Exodus from Hunger: The Long-Term Health Consequences of the 1959–1961 Chinese Famine

This article examines the long-term health consequences of China’s 1959–1961 famine by comparing people who stayed in Guangdong and endured the famine with people who crossed the border to immigrate to Hong Kong and thus escaped the famine. Based on data from the Hong Kong Panel Study of Social Dynamics (HKPSSD) and the China Family Panel Studies (CFPS), we focused on two health indicators—body mass index (BMI) and self-rated health (SRH)—of the cohort born before 1959. Our results show that the stayers who experienced the famine have a lower BMI than the emigrants, and they are likely to have a poor SRH. The difference-in-differences (DID) estimates further show that the famine exposure reduced the odds of giving higher ratings of SRH by 60 and 42 percent, respectively, for the 1923–1940 and 1941–1958 birth cohorts. For the 1923–1940 cohort, famine exposure also reduced their BMI by 1.5 points.     

DNA methylation of IGF2, GNASAS,INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR) and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (less than −1SDS; SGA) with 75 individuals born preterm but with a birth weight appropriate for their gestational age (greater than −1SDS) and a normal postnatal growth (greater than −1SDS at three months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (p = 3.3 × 10⁻¹³) and head circumference at birth (p = 4.1 × 10⁻¹³). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5, 47.5, 79.4 and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non-epigenetic mechanisms that may lead to similar later health outcomes.Key words: SGA, DOHAD, IUGR, DNA methylation, famine, IGF2, LEP, INS, GNASAS     

Intergenerational effects of maternal birth season on offspring size in rural Gambia

Environmental conditions experienced in early life can influence an individual's growth and long-term health, and potentially also that of their offspring. However, such developmental effects on intergenerational outcomes have rarely been studied. Here we investigate intergenerational effects of early environment in humans using survey- and clinic-based data from rural Gambia, a population experiencing substantial seasonal stress that influences foetal growth and has long-term effects on first-generation survival. Using Fourier regression to model seasonality, we test whether (i) parental birth season has intergenerational consequences for offspring in utero growth (1982 neonates, born 1976-2009) and (ii) whether such effects have been reduced by improvements to population health in recent decades. Contrary to our predictions, we show effects of maternal birth season on offspring birth weight and head circumference only in recent maternal cohorts born after 1975. Offspring birth weight varied according to maternal birth season from 2.85 to 3.03 kg among women born during 1975-1984 and from 2.84 to 3.41 kg among those born after 1984, but the seasonality effect reversed between these cohorts. These results were not mediated by differences in maternal age or parity. Equivalent patterns were observed for offspring head circumference (statistically significant) and length (not significant), but not for ponderal index. No relationships were found between paternal birth season and offspring neonatal anthropometrics. Our results indicate that even in rural populations living under conditions of relative affluence, brief variation in environmental conditions during maternal early life may exert long-term intergenerational effects on offspring.     

DNA methylation of IGF2, GNASAS,INSIGF and LEP and being born small for gestational age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (&lt;32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10^-13) and head circumference at birth (P=4.1x10^-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.     

What doesn’t kill her,will make her depressed

In this paper we study the long run effects of the 1959–61 Chinese Famine on mental health outcomes. We focus on cohorts that were born during the famine and examine their mental health as adults, when they are roughly 55 years of age. We find that early-life exposure to this famine leads to a large statistically significant negative impact on women’s mental health, while there is limited effect on men. This gender differential effect is observed because male fetuses experience a stronger natural selection as compared to female fetuses, which implies that in the longer run, surviving females may exhibit larger detrimental effects of early-life famine exposure. Thus, the observed effects are a composite of two well-established factors, the survival of the fittest and the Fetal Origins hypothesis.     

