Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research.

Mammalian experiments provide clear evidence of male line transgenerational effects on health and development from paternal or ancestral early-life exposures such as diet or stress. The few human observational studies to date suggest (male line) transgenerational effects exist that cannot easily be attributed to cultural and/or genetic inheritance. Here we summarise relevant studies, drawing attention to exposure sensitive periods in early life and sex differences in transmission and offspring outcomes. Thus, variation, or changes, in the parental/ancestral environment may influence phenotypic variation for better or worse in the next generation(s), and so contribute to common, non-communicable disease risk including sex differences. We argue that life-course epidemiology should be reframed to include exposures from previous generations, keeping an open mind as to the mechanisms that transmit this information to offspring. Finally, we discuss animal experiments, including the role of epigenetic inheritance and non-coding RNAs, in terms of what lessons can be learnt for designing and interpreting human studies. This review was developed initially as a position paper by the multidisciplinary Network in Epigenetic Epidemiology to encourage transgenerational research in human cohorts.

Change in paternal grandmothers' early food supply influenced cardiovascular mortality of the female grandchildren.

BACKGROUND: This study investigated whether large fluctuations in food availability during grandparents' early development influenced grandchildren's cardiovascular mortality. We reported earlier that changes in availability of food - from good to poor or from poor to good - during intrauterine development was followed by a double risk of sudden death as an adult, and that mortality rate can be associated with ancestors' childhood availability of food. We have now studied transgenerational responses (TGR) to sharp differences of harvest between two consecutive years' for ancestors of 317 people in Överkalix, Sweden. RESULTS: The confidence intervals were very wide but we found a striking TGR. There was no response in cardiovascular mortality in the grandchild from sharp changes of early exposure, experienced by three of the four grandparents (maternal grandparents and paternal grandfathers). If, however, the paternal grandmother up to puberty lived through a sharp change in food supply from one year to next, her sons' daughters had an excess risk for cardiovascular mortality (HR 2.69, 95% confidence interval 1.05-6.92). Selection or learning and imitation are unlikely explanations. X-linked epigenetic inheritance via spermatozoa seemed to be plausible, with the transmission, limited to being through the father, possibly explained by the sex differences in meiosis. CONCLUSION: The shock of change in food availability seems to give specific transgenerational responses.

Intergenerational health responses to adverse and enriched environments.

Health consequences of relative or absolute poverty constitute a definitive area of study in social medicine. As demonstrated in the extreme example of the Dutch Hunger Winter from 1944 to 1945, prenatal hunger can lead to adult schizophrenia and depression. A Norwegian study showed how childhood poverty resulted in a heightened risk of myocardial infarction in adulthood. In England, a study of extended impaired prenatal nutrition indicated three different types of increased cardiovascular risk at older ages. Current animal and human studies link both adverse and enriched environmental exposures to intergenerational transmission. We do not fully understand the molecular mechanisms for it; however, studies that follow up epigenetic marks within a generation combined with exploration of gametic epigenetic inheritance may help explain the prevalence of certain conditions such as cardiovascular disease, schizophrenia, and alcoholism, which have complex etiologies. Insights from these studies will be of great public health importance.

Accuracy of death certificates of cardiovascular disease in a community intervention in Sweden.

AIM: The aim was to investigate the possibility to evaluate the mortality pattern in a community intervention programme against cardiovascular disease by official death certificates. METHODS: For all deceased in the intervention area (Norsjö), the accuracy of the official death certificates were compared with matched controls in the rest of Västerbotten. The official causes of death were compared with new certificates, based on the last clinical record, issued by three of the authors, and coded by one of the authors, all four accordingly blinded. RESULTS: The degree of agreement between the official underlying causes of death in "cardiovascular disease" (CVD) and the re-evaluated certificates was not found to differ between Norsjö and the rest of Västerbotten. The agreement was 87% and 88% at chapter level, respectively, but only 55% and 55% at 4-digit level, respectively. The reclassification resulted in a 1% decrease of "cardiovascular deaths" in both Norsjö and the rest of Västerbotten. CONCLUSIONS: The disagreements in the reclassification of cause of death were equal but large in both directions. The official death certificates should be used with caution to evaluate CVD in small community intervention programmes, and restricted to the chapter level and total populations.

Association between attending cultural events and all-cause mortality: a longitudinal study with three measurements (1982-2017).

