Maternal undernutrition during pregnancy is associated with adverse effects in the offspring during adulthood and contributes to the risk of developing a number of chronic diseases. Historical events, such as famines, allow us to study the effects that food deprivation in utero has on the offspring's health. In particular, the Dutch Hunger Winter (1944-1945) and the Great Chinese Famine (1959-1961) have been extensively analysed, and it has been shown that prenatal exposure to starvation increases the risk of cardiometabolic, mental and kidney disease in adult life. More importantly, the risk can be transmitted to future generations. However, not all studies agree on the thresholds of risk of exposed subjects or on the timing of starvation during foetal life that could be held responsible for these deleterious lifelong consequences. Gender differences complicate the picture. In this narrative review, we discuss similarities and differences between the two famines and compare the available data, seeking to determine what can be learned from these tragedies.

Anisman, H., Doubad, D., Asokumar, A. & Matheson, K. Psychosocial and neurobiological aspects of the worldwide refugee crisis: From vulnerability to resilience. NEUROSCI BIOBEHAV REV, XXXX. Immigration occurs between countries either to obtain employment, for family reunification or to escape violence and other life-threatening conditions. Refugees and asylum seekers are often obligated to overcome a uniquely challenging set of circumstances prior to and during migration. Settlement following immigration may pose yet another set of stressors related to acculturation to the host country, as well as financial insecurity, discrimination, language barriers, and social isolation. Here we discuss the multiple consequences of immigration experiences, focusing on the health disturbances that frequently develop in adults and children. Aside from the psychosocial influences, immigration-related challenges may cause hormonal, inflammatory immune, and microbiota changes that favor psychological and physical illnesses. Some biological alterations are subject to modification by epigenetic changes, which have implications for intergenerational trauma transmission, as might disruptions in parenting behaviors and family dysfunction. Despite the hardships experienced, many immigrants and their families exhibit positive psychological adjustment after resettlement. We provide information to diminish the impacts associated with immigration and offer strength-based approaches that may foster resilience.

In this study, we aimed to assess the associations between early exposure to famine and the risks of diabetic complications in adult patients with type two diabetes.

The participants in this study were selected from China National HbA1c Surveillance System (2009-13) and further stratified according to the birth year. The participants born between 1956-59, 1959-61, and 1962-64 were classified as foetal exposed group with 70 852, infant/toddler exposed group with 93 616, and unexposed group with 72 723 participants. The association between exposure to famine in early life and risks of diabetic complications were analysed by logistic regression. We assessed the attributing effects of the interaction between exposure to famine in early life and modifiable risk factors by the multiplicative and additive interactive models.

After adjustments for sex, famine severity, economic status in adulthood, body mass index, blood pressure, low-density lipoprotein cholesterol, glycated haemoglobin, diabetes duration, and the use of antidiabetic agents, the increased risks of coronary heart disease (odds ratio (OR) = 1.31; 95% CI (confidence interval) = 1.26, 1.36), cerebrovascular disease (OR = 1.32; 95% CI = 1.24, 1.41), and diabetic retinopathy (OR = 1.06; 95% CI = 1.02, 1.10) were observed in patients with early-life exposure to famine. The reduced risk of diabetic kidney disease (OR = 0.94; 95% CI = 0.90, 0.99) was observed in patients with early-life exposure to famine compared with those without famine exposure. The interaction analyses indicated that obesity might exacerbate the increased risk of coronary heart disease (OR = 1.26; 95% CI = 1.22, 1.30), cerebrovascular disease (OR = 1.26; 95% CI = 1.21, 1.32), and diabetic retinopathy associated with early-life exposure to famine (OR = 1.09; 95% CI = 1.06, 1.12) in patients with type two diabetes. Moreover, high economic status in adulthood might also exacerbate the increased risk of coronary heart disease (OR = 1.35; 95% CI = 1.30, 1.40) and cerebrovascular disease (OR = 1.33; 95% CI = 1.23, 1.43) associated with early-life exposure to famine in patients with type two diabetes.

Early-life exposure to famine in patients with type two diabetes might be associated with increased risks of coronary heart disease, cerebrovascular disease, and diabetic retinopathy but a reduced risk of diabetic kidney disease in adulthood. Obesity and high economic status might further exacerbate the risk of diabetic complications associated with early-life exposure to famine. Improving early-life nutritional status may promote better risk prevention and management of diabetic complications in patients with type two diabetes.

Metabolic syndrome (MetS) is a major risk factor for non-communicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and cancer. The risk of MetS can be transmitted via epigenetic processes from both the mother and the father. Therefore, it is essential that both members of a couple are targeted in pre-conception nutrition and physical activity-based lifestyle programs. However, lifestyle interventions targeting both members of a couple are scarce in the literature. This study, therefore, aimed to explore the barriers and facilitators of a couples-based lifestyle intervention.

Nulliparous couples who had an interest in having children in the future were recruited to the study and each member interviewed separately to gain insight into to gain insight into designing future couples-based lifestyle interventions. Interviews were conducted between June and October 2021. Reflexive thematic analysis (RTA) was applied to conduct and analyse semi-structured, in-depth interviews with nulliparous couples who had an interest in having children in the future.

Four major themes were identified in nine couples aged 25-34 years (here referred to as "millennials"): Millennials are committed to preparation for their future offspring; millennials know features of a good program likely to have high adherence and long-term behavior change; millennials acknowledge the importance of couples-based programs; and millennials appreciate that future global emergencies may require lifestyle modifications.

This study found that millennial couples showed a strong intention to create optimal emotional, financial, and health conditions for their children. They supported couples-based approach (CBA) lifestyle interventions to mitigate potential epigenetic risks. Couples believed that participating together in these programs would enhance adherence to healthy habits, promoting long-term well-being. The findings advocate for exploring and testing CBA interventions that target both partners, as joint participation not only aids in healthy conception and reduces metabolic syndrome risks but also establishes a foundation for family health. These insights highlight the potential of CBA interventions to positively impact future generations.

