L. H. Lumey

DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific

Prenatal famine in humans has been associated with various later-life consequences, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Indeed, animal studies and our early human data on the imprinted IGF2 locus indicated a link between prenatal nutritional and DNA methylation. However, it remains unclear how common changes in DNA methylation are and whether they are sex- and timing-specific paralleling the later-life consequences of prenatal famine exposure. To this end, we investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to a war-time famine in 1944-45. Methylation of INSIGF was lower among individuals who were periconceptionally exposed to the famine (n = 60) compared with their unexposed same-sex siblings (P = 2 x 10(-5)), whereas methylation of IL10, LEP, ABCA1, GNASAS and MEG3 was higher (all P < 10(-3)). A significant interaction with sex was observed for INSIGF, LEP and GNASAS. Next, methylation of eight representative loci was compared between 62 individuals exposed late in gestation and their unexposed siblings. Methylation was different for GNASAS (P = 1.1 x 10(-7)) and, in men, LEP (P = 0.017). Our data indicate that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure and that these changes depend on the sex of the exposed individual and the gestational timing of the exposure.

Prenatal Famine and Adult Health

We review human studies on the relation between acute exposures to prenatal famine and adult physical and mental health. These studies are observational and include exposures to a famine environment by natural or man-made causes or, more commonly, from the interplay between natural and human factors. These natural experiments provide an opportunity to examine long-term outcomes after famine exposures by comparing exposed and nonexposed individuals. The studies show consistent associations between prenatal famine and adult body size, diabetes, and schizophrenia. For other measures of adult health, findings are less robust. A relation between prenatal famine and some reported epigenetic changes may provide a potential mechanism to explain specific associations. Much progress can be made if current separate studies are further analyzed with comparable definitions of exposures and outcomes and using common analytic strategies.

The epigenome: Archive of the prenatal environment

World-wide, research initiatives are in progress to establish the role of the epigenome in human disease. Empirical data are still scarce, but particularly studies investigating how the epigenome links early developmental and adult disease may rapidly change this situation. Recently, several reports showed that prenatal environmental conditions are associated with persistent changes of the human epigenome. The evaluation of candidate loci among individuals prenatally exposed to the Dutch Famine indicated that such changes may be common but individually relatively small and greatly depend on the timing of the exposure during gestation. These first findings suggest that the epigenomic contribution to disease risk may entail the combination of multiple changes especially when adaptive responses are involved to cope with environmental conditions. Well-designed epigenome-wide studies will be crucial in creating a catalogue of epigenomic regions that are sensitive to the prenatal environment to appreciate developmental influences on common human disease.

Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch Hunger Winter Families Study

BACKGROUND Many studies in humans have related birth weight to lipid profiles in adulthood. Fewer have estimated associations directly attributable to maternal nutrition during pregnancy. OBJECTIVE Our objective was to determine whether famine exposure during gestation is associated with a more atherogenic profile in adult offspring. DESIGN In 2003-2005, we studied 1) 359 singleton men and women born between January 1945 and March 1946 in clinics in Amsterdam, Rotterdam, and Leiden whose mothers were exposed to the famine during pregnancy; 2) 299 singletons born in the same 3 institutions during 1943 or 1947; and 3) 313 unexposed same-sex siblings of the above individuals. A lipid profile was obtained after an overnight fast. RESULTS Female offspring with prenatal famine exposure had a dyslipidemic pattern characterized by elevated total cholesterol (0.26 mmol/L; 95% CI: 0.07, 0.46; P = 0.007), triglycerides (0.17 mmol/L; 95% CI: 0.03, 0.31; P = 0.02), and LDL cholesterol (0.17 mmol/L; 95% CI: -0.01, 0.36; P = 0.06) compared with unexposed offspring. This pattern was not seen in men. The increases in total cholesterol and LDL cholesterol were independent of body mass index, waist circumference, and midthigh circumference. The increase in triglycerides was independent of midthigh circumference but was attenuated with control for either body mass index or waist circumference. There was no evidence for associations within specific gestational windows. No association was observed between prenatal famine exposure and HDL cholesterol in either sex. CONCLUSION In women, but not in men, aged approximately 58 y, we observed an association between prenatal undernutrition and elevated total cholesterol concentrations and triglycerides.

Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19

Both the early environment and genetic variation may affect DNA methylation, which is one of the major molecular marks of the epigenome. The combined effect of these factors on a well-defined locus has not been studied to date. We evaluated the association of periconceptional exposure to the Dutch Famine of 1944–45, as an example of an early environmental exposure, and single nucleotide polymorphisms covering the genetic variation (tagging SNPs) with DNA methylation at the imprinted IGF2/H19 region, a model for an epigenetically regulated genomic region. DNA methylation was measured at five differentially methylated regions (DMRs) that regulate the imprinted status of the IGF2/H19 region. Small but consistent differences in DNA methylation were observed comparing 60 individuals with periconceptional famine exposure with unexposed same-sex siblings at all IGF2 DMRs (PBH<0.05 after adjustment for multiple testing), but not at the H19 DMR. IGF2 DMR0 methylation was associated with IGF2 SNP rs2239681 (PBH = 0.027) and INS promoter methylation with INS SNPs, including rs689, which tags the INS VNTR, suggesting a mechanism for the reported effect of the VNTR on INS expression (PBH = 3.4×10−3). Prenatal famine and genetic variation showed similar associations with IGF2/H19 methylation and their contributions were additive. They were small in absolute terms (<3%), but on average 0.5 standard deviations relative to the variation in the population. Our analyses suggest that environmental and genetic factors could have independent and additive similarly sized effects on DNA methylation at the same regulatory site.

In utero exposure to famine and subsequent fertility: The Dutch Famine Birth Cohort Study.

OBJECTIVES We hypothesized that if prenatal caloric restriction due to nutritional deprivation had affected development of the organs responsible for producing and regulating female reproductive hormones, a womans fertility would be impaired. METHODS Women born in Amsterdam from August 1, 1944, through April 15, 1946, a period encompassing a severe 5-month famine, were identified (n = 700; 85% response rate). Date of birth and vital status of all offspring were ascertained by home interview between 1987 and 1991. Famine exposure was inferred from the mothers date of birth. RESULTS Of the study participants, 74 (10.6%) had no children. The remainder reported 1334 off-spring (1294 singletons, 20 pairs of twins), of whom 14 were stillborn and 22 died in the first 7 days of life. There was no detectable effect of famine exposure on age at menarche, the proportion having no children, age at first delivery, or family size. An excess of perinatal deaths occurred among offspring of famine-exposed women, particularly those exposed in their third trimester. CONCLUSIONS Acute famine exposure in utero appears to have no adverse consequences for a womans fertility. The excess perinatal mortality in the second generation is unexplained and should be confirmed by other studies.

Timing of prenatal starvation in women and birth weight in their first and second born offspring : the Dutch famine birth cohort study

OBJECTIVES To examine the long-term effects of severe in utero maternal undernutrition on offspring birth weight. STUDY DESIGN Birth weights were analyzed of 575 first born and 454 second born offspring of 683 women born in Amsterdam, the Netherlands, at the time of a severe famine at the end of World War II. In utero maternal undernutrition was defined separately for each pregnancy trimester by an average daily nutrition ration (supplied to the grandmother) of less than 1000 calories in that trimester of pregnancy. RESULTS Compared to controls, birth weights of first born infants of women prenatally exposed in the first trimester of pregnancy were 73 g heavier (95% CI: -64, 210), and birth weights of second born infants were 96 g lighter (95% CI: -249, 58). Birth weights of infants of women exposed in the second or third trimester were much closer to controls. CONCLUSIONS A substantial (200 g or more) impact of severe in utero maternal undernutrition on OBW can be ruled out. There may, however, be parity specific, moderate (50-100 g) effects of maternal undernutrition early in pregnancy on OBW. This suggestion requires confirmation in other populations.