OBJECTIVES: To examine the association between cultural attendance and all-cause mortality. DESIGN: A longitudinal cohort study over 36 years (1982-2017) with three 8-year interval measurements of exposure (1982/1983, 1990/1991 and 1998/1999) to cultural attendance and a follow-up period to 31 December 2017. SETTING: Sweden. PARTICIPANTS: The study included 3311 randomly selected individuals from the Swedish population with complete data for all three measurements. PRIMARY OUTCOME MEASUREMENTS: All-cause mortality during the study period in relation to level of cultural attendance. Cox regression models with time-varying covariates were used to estimate HRs adjusted for potential confounders. RESULTS: The HRs of cultural attendance in the lowest and middle levels compared with the highest level (reference; HR=1) were 1.63 (95% CI 1.34 to 2.00) and 1.25 (95% CI 1.03 to 1.51), respectively. CONCLUSION: Attending cultural events has a suggested gradient, the lesser cultural exposure the higher all-cause mortality during the follow-up.

A longitudinal study of the association between attending cultural events and coronary heart disease.

BACKGROUND: The experiences of art and music are an essential part of human life and this study aimed to examine the longitudinal association between cultural participation and coronary heart disease. METHODS: This was a longitudinal study on a randomly selected representative adult cohort (n = 3296) of the Swedish population. The study period was over 36 years (1982-2017) with three separate eight-year interval measurements of cultural exposure (for example, visiting theatres and museums) starting in 1982/83. The outcome was coronary heart disease during the study period. Marginal structural Cox models with inverse probability weighting were used to account for time-varying weights of the exposure and potential confounders during the follow-up. The associations were also examined through a time-varying Cox proportional hazard regression model. RESULTS: Cultural participation shows a graded association, the higher the exposure the lower the risk of coronary heart disease; the hazard ratio was 0.66 (95% confidence interval, 0.50 to 0.86) for coronary heart disease in participants with the highest level of cultural exposure compared with the lowest level. CONCLUSION: Although causality cannot be determined due to the remaining risk of residual confounding and bias, the use of marginal structural Cox models with inverse probability weighting strengthens the evidence for a potentially causal association with cardiovascular health, which warrants further studies.

This study examined whether people taking part in cultural activities, such as going to museums or theatres, were less likely to get coronary heart disease. The study included 3296 adults in Sweden over a period of 36 years. Information on cultural participation was collected by questionnaires on three occasions, eight-years apart. National healthcare data was used to identify cases of coronary heart disease. The main finding was that people who took part in more cultural activities were less likely to have coronary heart disease. This study suggests that taking part in cultural activities may be an important way to keep your heart healthy.

All-cause mortality of patients with dyslipidemia up to 19 years after a multidisciplinary lifestyle modification programme: a randomized trial.

BACKGROUND: Many studies have shown that individual lifestyle factors are associated with cardiovascular mortality and all-cause mortality. Observational studies of comprehensive programmes have reported risk reductions. The objectives were to assess the long-term all-cause mortality by diagnosis in patients referred to a lifestyle modification programme, aimed at combating coronary heart disease and stroke. METHODS: A randomized trial with 325 patients referred to the centre between 1988 and 1989 for dyslipidemia, hypertension, type 2 diabetes and coronary heart disease; 239 patients were randomized to the programme, 86 randomized to usual care. Cases were admitted to the centre in groups of 30 for a 4-week residential comprehensive activity, in total 114 full-time hours, focusing on food preferences and selections, and physical exercise. The activities were repeated during a 4-day revisit to the centre 1 year and 5 years after the 4-week intervention. Controls were referred back to their doctors, mainly in primary care, for usual care. Main outcome measure was all-cause mortality during 11­12 and 18­19 years after intervention. RESULTS: At follow-up 11­12 years after referral, the relative risk reduction (RRR) was 76% with the intention-to-treat analysis among cases admitted for dyslipidemia (hazards ratio 0.24, confidence interval 0.06­0.89, P = 0.033). After 18­19 years, the RRR was 66% (hazards ratio 0.34, confidence interval 0.13­0.88, P = 0.026). No RRR was found for the other three diagnoses. CONCLUSION: Patients admitted for dyslipidemia reached a real long-term RRR of all-cause mortality. They had by definition a need for this programme.

Cultural participation and health: a randomized controlled trial among medical care staff.