Malnutrition early in life may have adverse effects on health later in life. The relationship between malnutrition and obesity parameters (body mass index [BMI] and waist circumference [WC]) and type 2 diabetes is inconsistent. This study aimed to identify the effects of famine exposure and obesity parameters on type 2 diabetes individually or in combination among middle-aged and older adults in China. Data were extracted from the China Health and Retirement Longitudinal Study Wave1 in 2011. The sample involved 13,065 adults aged 45 to 90. The t- or F test was employed to compare age among groups. The chi-square test was utilized to compare baseline characteristics according to the categorical WC levels/BMI levels/famine exposure and examine between-group differences in type 2 diabetes (diabetes and non-diabetes). Odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression models to estimate the individual and combined associations of BMI/WC levels and famine exposure with the prevalence of type 2 diabetes. In this study, 1559 (11.93%) individuals were exposed to Chinese famine during their fetal stage, 5132 (39.28%) and 4428 (33.89%) in childhood and adolescence/adulthood, respectively. Among BMI measurements, 3780 (28.93%) were overweight, and 1487 (11.38%) were obese, whereas WC measurements showed that 5408 (41.39%) were obesity. In addition, 831 (45.48%) males and 996 (54.52%) females reported type 2 diabetes. In multivariable-adjusted regression models, obesity parameters and famine exposure were independently associated with type 2 diabetes prevalence among all participants (P < .001). In the interaction analysis, there existed a trend of higher odds for prevalence of type 2 diabetes across all groups compared to the combination of no-exposed and normal BMI/WC level group (the most increase in odds, adolescence/adulthood-exposed group with central obesity in WC levels: OR 4.51 (95% CI = 3.42-5.95); adolescence/adulthood-exposed group with obesity in BMI levels: OR 5.84 (95% CI = 4.11-8.30; P for interaction <.001). The findings for females exhibited similar to the overall participants, when by gender stratification. Our results suggest famine exposure and obesity parameters have positive combined effects on type 2 diabetes in middle-aged and older adults in China.

Although evidence from birth cohort analysis has indicated the metabolic risk of early-life exposure to the Great Leap Forward Famine (GLFF) in China, three confounding effects, including the exposure windows, aging, and geographical variations in famine severity, have been brought to debates for a decade. This study aimed to address these confounding effects and extensively examine how GLFF exposure is associated with diabetes risk in mid-to-late life and its interaction with urban-rural migration.

Data from the China Health and Retirement Longitudinal Study (CHARLS) were analyzed with age-stratification and stepped wedge approaches. Weighted prevalence and multivariable logistic regression were used to investigate the effects of GLFF exposure and urban-rural migration on mid-to-late life diabetes risk and the interaction between GLFF exposure and urban-rural migration. Birth provinces were controlled as a fixed effect to account for variations in famine severity across provinces.

Compared to those who were never exposed to GLFF, fetal GLFF exposure was associated with a higher risk of adult-onset diabetes after controlling for provinces, demographics, and health statuses. Yet, after adding the proxy of childhood growth environments into the model, fetal exposure to GLFF was not significantly associated with adult-onset diabetes risk (OR = 1.22, p = 0.10), compared to those who were never exposed to GLFF. Across the three age-stratification groups, static urban residents, in general, had a higher risk of diabetes compared to static rural residents. Interaction effects between GLFF exposure and urban-rural migration were insignificant across all three age-stratification groups.

Fetal exposure to GLFF might have a traceable effect on adult-onset diabetes risk. Yet, the growth environment and urban lifestyle outweigh and further confound the impact of GLFF exposure on adult-onset diabetes risk.

Intimate partner violence (IPV) and food insecurity are global health issues that affect millions of people worldwide. Numerous studies show that IPV and food insecurity are linked; however, there is a lack of synthesis of this research. Using a systematic search and review, we examined the international quantitative and qualitative research published on the link between IPV and food insecurity. We searched for peer-reviewed, English-language articles with participants above the age of 16 in 4 large online databases. Fifty-six studies were included from around the world that discussed the link between food insecurity and IPV perpetration and/or victimization. We found evidence in both qualitative and quantitative studies for a meaningful connection between these two global health isues. We also reviewed the literature on moderators and mediators (e.g., mental health). Our findings indicate the importance of implementing IPV prevention strategies which also address household food insecurity, and the potential for food insecurity resources to provide IPV resources. Future research should focus more frequently on IPV perpetration as opposed to victimization, and further examine the moderating and mediating mechanisms that inform the link between IPV and food insecurity.

Dietary restriction in the form of fasting is a putative key to a healthier and longer life, but these benefits may come at a trade-off with reproductive fitness and may affect the following generation(s). The potential inter- and transgenerational effects of long-term fasting and starvation are particularly poorly understood in vertebrates when they originate from the paternal line. We utilised the externally fertilising zebrafish amenable to a split-egg clutch design to explore the male-specific effects of fasting/starvation on fertility and fitness of offspring independently of maternal contribution. Eighteen days of fasting resulted in reduced fertility in exposed males. While average offspring survival was not affected, we detected increased larval growth rate in F1 offspring from starved males and more malformed embryos at 24 h post-fertilisation in F2 offspring produced by F1 offspring from starved males. Comparing the transcriptomes of F1 embryos sired by starved and fed fathers revealed robust and reproducible increased expression of muscle composition genes but lower expression of lipid metabolism and lysosome genes in embryos from starved fathers. A large proportion of these genes showed enrichment in the yolk syncytial layer suggesting gene regulatory responses associated with metabolism of nutrients through paternal effects on extra-embryonic tissues which are loaded with maternal factors. We compared the embryo transcriptomes to published adult transcriptome datasets and found comparable repressive effects of starvation on metabolism-associated genes. These similarities suggest a physiologically relevant, directed and potentially adaptive response transmitted by the father, independently from the offspring's nutritional state, which was defined by the mother.

Nowadays, a growing body of evidence suggests that the developmental programs of each individual could be modified. The acquired new phenotypic changes could be persistent throughout the individual's life and even transmitted to the next generation. While the exact mechanism for that preservation is not well understood yet, there are many evidences showing that epigenetic alterations, which are robust and dynamic in response to the influence of the environmental factors, could be responsible for that inheritance. A growing number of external factors such as social stress, environmental pollution and climate changes make adaptation to these environmental changes rather challenging. According to the Developmental Origin of Human Disease theory, formulated by David Barker, environmental conditions experienced during the first phases of development can have long term effects on later phases of life. This phenomenon is linked to the biological plasticity of development, which allows reprogramming of physiological functions in response to different stimuli. Consequently, in utero exposure to environmental pollutants can increase predisposition to different pathologies that can occur both in early and later phases of life not only in the living generation but also in subsequent ones. Here, we have summarised some findings in human epigenetic research studies performed for the past few years which address the question whether transgenerational effects observed in model organisms could also occur in humans.