Central hemodynamics and arterial stiffness in adult humans depend on the conditions of early development in the Northern Kola Peninsula

The month and place of birth, i.e., early-life conditions, at low and middle latitudes have proved to be associated with a wide range of later-life health outcomes, including cardiovascular diseases. A comparative observational study was carried out in 122 miners of both sexes residing on the northern Kola Peninsula to examine whether the early-life conditions have any effect on arterial stiffness in adult humans living in the North. The indices of aortic hemodynamics and arterial elasticity were measured using pulse wave analysis and applanation tonometry. The comparison showed that women born in the North have more compliant arteries than their counterparts born in the southern and temperate regions. The men born in summer and autumn have more distensible arteries compared to those born in winter and spring. It is supposed that these differences are due to early epigenetic modification of the genes responsible for the fibrous structure of connective tissue of the arterial wall.     

Timing of puberty and synchronization of seasonal rhythms by simulated natural photoperiods in female Siberian hamsters

The timing of puberty is a critical life history trait of short-lived species; spring-born individuals mature rapidly and breed in the season of birth, whereas young born in mid- to late summer delay puberty until the next spring. The cues that govern the transition from rapid to delayed maturation in natural populations remain unknown. To identify ecologically relevant photoperiod cues that control timing of puberty, we monitored nine cohorts of female Siberian hamsters (Phodopus sungorus) born every 2 wk from 4 wk before to 12 wk after the summer solstice in a simulated natural photoperiod (SNP). Hamsters born by the summer solstice underwent rapid somatic growth and achieved puberty that summer; among females born 2-4 wk after the solstice, some delayed puberty by many weeks, whereas others manifested early puberty. Hamsters born 6 or more weeks after the solstice generally delayed puberty until the following spring. The transition from accelerated to delayed pubertal development in the SNP occurred at day lengths that induce early puberty when presented as static photoperiods. Despite differences in timing of birth and timing of puberty, fall and subsequent spring seasonal events occurred at similar calendar dates in all cohorts. We found no evidence that prenatal photoperiod history influenced postnatal development of female hamsters. Considered together with a parallel study on males, the present findings point to sex differences in responsiveness to natural photoperiod variations. In both sexes, incrementally changing photoperiods exert a strong organizing effect on seasonal rhythms.     

Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959–1961

BackgroundExtensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity.MethodsUsing a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959–1961 and compared to 105 unexposed subjects born 1963–1964.ResultsThe single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions.ConclusionEarly-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.     

Race, health, and disease in 19th-century-born males

This study analyzed skeletal health disparities among African American and Euro-American males of low socioeconomic status born between 1825 and 1877. A total of 651 skeletons from the Cobb, Hamann-Todd, and Terry anatomical collections were macroscopically examined for skeletal pathologies related to dietary deficiencies and disease. Individuals were separated into age, ancestry, birth (Antebellum, Civil War, Pre-Reconstruction, and Reconstruction), combined ancestry/birth, enslaved versus liberated, and collection cohorts. These groups were statistically evaluated using ANOVA and χ(2) analyses to determine if age, ethnic, and temporal differences existed. Results indicated that African Americans, especially those born during Reconstruction, had significantly higher frequencies of tuberculosis (P = 0.004) and treponematosis (P = 0.006) than Euro-Americans. Historical sources are important in contextualizing why these different ethnic and temporal patterns were present, pointing to environmental conditions related to enslavement, postliberation migration to the industrialized North, crowded urban living conditions, and poor sanitation.     

Transgenerational effects of maternal diet on metabolic and reproductive ageing

The early-life environment, in particular maternal diet during pregnancy, influences a wide range of organs and systems in adult offspring. Mounting evidence suggests that developmental programming can also influence health and disease in grand-offspring. Transgenerational effects can be defined as those persisting into an F2 generation, where the F0 mother experiences suboptimal diet during her pregnancy. In this review, we critically examine evidence for transgenerational developmental programming effects in human populations, focusing on metabolic and reproductive outcomes. We discuss evidence from historical cohorts suggesting that grandchildren of women exposed to famine and other dietary alterations during pregnancy may experience increased rates of later health complications than their control counterparts. The methodological difficulties with transgenerational studies in human cohorts are explored. In particular, the problems with assessing reproductive outcomes in human populations are discussed. In light of the relative paucity of evidence available from human cohorts, we consider key insights from transgenerational experimental animal models of developmental programming by maternal diet; data are drawn from a range of rodent models, as well as the guinea-pig and the sheep. The evidence for different potential mechanisms of transgenerational inheritance or re-propagation of developmental programming effects is evaluated. Transgenerational effects could be transmitted through methylation of the gametes via the paternal and maternal lineage, as well as other possible mechanisms via the maternal lineage. Finally, future directions for exploring these underlying mechanisms further are proposed, including utilizing large, well-characterized, prospective pregnancy cohorts that include biobanks, which have been established in various populations during the last few decades.     