OBJECTIVE: Population studies demonstrate that attending cultural events is conducive to improved health when baseline health, income, education, and health habits are taken into account. Animal experiments suggest possible mechanisms. We studied the link in humans between attending cultural events and health in a randomized controlled trial. METHODS: Members of the local government officers' union in the health services in Umeå, Sweden, were invited to the experiment and 101 people registered for fine arts visits once a week for 8 weeks. They chose films, concerts, or art exhibitions visits, or singing in a choir and were then randomized into 51 cases, starting at once, and 50 controls starting after the trial. Health was assessed before randomization and after the experimental period using the instrument for perceived health, short form (SF)-36, and tests of episodic memory, saliva-cortisol and immunoglobulin. The results were analyzed using a mixed design analysis of variance. RESULTS: The SF-36 Composite Score called physical health improved in the intervention group and decreased among controls during the experiment (F(1,87) = 7.06, p = .009). The individual factor of the SF-36 called social functioning, improved more in the intervention group than among controls (F(1,98) = 8.11, p = .005) as well as the factor vitality (F(1,98) = 5.26, p = .024). The six other factors and the Mental Health Composite Score, episodic memory, cortisol and immunoglobulin levels did not change otherwise than among controls. Mechanisms are left to be identified. CONCLUSION: Fine arts stimulations improved perceived physical health, social functioning, and vitality.

Transgenerational response to nutrition, early life circumstances and longevity.

Nutrition might induce, at some loci, epigenetic or other changes that could be transmitted to the next generation impacting on health. The slow growth period (SGP) before the prepubertal peak in growth velocity has emerged as a sensitive period where different food availability is followed by different transgenerational response (TGR). The aim of this study is to investigate to what extent the probands own childhood circumstances are in fact the determinants of the findings. In the analysis, data from three random samples, comprising 271 probands and their 1626 parents and grandparents, left after exclusions because of missing data, were utilized. The availability of food during any given year was classified based on regional statistics. The ancestors' SGP was set at the ages of 8-12 years and the availability of food during these years classified as good, intermediate or poor. The probands' childhood circumstances were defined by the father's ownership of land, the number of siblings and order in the sibship, the death of parents and the parents' level of literacy. An earlier finding of a sex-specific influence from the ancestors' nutrition during the SGP, going from the paternal grandmother to the female proband and from the paternal grandfather to the male proband, was confirmed. In addition, a response from father to son emerged when childhood social circumstances of the son were accounted for. Early social circumstances influenced longevity for the male proband. TGRs to ancestors' nutrition prevailed as the main influence on longevity.

Are variations in rates of attending cultural activities associated with population health in the United States?

BACKGROUND: Population studies conducted in Sweden have revealed an association between attendance at cultural activities and health. Using data from US residents, we examined whether the association could be observed in the US. METHODS: Participants in the current study included 1,244 individuals who participated in the 1998 General Social Survey. RESULTS: A significant association between cultural activities and self-reported health (SRH) was observed, even after controlling for age, gender, marital status, race, number of children, subjective social class, employment status, household income, and educational attainment. Specifically, the more cultural activities people reported attending, the better was their SRH. CONCLUSION: The data confirm that an association between cultural activity and health is present in a US sample. The data do not mean that the association is causal, but they suggest that further longitudinal research is warranted.

Sex-specific, male-line transgenerational responses in humans.

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 Overkalix 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 Overkalix 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.

Outcomes of comprehensive lifestyle modification in inpatient setting.

OBJECTIVE: To examine the effectiveness of a 4-week inpatient non-pharmacological risk factor modification programme for individuals with the metabolic syndrome. The aim of the program was to reduce patients' over risks for stroke and myocardial infarction. METHODS: A prospective clinical study including 2468 patients--1096 men and 1372 women--with and average age of 50 +/- 10 years. The patients were referred to the programme from primary care units and hospitals where treatment options were exhausted. RESULTS: All risk factor levels for stroke and myocardial infarction decreased. The reduction of weight among men was 4.7 +/- 2.6 kg and 3.8 +/- 1.8 kg among women from an initial weight of 96 +/- 17 kg and 85 +/- 16 kg, respectively. The patients systolic and diastolic blood pressure decreased by 15/10 mmHg for men and 14/9 mmHg among women from initial average for the whole population of 148/90 +/- 19/11 mmHg and 146/87 +/- 19/12 mmHg, respectively. The greatest decrease in weight and blood pressure occurred in men and women with an initial body mass index of > or = 30 and with a diastolic blood pressure of > or = 90; in this group, the average reductions in weight were 5.8 +/- 2.4 kg for men and 4.4 +/- 1.7 kg for women; the reductions in systolisk/diastolisk blood pressure were 22/15 +/- 16/9 mmHg (p < 0.001) for both men and women. A reduction of medication (DDD) although not a goal was also achieved. CONCLUSION: The results prove the value of a comprehensive and highly structured inpatient approach to lifestyle modification. PRACTICE IMPLICATIONS: The results should give cause to trials with half-way strategies integrating features from the inpatient programme into the design of risk factor interventions.