The concept of the inheritance of acquired traits, a foundational principle of Lamarck's evolutionary theory, has garnered renewed attention in recent years. Evidence for this phenomenon remained limited for decades but gained prominence with the Överkalix cohort study in 2002. This study revealed a link between cardiovascular disease incidence and the food availability experienced by individuals' grandparents during their slow growth periods, reigniting interest in the inheritance of acquired traits, particularly in the context of non-communicable diseases. This scientometric analysis and systematic review comprehensively explores the current landscape of paternally transmitted acquired metabolic traits.

Utilizing Scopus Advanced search and meticulous screening, we included mammalian studies that document the inheritance or modification of metabolic traits in subsequent generations of unexposed descendants. Our inclusive criteria encompass intergenerational and transgenerational studies, as well as multigenerational exposures. Predominantly, this field has been driven by a select group of researchers, potentially shaping the design and focus of existing studies. Consequently, the literature primarily comprises transgenerational rodent investigations into the effects of ancestral exposure to environmental pollutants on sperm DNA methylation. The complexity and volume of data often lead to multiple or redundant publications. This practice, while understandable, may obscure the true extent of the impact of ancestral exposures on the health of non-exposed descendants. In addition to DNA methylation, studies have illuminated the role of sperm RNAs and histone marks in paternally acquired metabolic disorders, expanding our understanding of the mechanisms underlying epigenetic inheritance.

This review serves as a comprehensive resource, shedding light on the current state of research in this critical area of science, and underscores the need for continued exploration to uncover the full spectrum of paternally mediated metabolic inheritance.

The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes.

We profiled the gut microbial composition among 11,513 adults (18-97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis.

Compared with the no-exposed control group (born during 1962-1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta - 0.29, 95% CI - 0.43, - 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts.

These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.

Famine exposure during early life development can affect disease risk in late-life period, yet, transmission of phenotypic features from famine-exposed individuals to the next generations has not been well characterized. The purpose of our case-control study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad siege survivors. We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War. Controls from the population-based national epidemiological ESSE-RF study (n = 175) were matched on sex, age and body mass index (BMI). Phenotypes of controls and descendants (both generations, children and grandchildren separately) were compared, taking into account multiple testing. Comparison of two generations descendants with corresponding control groups revealed significantly higher creatinine and lower glomerular filtration rate (GFR), both in meta-analysis and in independent analyses. The mean values of GFR for all groups were within the normal range (GFR less than 60 mL/min/1.73 m² was recorded in 2 controls and no one in DLSS). Additionally, independent of the creatinine level, differences in the eating pattern were detected: insufficient fish and excessive red meat consumption were significantly more frequent in the children of the Leningrad siege survivors compared with controls. Blood pressure, blood lipids and glucose did not differ between the groups. Parental famine exposure in early childhood may contribute to a decrease in kidney filtration capacity and altered eating pattern in the offspring of famine-exposed individuals.

Famine is a risk factor for non-communicable chronic diseases (NCDs), which account for over 80% of deaths in China. The effect of famine on the prevalence of NCDs in terms of various age groups, time periods and cohorts is currently poorly understood.

This study aims to explore long-term trends in the impact of China's Great Famine (1959-1961) on NCDs in China.

This study used data from the 2010-2020 China Family Panel Longitudinal Survey across 25 provinces in China. The subjects were aged 18-85 years, and the total number of subjects was 174,894. The prevalence of NCDs was derived from the China Family Panel Studies database (CFPS). An age-period-cohort (APC) model was used to estimate the age, period and cohort effects of NCDs in 2010-2020 and the effect of famine on the risk of NCDs in terms of cohort effects.

The prevalence of NCDs increased with age. Additionally, the prevalence did not clearly decrease over the survey period. Regarding the cohort effect, people born in the years adjacent to the famine period had a higher risk of NCDs; additionally, females, those born in rural areas, and those who lived in provinces with severe famine and post-famine had a higher likelihood of NCDs.

Experiencing famine at an early age or the experience of famine in a close relative's generation (births after the onset of famine) are associated with an increased risk of NCDs. Additionally, more severe famine is associated with a higher risk of NCDs.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.

Historical and demographical human cohorts of populations exposed to famine, as well as animal studies, revealed that exposure to food deprivation is associated to lasting health-related effects for the exposed individuals, as well as transgenerational effects in their offspring that affect their diseases' risk and overall longevity. Autophagy, an evolutionary conserved catabolic process, serves as cellular response to cope with nutrient starvation, allowing the mobilization of an internal source of stored nutrients and the production of energy. We review the evidence obtained in multiple model organisms that support the idea that autophagy induction, including through dietary regimes based on reduced food intake, is in fact associated to improved health span and extended lifespan. Thereafter, we expose autophagy-induced chromatin remodeling, such as DNA methylation and histone posttranslational modifications that are known heritable epigenetic marks, as a plausible mechanism for transgenerational epigenetic inheritance of hunger.

Prenatal exposure to famine has been linked to increased diabetes risk in adulthood. However, one fundamental issue to be addressed is that the reported famine-diabetes relation may be confounded by the age differences between the exposed and non-exposed groups. We aimed to determine the association between prenatal exposure to the Chinese famine of 1959-1962 and risk of diabetes by applying age well-controlled strategies.

Among 20,535 individuals born in 1955-1966 who participated in the China Health and Nutrition Survey from 1997 to 2015, we constructed age-matched exposed vs. non-exposed groups to investigate the role of prenatal exposure to the Chinese famine of 1959-1962 in relation to diabetes. We also built a hierarchical age-period-cohort (HAPC) model to specifically examine the relation of famine to diabetes risk independent of age.