Simulated natural day lengths synchronize seasonal rhythms of asynchronously born male Siberian hamsters

Photoperiodism research has relied on static day lengths and abrupt transitions between long and short days to characterize the signals that drive seasonal rhythms. To identify ecologically relevant critical day lengths and to test the extent to which naturally changing day lengths synchronize important developmental events, we monitored nine cohorts of male Siberian hamsters (Phodopus sungorus) born every 2 wk from 4 wk before to 12 wk after the summer solstice in a simulated natural photoperiod (SNP). SNP hamsters born from 4 wk before to 2 wk after the solstice underwent rapid somatic and gonadal growth; among those born 4-6 wk after the solstice, some delayed puberty by many weeks, whereas others manifested early puberty. Hamsters born eight or more weeks after the solstice failed to undergo early testicular development. The transition to delayed development occurred at long day lengths, which induce early puberty when presented as static photoperiods. The first animals to delay puberty may do so predominantly on the basis of postnatal decreases in day length, whereas in later cohorts, a comparison of postnatal day length to gestational day length may contribute to arrested development. Despite differences in timing of birth and timing of puberty, autumn gonadal regression and spring gonadal and somatic growth occurred at similar calendar dates in all cohorts. Incrementally changing photoperiods exert a strong organizing effect on seasonal rhythms by providing hamsters with a richer source of environmental timing cues than are available in simple static day lengths.     

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.     

Density-dependent variation in lifetime breeding success and natural and sexual selection in Soay rams

Variation in male lifetime breeding success (LBS) is central to understanding selection, yet it has rarely been measured in natural populations of large mammals. Here, we first describe variation in the opportunity for selection in cohorts of Soay rams (Ovis aries) on the archipelago of St. Kilda, Scotland, that were born during years of varying population density. Variation in LBS is closely coupled with demography, as rams born in years of low density following population crashes enjoy greater LBS than do those born in high-density years. Paradoxically, the opportunity for selection was greatest in the largest cohorts, those born in years of high population density, owing to low juvenile breeding success and overwinter survival. Variation in longevity and the contribution of nonbreeders were the most important components of the total variance in LBS in cohorts born in years of high density, while variation in fecundity was more important in cohorts born in low-density years. The opportunity for sexual selection is thus stronger in cohorts born in low-density years, as many rams in these cohorts survive to compete for mates as adults in subsequent ruts. Variation in population density in the year of birth also influenced the intensity of selection. Individuals born in years of high population density underwent strong natural selection in favor of longer hindlimbs over their first winter. In contrast, in cohorts born in low-density years, there was no natural selection on hindlimb in the first year of life. Longer hindlimbs were associated with increased fecundity over the entire lifetime of individuals born in low-density years. Natural and sexual selection thus act on the same trait in the same direction at different life-history stages in Soay rams, depending on the population density experienced in the year of birth.     

Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview.