Associations of Gestational Exposure to Famine with Energy Balance and Macronutrient Density of the Diet at Age 58 Years Differ According to the Reference Population Used

Individuals exposed to the Dutch Famine of 1944-45 during gestation have increased adiposity, which might be due to changes in energy intake, physical activity, or metabolic efficiency. We studied 357 persons born between January 1945 and March 1946 whose mothers experienced famine during or immediately preceding pregnancy, 298 persons born in the same 3 institutions during 1943 or 1947 (time controls), and 311 same-sex sibling controls. We obtained food frequency and physical activity data by questionnaire between 2003 and 2005 (mean age 58 y). We defined gestational exposure as exposure to a ration of <3762 kJ/d (<900 kcal/d) for at least 10 wk. For the whole study population, energy intake was 9225 +/- 2650 kJ/d and physical activity was 7380 +/- 4331 metabolic equivalents (MET).min/wk. Compared with time controls, gestational famine exposure was associated with 113 kJ/d (95% CI, -272, 502) higher energy intake, 0.01 percentage point (95% CI, -0.88, 0.89) higher fat density, 688 MET.min/wk (95% CI, -1398, 23) lower physical activity, and 63 kJ/d (95% CI, -130, 259) higher predicted energy expenditure (pEE). Compared with sibling controls, gestational famine exposure was associated with 4 kJ/d (95% CI, -702, 711) higher energy intake, 2.01 percentage points (95% CI, 0.38, 3.63) higher fat density, 97 MET.min/wk) (95% CI, -1243, 1050) lower physical activity score, and 188 kJ/d (95% CI, -163, 539) higher pEE. Gender-specific associations (P < 0.05 for heterogeneity) emerged for protein density and pEE using time controls and for energy intake using sibling controls. Associations were weak, differed by choice of control, and may reflect sampling variability or methodological differences. Persistent small energy imbalances could explain the increased weight of famine-exposed individuals.

Maternal exposure to the dutch famine before conception and during pregnancy quality of life and depressive symptoms in adult offspring

Background: Gestational exposure to famine has been associated with several chronic diseases in adulthood, but few studies in humans have related prenatal famine exposure to health-related quality of life. We used the circumstances of the Dutch Famine of 1944–1945 (during which official rations were <900 kcal/day for 24 weeks) to assess whether exposure to famine prior to conception or at specified stages of pregnancy was related to self-reported health-related quality of life and depressive symptoms in adulthood. Methods: We studied 923 individuals, including persons born in western Holland between January 1945 and March 1946, persons born in the same 3 institutions in 1943 and 1947 and same-sex siblings of persons in series 1 or 2. Between 2003 and 2005 (mean age: 59 years), we assessed self-reported quality of life with the Short Form 36 questionnaire and derived mental and physical component scores. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression scale. Results: Mean mental and physical component scores were 52.4 (SD = 9.4) and 48.9 (9.0), respectively. The mean depression score was 11.6 (7.4). Age-, sex-, and schooling-adjusted estimates for mutually adjusted exposures were −2.48 for the mental component score with exposure before conception (95% confidence interval = −4.46 to −0.50) and 0.07 with exposure during pregnancy (−1.15 to 1.29). Adjusted estimates for the physical component score were 1.26 with exposure before conception (−0.67 to 3.19) and −0.73 with exposure during pregnancy (−1.94 to 0.48). Adjusted estimates for the depression score were 2.07 with exposure before conception (0.60 to 3.54) and 0.96 with exposure during pregnancy (0.09 to 1.88). There was no evidence of heterogeneity of effects by specific periods of pregnancy exposed to famine. Conclusions: A mothers exposure to famine prior to conception of her offspring was associated with lower self-reported measures of mental health and quality of life in her adult offspring.

Prenatal cocaine exposure and school-age intelligence

Assessments of the possible consequences of prenatal exposure to cocaine have been limited by lack of control for socio-demographic confounders and lack of follow-up into the school years. We evaluated intelligence at ages 6-9 years in 88 children from a cohort of 280 born between September 1, 1985 and August 31, 1986 and identified at birth as cocaine-exposed, and in a group of unexposed (n = 96) births of comparable gender and birthweight. IQ scores did not differ between children with and without prenatal exposure to cocaine (mean 82.9 vs. 82.4, difference = 0.5 points, 95% CI-3.1, 4.1); results were unchanged with adjustment for child height, head circumference and prior residence in a shelter or on the street, and for caregiver IQ and home environment (mean difference = 2.2 points, 95% CI-1.5, 5.8).