Compared to the age-balanced men in the non-exposed group, the exposed men born in 1961 had a 154% increased risk of diabetes [odds ratio (OR) 2.54 (95% CI 1.07-6.03), P = 0.04). In the HAPC analysis, the predicted probabilities of diabetes peaked in the 1961-birth cohort of men [3.4% (95% CI 2.4%-5.0%)], as compared to the average probability of diabetes (reference) of 1.8% for men overall. Neither analytical strategy revealed any strong relation between famine exposure and diabetes risk in women.

Among the pre-defined Chinese famine period of 1959-1962, early-life exposure to famine was associated with increased diabetes risk in men but not in women, and these relations were independent of age.

Metabolic Syndrome (MetS), is a major risk factor for non-communicable diseases including type 2 diabetes mellitus, cardiovascular disease, and cancer. Although MetS risk is transferred via the epigenome from both biological parents, periconceptional lifestyle interventions are generally directed towards mothers. There is a need for interventions to reflect the shared nature of epigenetic MetS risk between both biological parents. Couples-based lifestyle interventions have previously been used to improve adherence to behaviour change in conditions with shared risk responsibility such as sexually transmitted diseases. This systematic literature review sought to answer the research question: Are couples-based interventions more effective than individual interventions to address overweight and obesity as the primary modifiable risk for MetS in addition to other associated factors.

Couples-based studies involving randomised controlled trials, published between 01/01/1990-31/12/2021, were identified in Medline, CINAHL, PsycINFO, Psychology and Behavioural Sciences Collection, Cochrane, and Scopus.

After screening 4742 articles, only five eligible trials remained. Statistically significant post-intervention maintenance of low glycaemic levels was observed in one study. Otherwise, no statistically significant group differences between couples' groups and control groups were observed in any of the five included studies.

The included studies concluded that couple-based interventions can lead to weight reduction, maintenance, and adherence to modified health behaviours similar to interventions that target individuals. Overall, the findings indicate that, notwithstanding the paucity of authentic couples-based interventions, there is potential for such approaches to moderate MetS risk factors likely to flow onto epigenetic transmission of risk.

Silver nanoparticles (AgNPs) possess unique antimicrobial properties. As a result, they are being increasingly used in a wide range of applications. Several studies have shown detrimental effects of AgNPs exposure, including inflammation, accumulation, and cellular damage to different organs. However, the effect of AgNPs exposure during gestation, a critical and susceptible period of human development, on pregnant females and its long-term effects on offspring's health has not been studied. Therefore, we conducted a long-term study where we assessed the effect of gestational AgNPs exposure on pregnant mice and followed their offspring until the age of 12 months. Gestational exposure to AgNPs induced systemic inflammation in the pregnant mice at gestational day (GD) 18. Interestingly, developing fetuses exposed to AgNPs, showed anti-inflammatory conditions as indicated by reduced expression of inflammatory genes in fetal organs at GD 18 and reduced serum levels of TNF-α, IFN-γ, IL-17A, IL-6, and MCP-1 in AgNPs exposed pups at postnatal day (PD) 2. Surprisingly, post-weaning, AgNPs exposed offspring showed a heightened immune activation as shown by upregulation of inflammatory cytokines at PD 28, which persisted till late in life. Moreover, we observed metabolic alterations which persisted until adulthood in mice. To understand the impact of long-term immunometabolic changes on the progression of diabetes and kidney diseases under stressed conditions, we exposed offspring to streptozotocin which revealed a protective role of low-dose gestational AgNPs exposure against streptozotocin-induced diabetes and associated nephropathy.

The fast-growing literature suggests that the Chinese famine of 1959-1961 drives current and future type 2 diabetes (T2D) epidemics in China. This conclusion may be premature, as many Chinese famine studies have major methodological problems. We examine these problems, demonstrate how they bias the study results, and formulate recommendations to improve the quality of future studies.

We searched English and Chinese databases for studies that examined the relationship between prenatal exposure to the Chinese famine and adult T2D from inception to 8 February 2022. We extracted information on T2D cases and study populations of individuals born during the famine (famine births), before the famine (prefamine births), and after the famine (postfamine births). We used random-effects models to compare the odds of T2D in famine births to several control groups, including postfamine births, combined pre- and postfamine births, and prefamine births. We used meta-regressions to examine the impacts of age differences between comparison groups on famine effect estimates and the role of other characteristics, including participant sex, age, and T2D assessments; famine intensity; residence; and publication language. Potential sources of heterogeneity and study quality were also evaluated.

Twenty-three studies met our inclusion criteria. The sample sizes ranged from less than 300 to more than 360,000 participants. All studies defined the famine exposure based on the participants' dates of birth, and 18 studies compared famine births and postfamine births to estimate famine effects on T2D. The famine and postfamine births had an age difference of three years or more in all studies. The estimates of the famine effect varied by the selection of controls. Using postfamine births as controls, the OR for T2D among famine births was 1.50 (95% CI 1.34-1.68); using combined pre- and postfamine births as controls, the OR was 1.12 (95% CI 1.02-1.24); using prefamine births as controls, the OR was 0.89 (95% CI 0.79-1.00). The meta-regressions further showed that the famine effect estimates increased by over 1.05 times with each one-year increase in ignored age differences between famine births and controls. Other newly identified methodological problems included the poorly assessed famine intensity, unsuitable study settings for famine research, and poor confounding adjustment.

The current estimates of a positive relationship between prenatal exposure to the Chinese famine and adult T2D are mainly driven by uncontrolled age differences between famine births and postfamine births. Studies with more rigorous methods, including age-balanced controls and robust famine intensity measures, are needed to quantify to what extent the famine exposure is related to current T2D patterns in China.

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944-45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.

The policies and actions that were enacted to colonize Indigenous Peoples in Canada have been described as constituting cultural genocide. When one considers the long-term consequences from the perspective of the social and environmental determinants of health framework, the impacts of such policies on the physical and mental health of Indigenous Peoples go well beyond cultural loss. This paper addresses the impacts of key historical and current Canadian federal policies in relation to the health and well-being of Indigenous Peoples. Far from constituting a mere lesson in history, the connections between colonialist policies and actions on present-day outcomes are evaluated in terms of transgenerational and intergenerational transmission processes, including psychosocial, developmental, environmental, and neurobiological mechanisms and trauma responses. In addition, while colonialist policies have created adverse living conditions for Indigenous Peoples, resilience and the perseverance of many aspects of culture may be maintained through intergenerational processes.

