84:322–327.

30. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of

14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661– 678.

31. Ehrich M, et al. (2008) Cytosine methylation proﬁling of cancer cell lines. Proc Natl Acad

Sci USA 105:4844 – 4849.

Heijmans et al. PNAS

兩

November 4, 2008

兩

vol. 105

兩

no. 44

兩

17049

GENETICS

Discussion

Important: "Our study provides the first evidence that transient environmental conditions early in human gestation can be recorded as persistent changes in epigenetic information." We know so much less about epigenetics than genetics, yet the former could help us understand heritability even more than the later. An example - as humans share 98% of our DNA with chimpanzees, it is the regulation of those genes that could drive the biggest differences, the regulation of genes can separate species and individuals within species, and could be the next frontier. "A key area to explore in future studies will be to assess the phenotypic consequences of changes in epigenetic marks." Important: "These data are the ﬁrst to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life." This is the truly groundbreaking finding: epigenetic effects that were passed down over 6 decades. "The Dutch Hunger Winter has proved unique in unexpected ways. Because it started and ended so abruptly, it has served as an unplanned experiment in human health. Pregnant women, it turns out, were uniquely vulnerable, and the children they gave birth to have been influenced by famine throughout their lives. When they became adults, they ended up a few pounds heavier than average. In middle age, they had higher levels of triglycerides and LDL cholesterol. They also experienced higher rates of such conditions as obesity, diabetes and schizophrenia. By the time they reached old age, those risks had taken a measurable toll, according to the research of L.H. Lumey, an epidemiologist at Columbia University. In 2013, he and his colleagues reviewed death records of hundreds of thousands of Dutch people born in the mid-1940s. They found that the people who had been in utero during the famine — known as the Dutch Hunger Winter cohort — died at a higher rate than people born before or afterward. “We found a 10 percent increase in mortality after 68 years,” said Dr. Lumey. The patterns that Dr. Lumey and his colleagues documented are not disputed, but scientists still are struggling to understand how they come about. “How on earth can your body remember the environment it was exposed to in the womb — and remember that decades later?” wondered Bas Heijmans, a geneticist at Leiden University Medical Center in the Netherlands." Source: Carl Zimmer, NY Times: https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html 'The Dutch famine of 1944–45 was a famine that took place in the German-occupied Netherlands, especially in the densely populated western provinces north of the great rivers, during the winter of 1944–45, near the end of World War II. A German blockade cut off food and fuel shipments from farm towns. Some 4.5 million were affected and survived thanks to soup kitchens. It is estimated that at least 22,000 deaths occurred due to the famine. The famine was finally alleviated by the liberation of the provinces by the Allies in May 1945.' Source: https://en.wikipedia.org/wiki/Dutch_famine_of_1944%E2%80%9345

Comments

Products

Project