Periodic Reporting for period 5 - MULTIEPIGEN (Ancestral environmental exposures and offspring health – a multigenerational epidemiologic cohort study across 3 generations)
Periodo di rendicontazione: 2023-11-01 al 2024-10-31
Experimental studies in animals have indicated that exposure to certain stressors can lead to phenotypic changes in the future generations, such that individuals can acquire phenotypes caused by exposures of their ancestors. Such transfer of information across generations does not involve new DNA mutations, but occurs via epigenetic (non-genetic) mechanisms that include special RNA moleculer in the sex cells. In humans, this phenomen has been examined extremely little because a priori designed population-based studies across several generations are lacking. The MULTIEPIGEN projects seeks to demonstrate that such epigenetic inheritance occurs also in humans. To test this hypothesis, we have expanded the well-characterized Cardiovascular Risk in Young Finns Study (YFS) to the parents and offspring of the original YFS participants. We have performed field studies involving individuals across 3 generations with the aim to test paternal exposures with very high plausibility causing intergenerational effects on offspring phenotypes, including metabolism, cognitive function and psychological well-being. The studied paternal exposures include obesity, tobacco smoke, organic pollutants, and accumulation of psychosocial adversities. We have collected serum, blood and semen samples for epigenetic marker analysis to provide understanding of the mechanisms of intergenerational transmission in humans. The study design, methods and detailed statistical plan have been made publicly available (https://www.medrxiv.org/content/10.1101/2024.11.24.24317769v1(si apre in una nuova finestra)).
The protocol-defined field activities have now been completed. The field study examinations were started in March 2018 in five study centres in Finland, and ended in February 2020. In total, 7,345 individuals participated in the study: Generation 1 (original YFS cohort members, N=2,128, 66.2% participation rate); Generation 0 (parents of the original cohort members, N=2,460, 62.8%), and Generation 2 (offspring of the original cohort memners, N=2,757, 48.6%). In total, 1,378 sperm samples have been collected for RNA sequencing across three generations of males aged 18 and over.
The data are being used to test the hypothesis that paternal exposures can lead to phenotypic changes in the offspring via non-coding RNA molecules in the semen. As there are no standard approaches for analysing such multigenerational mediation questions, our team of statisticians has devoted considerable efforts in developing statistical framework to examine epigenetic inheritance in a multigenerational setting.
The MULTIEPIGEN project’s preliminary main results thus far represent the most recent advancements in the field of epigenetic inheritance in humans. These can be summarised as follows: First, we observe several anticipated links between paternal exposures and offspring phenotypes. The existence of these associations is the prerequisite for further enquiry into causality. For example, paternal exposure to some organic pollutants is associated with increased risk of obesity and higher serum cholesterol levels in the offspring. In addition, paternal smoking before conception is associated with higher risk of obesity and the metabolic syndrome in the offspring, as well as with higher risk of anxiety. Furthermore, paternal obesity before conception associates with many components of the metabolic syndrome in the offspring. Second, we see that the pre-specified paternal exposures associate with sperm epigenome. For example, exposure to certain organic pollutants during childhood and adolescence is associated with changes in sperm non-coding RNA profile in adulthood. In addition, we see links between increased adiposity and sperm RNA profile – confirming previous studies in humans. Third, we can identify several links between paternal epigenome and offspring phenotype, including cardio-metabolic phenotypes, cognitive function parameters and psychological well-being. Fourth, the preliminary analyses suggest that some epigenetic markers could be candidate carries of the information between the generations. Thus, the results of the MULTIEPIGEN project provide novel observations in support of the hypothesis that non-genetic inheritance may occur in humans.
The data are being used to test the hypothesis that paternal exposures can lead to phenotypic changes in the offspring via non-coding RNA molecules in the semen. As there are no standard approaches for analysing such multigenerational mediation questions, our team of statisticians has devoted considerable efforts in developing statistical framework to examine epigenetic inheritance in a multigenerational setting.
The MULTIEPIGEN project’s preliminary main results thus far represent the most recent advancements in the field of epigenetic inheritance in humans. These can be summarised as follows: First, we observe several anticipated links between paternal exposures and offspring phenotypes. The existence of these associations is the prerequisite for further enquiry into causality. For example, paternal exposure to some organic pollutants is associated with increased risk of obesity and higher serum cholesterol levels in the offspring. In addition, paternal smoking before conception is associated with higher risk of obesity and the metabolic syndrome in the offspring, as well as with higher risk of anxiety. Furthermore, paternal obesity before conception associates with many components of the metabolic syndrome in the offspring. Second, we see that the pre-specified paternal exposures associate with sperm epigenome. For example, exposure to certain organic pollutants during childhood and adolescence is associated with changes in sperm non-coding RNA profile in adulthood. In addition, we see links between increased adiposity and sperm RNA profile – confirming previous studies in humans. Third, we can identify several links between paternal epigenome and offspring phenotype, including cardio-metabolic phenotypes, cognitive function parameters and psychological well-being. Fourth, the preliminary analyses suggest that some epigenetic markers could be candidate carries of the information between the generations. Thus, the results of the MULTIEPIGEN project provide novel observations in support of the hypothesis that non-genetic inheritance may occur in humans.
The idea of germline inheritance of acquired traits has the potential to increase our understanding of the aetiology of many human diseases that may have originated from environmentally induced transgenerational effects and thus may have widespread medical and social implications. MULTIEPIGEN is the first a priori designed epidemiologic study exploring the hypothesis in man that ancestral life experiences acquired in the environment can be inherited by offspring. Because it is not possible to perform controlled experiments in humans, measuring ancestral exposures in an existing population sample and expanding the data collections to their first degree relatives is the only realistic way to test this hypothesis in humans. MULTIEPIGEN is the first multigenerational large-scale epidemiologic study that have collected sex cells across three generations of males. Epidemiologic data showing robust links between ancestral exposures and offspring phenotypes that operate with biologically plausible epigenetic mechanism would give important insights into the developmental biology in humans and provide sufficient evidence to have an impact on health policies with potentially important implications on public health. Understanding epigenetic inheritance in humans may provide us opportunity for reducing certain exposures of individuals in reproductive age to prevent adverse effects on offspring. The results are also important as we aim to change how pre-conception healthcare is practiced to being preventative and inclusive of fathers’ role in child health. Therefore, potentially the results of the MULTIEPIGEN will have public health implications in the development and implementation of international policies and programs aimed at protecting individuals and their future offspring.