Famine exposure or air pollution is linked to type 2 diabetes mellitus (T2DM). However, their combined effects on T2DM remain largely unknown. A total of 11,640 individuals were obtained from the Henan Rural Cohort Study. According to their birthdate, participants were divided into three famine exposure subgroups: fetal exposed, childhood exposed, and unexposed groups. The air pollutants (particles with aerodynamics diameters ≤ 1.0 µm (PM1), ≤ 2.5 µm, and ≤ 10 µm, and nitrogen dioxide) concentrations of each individual were estimated by a spatiotemporal model. Participants were divided into low or high air pollution exposure groups taking the 1st quartile value of air pollutants as the cut-off point. Logistic regression model was used to analyze independent and joint associations between air pollution exposure, famine exposure, and T2DM. Positive associations of air pollution and famine exposure with T2DM were found. Participants who experienced fetal or childhood famine and also were exposed to high concentrations of any kind of the air pollutants had a much higher risk for T2DM than those with no famine and low air pollutants exposure (taking PM1.0 for example, the odds ratio [OR]: 1.76, 95% confidence interval [CI]: 1.25, 2.47 for fetal famine, and OR: 1.64, 95%CI: 1.13, 2.40 for childhood famine). After stratified analysis, similar results were observed in women. The results indicated that both famine exposure in early life and air pollution exposure in adulthood are related to increased risk for prevalent T2DM, and they have combined effects on T2DM.

The COVID-19 pandemic has a major impact on society, particularly affecting its vulnerable members, including pregnant women and their unborn children. Pregnant mothers reported fear of infection, fear of vertical transmission, fear of poor birth and child outcomes, social isolation, uncertainty about their partner's presence during medical appointments and delivery, increased domestic abuse, and other collateral damage, including vaccine hesitancy. Accordingly, pregnant women's known vulnerability for mental health problems has become a concern during the COVID-19 pandemic, also because of the known effects of prenatal stress for the unborn child. The current narrative review provides a historical overview of transgenerational effects of exposure to disasters during pregnancy, and the role of maternal prenatal stress. We place these effects into the perspective of the COVID-19 pandemic. Hereby, we aim to draw attention to the psychological impact of the COVID-19 pandemic on women of reproductive age (15-49 year) and its potential associated short-term and long-term consequences for the health of children who are conceived, carried, and born during this pandemic. Timely detection and intervention during the first 1000 days is essential to reduce the burden of transgenerational effects of the COVID-19 pandemic.

In recent years, the developmental origins of diseases have been increasingly recognized and accepted. As such, it has been suggested that most adulthood chronic diseases such as diabetes, obesity, cardiovascular disease, and even tumors may develop at a very early stage. In addition to intrauterine environmental exposure, germ cells carry an important inheritance role as the primary link between the two generations. Adverse external influences during differentiation and development can cause damage to germ cells, which may then increase the risk of chronic disease development later in life. Here, we further elucidate and clarify the concept of gamete and embryo origins of adult diseases by focusing on the environmental insults on germ cells, from differentiation to maturation and fertilization.

Despite substantial strides in diagnosis and treatment, cardiovascular diseases (CVDs) continue to represent the leading cause of death in the USA and around the world, resulting in significant morbidity and loss of productive years of life. It is increasingly evident that environmental exposures during early development can influence CVD risk across the life course. CVDs exhibit marked sexual dimorphism, but how sex interacts with environmental exposures to affect cardiovascular health is a critical and understudied area of environmental health. Emerging evidence suggests that developmental exposures may have multi- and transgenerational effects on cardiovascular health, with potential sex differences; however, further research in this important area is urgently needed. Lead (Pb), phthalate plasticizers, and perfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with numerous adverse human health effects. Notably, recent evidence suggests that developmental exposure to each of these toxicants has sex-specific effects on cardiovascular outcomes, but the underlying mechanisms, and their effects on future generations, require further investigation. This review article will highlight the role for the developmental environment in influencing cardiovascular health across generations, with a particular emphasis on sex differences and epigenetic mechanisms. In particular, we will focus on the current evidence for adverse multi and transgenerational effects of developmental exposures to Pb, phthalates, and PFAS and highlight areas where further research is needed.

Early-life exposures play key roles in the development of metabolic diseases. Whether such effects exist beyond one generation remains unclear. This study aimed to determine the transgenerational association of early-life exposure to the Chinese famine of 1959 to 1962 with the trajectories of body mass index (BMI), waist circumference (WC), and blood pressure (BP) in 2 consecutive generations. We included 21 106 F1 observations born between 1954 and 1967 (median age: 45 years) and 1926 F2 observations (median age: 23 years) from the longitudinal household-based China Health and Nutrition Survey from 1993 to 2015. Trajectories of BMI, WC, systolic BP, and diastolic BP were fitted and compared between groups using linear mixed effect models. Early-life exposure to famine was associated with increased BMI, WC, and BP in 2 consecutive generations with sex and age disparities. In F1, famine was associated with increased BMI, WC, systolic BP, and diastolic BP, especially in men or those aged older than 50 years (P ranged from <0.001 to 0.02). In F2 men but not women, the parental exposure to famine was associated with 0.59 kg/m² ([95% CI, 0.10-1.08], P=0.02) increase in BMI. In F2 aged ≥25 years but not those younger ones, the parental exposure to famine was associated with increased BMI (0.83 kg/m² [0.14-1.51], P=0.03), systolic BP (2.04 mm Hg [0.20-3.88], P=0.03), and diastolic BP (1.73 mm Hg [0.28-3.18], P=0.02). The effects of an adverse developmental environment through famine in early life on BMI and BP later in life may persist beyond one generation.