Change in food availability during pregnancy: Is it related to adult sudden death from cerebro- and cardiovascular disease in offspring?

Maternal access to food during pregnancy affects birth weight and other characteristics of offspring. It has been suggested that fluctuations in food availability during infancy, ranging from plentiful to starvation, may influence cerebro-cardiovascular risk factors for the offspring during adult life. This study was designed to test the correlation between food availability changes during life before birth and adult sudden death from disease. This was a follow-up study of ancient cohorts in the parish of Skellefteå, Sweden, comprising 7,572 individuals born between 1805 and 1849 and still alive at age 40. Food availability variations in the parish during their prenatal life were ascertained from historical sources, the main outcome measures being overall mortality and mortality from sudden death in the age range 40-70 years. The risk of sudden death was almost doubled for those whose mothers were struck by a poor harvest during the early stages of pregnancy, but who experienced a good harvest toward the end. Yet almost the same over-risk was evident for the converse case: plentiful food supply in early pregnancy followed by a poor harvest toward the end. A stable maternal access to food during pregnancy is important for the offspring's risk of sudden death from cerebro- and cardiovascular disease as an adult. Am. J. Hum. Biol. 12:447-453, 2000. Copyright 2000 Wiley-Liss, Inc.

Patterns of receptive and creative cultural activities and their association with perceived health, anxiety, depression and satisfaction with life among adults: the HUNT study, Norway.

BACKGROUND: Cultural participation has been used both in governmental health policies and as medical therapy, based on the assumption that cultural activities will improve health. Previous population studies and a human intervention study have shown that religious, social and cultural activities predict increased survival rate. The aim of this study was to analyse the association between cultural activity and perceived health, anxiety, depression and satisfaction with life in both genders. METHODS: The study is based on the third population-based Nord-Trøndelag Health Study (2006-2008), including 50,797 adult participants from Nord-Trøndelag County, Norway. Data on cultural activities, both receptive and creative, perceived health, anxiety, depression and satisfaction with life were collected by comprehensive questionnaires. RESULTS: The logistic regression models, adjusted for relevant cofactors, show that participation in receptive and creative cultural activities was significantly associated with good health, good satisfaction with life, low anxiety and depression scores in both genders. Especially in men, attending receptive, rather than creative, cultural activities was more strongly associated with all health-related outcomes. Statistically significant associations between several single receptive, creative cultural activities and the health-related outcome variables were revealed. CONCLUSION: This population-based study suggests gender-dependent associations between cultural participation and perceived health, anxiety, depression and satisfaction with life. The results support hypotheses on the effect of cultural activities in health promotion and healthcare, but further longitudinal and experimental studies are warranted to establish a reliable cause-effect relationship.

Migration and mortality trajectories: a study of individuals born in the rural community of Överkalix, Sweden.

Migration may result in exposure to factors that are both beneficial and harmful for good health. How the act of migration is associated with mortality, or whether the socio-economic condition of migrants prior to migration influences their mortality trajectory, is not well understood. In the present study, a cohort of 413 randomly selected individuals born in the rural community of Överkalix, Sweden, between 1890 and 1935 were followed from birth to either death or old age. Around 50% of the study-population moved away from Överkalix at one time or another. To adjust for a potential bias resulting from self-selection among the migrants, the father's occupational status was used together with parents' and grandparents' longevity. Overall, migration could not be shown to predict mortality when the backgrounds of the migrants were taken into account. Nonetheless, socio-economic background conditions appeared to moderate the association, decreasing the mortality rates for migrants with relatively good pre-migratory socio-economic conditions, while increasing it for migrants with poorer pre-migratory conditions. However, further scrutiny revealed that this effect modification mainly affected the female migrants' mortality. In conclusion, the study suggests that there is no general association between migration and mortality, but that migrants with better socio-economic resources are more likely to improve their mortality trajectories than migrants with poorer resources. Better pre-migratory conditions hence appear to be important for avoiding health-adverse circumstances and gaining access to health beneficial living conditions when moving to foreign environments - especially for women.