People who were small at birth have been shown to have an increased risk of CHD and chronic bronchitis in later life. These findings have led to the fetal origins hypothesis that proposes that the fetus adapts to a limited supply of nutrients, and in doing so it permanently alters its physiology and metabolism, which could increase its risk of disease in later life. The Dutch famine--though a historical disaster--provides a unique opportunity to study effects of undernutrition during gestation in humans. People who had been exposed to famine in late or mid gestation had reduced glucose tolerance. Whereas people exposed to famine in early gestation had a more atherogenic lipid profile, somewhat higher fibrinogen concentrations and reduced plasma concentrations of factor VII, a higher BMI and they appeared to have a higher risk of CHD. Though the latter was based on small numbers, as could be expected from the relatively young age of the cohort. Nevertheless, this is the first evidence in humans that maternal undernutrition during gestation is linked with the risk of CHD in later life. Our findings broadly support the hypothesis that chronic diseases originate through adaptations made by the fetus in response to undernutrition. The long-term effects of intrauterine undernutrition, however, depend upon its timing during gestation and on the tissues and systems undergoing critical periods of development at that time. Furthermore, our findings suggest that maternal malnutrition during gestation may permanently affect adult health without affecting the size of the baby at birth. This gives the fetal origins hypothesis a new dimension. It may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences for health in later life. CHD may be viewed as the price paid for successful adaptations to an adverse intra-uterine environment. It also implies that the long-term consequences of improved nutrition of pregnant women will be underestimated if these are solely based on the size of the baby at birth. We need to know more about what an adequate diet for pregnant women might be. In general, women are especially receptive to advice about diet and lifestyle before and during a pregnancy. This should be exploited to improve the health of future generations.     

Culled males,infant mortality and reproductive success in a pre-industrial Finnish population

Theoretical and empirical literature asserts that the sex ratio (i.e. M/F) at birth gauges the strength of selection in utero and cohort quality of males that survive to birth. We report the first individual-level test in humans, using detailed life-history data, of the ‘culled cohort’ hypothesis that males born to low annual sex ratio cohorts show lower than expected infant mortality and greater than expected lifetime reproductive success. We applied time-series and structural equation methods to a unique multigenerational dataset of a natural fertility population in nineteenth century Finland. We find that, consistent with culled cohorts, a 1 s.d. decline in the annual cohort sex ratio precedes an 8% decrease in the risk of male infant mortality. Males born to lower cohort sex ratios also successfully raised 4% more offspring to reproductive age than did males born to higher cohort sex ratios. The offspring result, however, falls just outside conventional levels of statistical significance. In historical Finland, the cohort sex ratio gauges selection against males in utero and predicts male infant mortality. The reproductive success findings, however, provide weak support for an evolutionarily adaptive explanation of male culling in utero.     

THE EFFECT OF BIRTH DATE ON FITNESS OF FEMALE DWARF PERCH,MICROMETRUS MINIMUS (PERCIFORMES: EMBIOTOCIDAE)

Lifetime reproductive success may vary considerably with birth date. I measured phenotypic selection on female birth date in a viviparous teleost fish (Embiotocidae: Micrometrus minimus) by sampling birth-date cohorts over time in Tomales Bay, California. Four episodes of selection were measured: survival from birth to first reproduction, reproductive success in the first breeding season, survival to second reproduction, and reproductive success in the second season. Birth date had a significant impact on fitness in the first two episodes. Early born females were more successful in their first breeding season than late born females (directional selection on birth date), but early born females were less likely to survive the period between birth and first reproduction, relative to females born in the middle of the season (stabilizing selection on birth date). The final two episodes of selection had no detectable effect on birth date. Because of the relationship between birth date and survival in the first year, overall selection on female birth date was stabilizing.     

Two decades of genetic profiling yields first evidence of natal philopatry and long‐term fidelity to parturition sites in sharks

Sharks are a globally threatened group of marine fishes that often breed in their natal region of origin. There has even been speculation that female sharks return to their exact birthplace to breed (‘natal philopatry’), which would have important conservation implications. Genetic profiling of lemon sharks (Negaprion brevirostris) from 20 consecutive cohorts (1993–2012) at Bimini, Bahamas, showed that certain females faithfully gave birth at this site for nearly two decades. At least six females born in the 1993–1997 cohorts returned to give birth 14–17 years later, providing the first direct evidence of natal philopatry in the chondrichthyans. Long‐term fidelity to specific nursery sites coupled with natal philopatry highlights the merits of emerging spatial and local conservation efforts for these threatened predators.