This study investigated whether and how fetal malnutrition would influence endogenous melatonin synthesis, and whether such effect of fetal malnutrition would transmit to the next generation. We enrolled 2466 participants and 1313 of their offspring. The urine 6-hydroxymelatonin sulfate and serum melatonin rhythm were measured. Methylation microarray detection and bioinformatics analysis were performed to identify hub methylated sites. Additionally, rat experiment was performed to elucidate mechanisms. The participants with fetal malnutrition had lower 6-hydroxymelatonin sulfate (16.59 ± 10.12 μg/24 hours vs 24.29 ± 11.99 μg/24 hours, P < .001) and arear under curve of melatonin rhythm (67.11 ± 8.16 pg/mL vs 77.11 ± 8.04 pg/mL, P < .001). We identified 961 differentially methylated sites, in which the hub methylated sites were locating on protein kinase C alpha (PRKCA) and cAMP response element-binding protein (CREB1) promoters, mediating the association of fetal malnutrition with impaired melatonin secretion. However, such effects were not observed in the offspring (all P > .05). Impaired histomorphology of pineal, decreased melatonin in serum, pineal, and pinealocyte were also found in the in vivo and in vitro experiments (P < .05 for the differences of the indicators). Hypermethylation of 10 CpG sites on the PRKCA promoter and 8 CpG sites on the CREB1 promoter were identified (all P < .05), which down-regulated PRKCA and CREB1 expressions, leading to decreased expression of AANAT, and then resulting in the impaired melatonin synthesis. Collectively, fetal malnutrition can impair melatonin synthesis through hypermethylation of PRKCA and CREB1 promoters, and such effects cannot be transmitted to the next generation.

Gestational high butterfat (HFB) and/or endocrine disruptor exposure was previously found to disrupt spermatogenesis in adulthood. This study addresses the data gap in our knowledge regarding transgenerational transmission of the disruptive interaction between a high-fat diet and endocrine disruptor bisphenol A (BPA). F0 generation Sprague-Dawley rats were fed diets containing butterfat (10 kcal%) and high in butterfat (39 kcal%, HFB) with or without BPA (25 µg/kg body weight/day) during mating and pregnancy. Gestationally exposed F1-generation offspring from different litters were mated to produce F2 offspring, and similarly, F2-generation animals produced F3-generation offspring. One group of F3 male offspring was administered either testosterone plus estradiol-17β (T + E2) or sham via capsule implants from postnatal days 70 to 210. Another group was naturally aged to 18 months. Combination diets of HFB + BPA in F0 dams, but not single exposure to either, disrupted spermatogenesis in F3-generation adult males in both the T + E2-implanted group and the naturally aged group. CYP19A1 localization to the acrosome and estrogen receptor beta (ERbeta) localization to the nucleus were associated with impaired spermatogenesis. Finally, expression of methyl-CpG-binding domain-3 (MBD3) was consistently decreased in the HFB and HFB + BPA exposed F1 and F3 testes, suggesting an epigenetic component to this inheritance. However, the severe atrophy within testes present in F1 males was absent in F3 males. In conclusion, the HFB + BPA group demonstrated transgenerational inheritance of the impaired spermatogenesis phenotype, but severity was reduced in the F3 generation.

Undernutrition early in life may increase the incidence of adverse effects on adult health. The relations between undernutrition and obesity parameters (body mass index (BMI) and WC (waist circle)) and hypertension were often contradictory. Our study is aimed at identifying the combined effects of famine exposure and obesity parameters on hypertension in middle-aged and older Chinese.

A population-based cross-sectional study. Setting. Data were selected from the China Health and Retirement Longitudinal Study Wave2011 (CHARLS Wave2011). Participants. The sample included 12945 individuals aged 45 to 96. Main Outcome Measurements. The study analyzed data from 12945 middle-aged and older Chinese selected from CHARLS Wave2011. Differences between baseline characteristics and famine exposure/BMI levels/WC levels were evaluated using the t-, Chi-square- (χ 2-), and F-test. Then, the difference in the prevalence of hypertension between baseline characteristics was estimated by the t- and χ 2-test. Finally, multivariable-adjusted logistic regression models were used to explore the associations of famine exposure and obesity parameters with odds of prevalence of hypertension.

Among the 12945 participants, 1548 (11.96%) participants had been exposed to the Chinese famine during the fetal group, whereas 5101 (39.41%) participants and 4362 (33.70%) participants had been exposed to the famine during childhood and adolescence/adult group, respectively. Regarding the participants with BMI levels, 3746 (28.94%) were overweight, and 1465 (11.32%) were obese, whereas 5345 (41.29%) of the participants with WC levels were obese, respectively. Furthermore, 1920 (31.17%) had hypertension in males and 2233 (32.91%) in females. In multivariable-adjusted models, famine exposure and obesity parameters were related with prevalence of hypertension independently in total populations ((1) model threec, famine exposure with prevalence of hypertension: the fatal-exposed vs. no-exposed group (OR1.27; 95% CI 1.08, 1.49); childhood-exposed vs. no-exposed group (OR1.64; 95% CI 1.44, 1.87); the adolescence/adult-exposed vs. no-exposed group (OR3.06; 95% CI 2.68, 3.50); P for trend < 0.001; (2) model threee, famine exposure with prevalence of hypertension: the fatal-exposed vs. no-exposed group (OR1.25; 95% CI 1.06, 1.47); childhood-exposed vs. no-exposed group (OR1.52; 95% CI 1.34, 1.73); the adolescence/adult-exposed vs. no-exposed group (OR2.66; 95% CI 2.33, 3.03); P for trend < 0.001; (3) model threeg, BMI levels with prevalence of hypertension: overweight vs. normal (OR1.75; 95% CI 1.60, 1.91); obesity vs. normal (OR2.79; 95% CI 2.48, 3.15); P for trend < 0.001; (4) WC levels with prevalence of hypertension: overweight vs. normal (OR1.42; 95% CI 1.36, 1.48)). When stratified by sex, results in both males and females were mostly similar to those in the total population. In general, interaction analysis in the multivariable-adjusted model, compared with the combination of normal BMI/WC levels and no-exposed famine group, all groups trended towards higher odds of prevalence of hypertension (the greatest increase in odds, adolescence/adult-exposed group with obesity in BMI levels: (OR8.13; 95% CI 6.18, 10.71); adolescence/adult-exposed group with obesity in WC levels: (OR6.36; 95% CI 5.22, 7.75); P for interaction < 0.001). When stratified by sex, the results in both males and females were also similar to those in the total population.

Our data support a strongly positive combined effect of famine exposure and obesity parameters on hypertension in middle-aged and elderly Chinese.