Socio-demographic determinants of initiation and duration of breastfeeding in northwest Russia.

AIM: This study examines socio-demographic determinants of initiation and duration of breastfeeding in a community-based cohort in northwest Russia. METHODS: All infants born to women who were registered at the antenatal clinics in Severodvinsk in 1999 comprised the cohort (n=1399) and were followed up at 1 y. Data on maternal and infant characteristics as well as the duration of breastfeeding were obtained from medical records. Proportional hazard analysis was applied to quantify the effect of the selected factors on the risk of breastfeeding discontinuation adjusted for potential confounders. RESULTS: Only 1.3% of infants were never breastfed. Breastfeeding rates were 75.0% and 47.2% at 3 and 6 mo, respectively. Maternal age and early initiation of prenatal care were positively associated with breastfeeding initiation rates. Increased risks of breastfeeding discontinuation were found in teenage mothers (OR=1.45, 95% CI: 1.06-1.99), in mothers with basic education (OR=1.68, 95% CI: 1.06-2.66) and in unmarried mothers (OR=1.19, 95% CI: 1.03-1.38). Women with no previous deliveries were more likely to breastfeed longer (OR=0.74, 95% CI: 0.62-0.90). CONCLUSIONS: Compared with previous studies in Russia, almost universal initiation and considerably higher rates of breastfeeding at specific time points were found. Social variations in initiation and duration of breastfeeding should raise concern of inequalities in breastfeeding practices in transitional Russia.

Socio-demographic determinants of poor infant outcome in north-west Russia.

The infant outcome determinants vary in different settings, and there is still a need for analysis within environments. This study was designed to examine the relation between poor infant outcome (PIO), (i.e. any of the following indicators: preterm delivery, low birthweight, perinatal death and low first-minute Apgar score) and socio-demographic factors, smoking and alcohol consumption in a Russian setting. The study was conducted in the town of Severodvinsk, north-west Russia. A total of 1404 pregnant women who attended antenatal care clinics in 1999 and delivered at the municipal maternity home comprised the cohort. Data on women and infants were collected from the medical files and a questionnaire on social indicators, smoking and alcohol consumption was administered. The adjusted odds ratio (OR) calculated by multivariable logistic regression was used as the measure of association between PIO and the variables studied. Education was found to be the most significant factor associated with PIO (OR = 1.9, 95% CI 1.2, 3.0 for secondary or less education compared with at least 3 years of university studies). Increased risks of PIO were also found in mothers aged 30 years and older (OR = 1.6, 95% CI 1.1, 2.5 compared with other age groups) and in unmarried mothers (OR = 1.4, 95% CI 1.0, 1.9) after control for the possible confounders. Other socio-demographic determinants studied (smoking, alcohol use, stress, maternal occupation, housing and young age of the mother) could not be found to influence PIO. The findings contribute to the hypothesis that maternal education is one of the most important social factors influencing pregnancy outcomes in countries in transition.

Housing conditions, perceived stress, smoking, and alcohol: determinants of fetal growth in Northwest Russia.

BACKGROUND: Social determinants of health have become important in countries of the former Soviet Union during the time of transition. AIM: This article estimates the influence of living conditions, smoking, alcohol, and maternal stress on fetal growth indices in an urban Russian setting. METHODS: All pregnant women registered at antenatal care centres in Severodvinsk (Northwest Russia) and their infants comprised the study base (n = 1399). Multivariate linear regression analysis was applied to quantify the effects of the studied factors on birth weight and the ponderal index (PI) adjusted for maternal education, age, occupation, marital status, parity, pre-pregnancy weight, paternal employment, gestational age, and others. RESULTS: Infants of smoking mothers were 126 g lighter compared with non-smokers [95% confidence interval (CI): -198; -54]. On average, birth weight decreased 27 g per cigarette smoked during pregnancy. Living in shared apartments, living in crowded housing situations, and perceived stress were associated significantly with birth weight loss: -89 g (95% CI: -153; -25), -82 g (95% CI: -136; -28), and -61 g (95% CI: -116; -7), respectively. A positive association between maternal alcohol consumption and birth weight was found. Living with parents was associated positively with both birthweight and PI. Infants whose fathers consumed more than 100 ml of absolute alcohol per week were thinner at birth compared with those of non-drinking and moderate drinking fathers. CONCLUSIONS: Poor housing conditions, maternal stress, smoking, and alcohol consumption are independent determinants of fetal growth in Northwest Russia.