Environmental exposures, psychosocial stressors and nutrition are all potentially important influences that may impact health outcomes directly or via interactions with the genome or epigenome over generations. While there have been clear successes in large-scale human genetic studies in recent decades, there is still a substantial amount of missing heritability to be elucidated for complex childhood disorders. Mounting evidence, primarily in animals, suggests environmental exposures may generate or perpetuate altered health outcomes across one or more generations. One putative mechanism for these environmental health effects is via altered epigenetic regulation. This review highlights the current epidemiologic literature and supporting animal studies that describe intergenerational and transgenerational health effects of environmental exposures. Both maternal and paternal exposures and transmission patterns are considered, with attention paid to the attendant ethical, legal and social implications.

Exposure to malnutrition in early life has been found to significantly elevate type 2 diabetes risk in adulthood. However, the changes in metabolites resulting from malnutrition in early life have not been studied. The aim of this study was to identify metabolites with levels associated with type 2 diabetes resulting from exposure to China's Great Famine (1959-1962).

Participants were from SPECT-China 2014 and SPECT-China2 2019, two cross-sectional studies performed at the same site. In total, 2171 subjects participated in SPECT-China and SPECT-China2 simultaneously. The sample size of fetal-exposed (1959-1962) versus non-exposed (1963-1974) individuals was 82 vs 79 in 2014 and 97 vs 94 in 2019. Metabolomic profiling was performed between famine-exposed and non-exposed groups.

Among the different famine exposure groups, the fetal-exposed group (1959-1962) had the greatest incidence rate (12.5%), with an OR of 2.11 (95% CI 1.01 to 4.44), compared with the non-exposed group (1963-1974). Moreover, compared with those in the non-exposed group (1963-1974), four metabolites (indole-3-carbinol (I3C), phosphatidylcholine (PC) (22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:1(9Z)), pyrimidine, and PC(16:1(9Z)/22:5(4Z,7Z,10Z,13Z,16Z))) showed significantly lower relative intensities in the famine and diabetes groups both in 2014 and 2019. Pyrimidine significantly mediated the association of famine exposure with diabetes, and I3C marginally mediated this association.

Famine exposure in the fetal period could increase type 2 diabetes risk in adults, even those in their 60s. I3C and pyrimidine are potential mediators of the effects of famine exposure on diabetes development.

Previous studies investigated the association between gestational anemia and neonatal outcomes. However, few studies explored whether the effects of gestational anemia could be eliminated by subsequent correction of anemia in the later stages of pregnancy. This study aimed to investigate the relationship between anemia in different trimesters and neonatal outcomes.

The study was conducted in Shanghai, China, with a sample of 46,578 pregnant women who delivered between January 1, 2016 and July 1, 2019. A multivariable logistic regression model was adopted to analyse the associations between maternal anemia and neonatal outcomes.

The incidence of gestational anemia was 30.2%, including 4.4% in the first trimester, 9.6% in the second trimester, and 16.2% in the third trimester. Only 24.5% (507/2066) of anemia that occurred in the first trimester and 29.6% (1320/4457) that occurred in the second trimester could be corrected in the later stages of pregnancy. Anemia occurring in the first trimester was associated with small for gestational age [odds ratio (OR) 1.46; 95% confidence interval (CI) 1.20-1.78] and with fetal distress (OR 1.23; 95% CI 1.08-1.40). Anemia corrected in the first trimester also was associated with a higher risk of small for gestational age.

Gestational anemia is a public health problem in China impacting neonatal health. Anemia in pregnancy could be corrected in only about a quarter of the women. Anemia in the first trimester, whether corrected or not, still led to lower birth weight; therefore, the prevention of anemia prior to pregnancy is important.

There is lots of evidence that maternal peri-gestational metabolic, genomic and environmental conditions are closely linked to metabolic and cardiovascular outcomes in their offspring later in life. Moreover, there is also lotsof evidence that underlining mechanisms, such as molecular as well as epigenetic changes may alter the intrauterine environment leading to cardio-metabolic diseases in their offspring postnatal. But, there is also increasing evidence that cardio-metabolic diseases may be closely linked to their paternal metabolic risk factors, such as obesity, Type 2 Diabetes and other risk factors.

To analyse the evidence as well as specific risk factors of paternal trans-generational programming of cardio-metabolic diseases in their offspring.

Within a systematic scoping review, we performed a literature search in MEDLINE (PubMed) and EMBASE databases in August 2020 considering original research articles (2000-2020) that examined the impact of paternal programming on metabolic and cardiovascular offspring health. Epidemiological, clinical and experimental studies as well as human and animal model studies were included.

From n = 3.199 citations, n = 66 eligible studies were included. We selected n = 45 epidemiological as well as clinical studies and n = 21 experimental studies. In brief, pre-conceptional paternal risk factors, such as obesity, own birth weight, high-fat and low-protein diet, undernutrition, diabetes mellitus, hyperglycaemia, advanced age, smoking as well as environmental chemical exposure affect clearly metabolic and cardiovascular health of their offspring later in life.

There is emerging evidence that paternal risk factors, such as paternal obesity, diabetes mellitus, nutritional habits, advanced age and exposure to environmental chemicals or cigarette smoke, are clearly associated with adverse effects in metabolic and cardiovascular health in their offspring. Compared to maternal programming, pre-conceptional paternal factors might also have also a substantial effect in the sense of trans-generational programming of their offspring and need further research.

Epidemiological studies have reported an association between famine exposure and increased risk of cardiovascular disease. However, it is unclear whether fetal exposure to the Great Chinese Famine of 1959 to 1961 was associated with risk of ischemic stroke in midlife.

A total of 17,787 participants of the Kailuan study, who were free of cardiovascular disease and cancer at baseline (2006) were enrolled in the study. All participants were divided into three groups: unexposed (born between 1 October 1962 and 30 September 1964, used as the reference group in current analyses), fetal exposure (born between 1 October 1959 and 30 September 1961), and early childhood exposure (born between 1 October 1956 and 30 September 1958). Incident ischemic stroke cases between 2006 and 2017 were confirmed by review of medical records. Cox proportional hazards regression was applied to analyze the effect of fetal famine exposure on ischemic stroke risk.

During the mean (10.4 ± 2.2) years of follow-up, 547 incident ischemic stroke cases were identified. After adjustment for potential confounders, the hazard ratio (HR) for ischemic stroke was 1.45, and the 95% confidence interval (CI) was 1.14, 1.84 for fetal famine-exposed compared with unexposed individuals. Similar associations were observed in men (adjusted HR: 1.40; 95% CI: 1.08, 1.80) and overweight individuals (adjusted HR: 1.56; 95% CI: 1.18, 2.07), but not in their counterparts. The results of the early childhood-exposed group were similar to the above.

Our findings support an association between fetal malnutrition and higher risk of ischemic stroke in adulthood.

Increasing studies have demonstrated that gene and famine may interact on type 2 diabetes risk. The data derived from the cross-sectional 2010-2012 China National Nutrition and Health Survey (CNNHS) was examined to explore whether gene and famine interacted to influence type 2 diabetes risk. In total, 2216 subjects were involved. The subjects born in 1960 and 1961 were selected as the famine-exposed group, whereas subjects born in 1963 were selected as the unexposed group. A Mass Array system was used to detect the genotypes of 50 related single-nucleotide polymorphisms (SNPs). Interactions were found between prenatal exposure to famine and ten SNPs (rs10401969, rs10886471, rs10946398, rs1470579, rs2796441, rs340874, rs3794991, rs5015480, rs7961581, and rs9470794) on type 2 diabetes risk after adjustments. The stratified results showed that famine exposure exacerbated the effect of CILP2-rs10401969 to fasting serum insulin (FINS), GRK5-rs10886471 to fasting plasma glucose (FPG) and FINS, IGF2BP2-rs1470579 to FINS, TLE1-rs2796441 to impaired fasting glucose (IFG), PROX1-rs340874 to impaired glucose tolerance (IGT), GATAD2A-rs3794991 to FINS, TSPAN8/LGR5-rs7961581 to FPG, and ZFAND3-rs9470794 to IGT and FINS. Famine exposure weakened the effect of CDKAL1-rs10946398 to type 2 diabetes. Famine exposure weakened the effect of HHEX-rs5015480 to IFG, but exacerbated the effect of HHEX-rs5015480 to FINS. The present study suggests that ten SNPs may affect type 2 diabetes risk in interaction with prenatal exposure to Chinese famine.

Hurricane Maria struck Puerto Rico on 20 September 2017 causing catastrophic devastation. Prolonged shortage of food had been a substantial challenge to the residents after Maria. Experiencing food insecurity in utero has been associated with negative health outcomes later in life. We aim to examine whether there is any alteration in the infant gut microbiome that is associated with prenatal food insecurity.

We established a cohort of infants aged 2-6 months who were exposed in utero to Hurricane Maria near San Juan, Puerto Rico and examined the gut microbiota (n = 29) using 16S ribosomal RNA gene sequencing.

Among the enrolled infants, 30% of their mothers experienced "post-Maria poor access to food" for at least 1 month during pregnancy. The relative abundance of gut Veillonella spp. is significantly decreased among infants who experienced prenatal food insecurity, compared to those who did not (adjusted p = 0.025). There is no significant difference observed by prenatal food insecurity at the microbial community level in this cohort.

Our finding indicated that infants who experienced prenatal food insecurity post hurricane harbor microbial alternations of specific bacterial taxa, which may further influence the microbial maturation and place the individual at a high-risk health trajectory.

We identified that in utero exposure to food insecurity post Hurricane Maria is associated with decreased abundance of Veillonella in the infant gut. Our findings indicated that infants who experienced prenatal food insecurity post hurricane may harbor alterations of specific bacterial taxa in their gut microbiota. This study showed the association between prenatal adverse exposure and alterations of gut microbiome early in life in the context of an extreme event. This study provided insights into the mechanisms underlying prenatal adverse exposure and increased disease risks later in life. Our findings will potentially raise awareness of the negative impact of extreme climate events on the unborn.

Although in all sexually reproducing organisms an individual has a mother and a father, non-genetic inheritance has been predominantly studied in mothers. Paternal effects have been far less frequently studied, until recently. In the last 5 years, research on environmentally induced paternal effects has grown rapidly in the number of publications and diversity of topics. Here, we provide an overview of this field using synthesis of evidence (systematic map) and influence (bibliometric analyses).

We find that motivations for studies into paternal effects are diverse. For example, from the ecological and evolutionary perspective, paternal effects are of interest as facilitators of response to environmental change and mediators of extended heredity. Medical researchers track how paternal pre-fertilization exposures to factors, such as diet or trauma, influence offspring health. Toxicologists look at the effects of toxins. We compare how these three research guilds design experiments in relation to objects of their studies: fathers, mothers and offspring. We highlight examples of research gaps, which, in turn, lead to future avenues of research.

The literature on paternal effects is large and disparate. Our study helps in fostering connections between areas of knowledge that develop in parallel, but which could benefit from the lateral transfer of concepts and methods.

Global food security is a major driver of population health, and food system collapse may have complex and long-lasting effects on health outcomes. We examined the effect of prenatal exposure to the Great Chinese Famine (1958-1962)-the largest famine in human history-on pulmonary tuberculosis (PTB) across consecutive generations in a major center of ongoing transmission in China. We analyzed >1 million PTB cases diagnosed between 2005 and 2018 in Sichuan Province using age-period-cohort analysis and mixed-effects metaregression to estimate the effect of the famine on PTB risk in the directly affected birth cohort (F1) and their likely offspring (F2). The analysis was repeated on certain sexually transmitted and blood-borne infections (STBBI) to explore potential mechanisms of the intergenerational effects. A substantial burden of active PTB in the exposed F1 cohort and their offspring was attributable to the Great Chinese Famine, with more than 12,000 famine-attributable active PTB cases (>1.23% of all cases reported between 2005 and 2018). An interquartile range increase in famine intensity resulted in a 6.53% (95% confidence interval [CI]: 1.19-12.14%) increase in the ratio of observed to expected incidence rate (incidence rate ratio, IRR) in the absence of famine in F1, and an 8.32% (95% CI: 0.59-16.6%) increase in F2 IRR. Increased risk of STBBI was also observed in F2. Prenatal and early-life exposure to malnutrition may increase the risk of active PTB in the exposed generation and their offspring, with the intergenerational effect potentially due to both within-household transmission and increases in host susceptibility.