Epidemiological studies of human transgenerational responses (TGR) to paternal and ancestral exposure

This research concerns a new aspect of human inheritance that we call transgenerational responses. Our adult constitution, including our susceptibility to common chronic diseases, depends on how our experience - in the form of nutrition and the physical and social environment - interacts with our inheritance, our individual genomes. Until recently biological inheritance was regarded as the genes and their variations ? the makeup of our DNA that we inherit from our parents. Of course, during pregnancy there is an overlap of generations in the same body, so the mother?s lifestyle can directly impact on the baby she is carrying. If she smokes, the baby ?smokes?, but that is part of Nurture (or rather poor nurturing!) not Nature or inheritance. There was no room in this view for the environmental ?exposures? that father experienced during his lifetime to be directly passed on to the next generation via his sperm.

However, over the last few decades animal experiments have hinted at the possibility that drugs and other toxic exposures in the male might influence development in the next generation(s). Human evidence is harder to come by, but the present applicants and collaborators have already made a start by examining data from more than one generation in circumstances that represent a natural experiment. Using historical records of swings in food supply in the 1800?s in Overkalix, Northern Sweden, Bygren?s group showed that the longevity (and diabetic deaths) of people born in Overkalix around 1900 was influenced by whether their paternal grandparents experienced famine or plenty during their mid childhood. It seemed that information about the ancestral environment was being transmitted by sperm. Supporting evidence came from the applicants? study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). If the study father started smoking before 11 years his future sons would have a greater body mass index.

The present research exploits the unrivaled collection of data on the ALSPAC participants during development and records on their parents to further characterise these transgenerational responses. We will look at the effect of the study parents being exposed as a fetus (via maternal smoking) on the growth and development of the study participants. In line with animal research we will also look at the impact of emotionally traumatic events (e.g. death of a parent) during the childhood of the study parents on the psychological and physical development of the next generation.

There is growing evidence from animal and human studies that sperm carry information about the paternal and ancestral environment that influences the health of the next generation(s). Understanding these transgenerational responses (TGR) is likely to bring substantial public health and medical benefits. This project builds on the results of an earlier collaboration between the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Overkalix cohort in Northern Sweden that provided clear evidence that sex-specific, male-line TGR exist in humans (Pembrey et al EJHG 2006;14:159). The Overkalix historical data shows associations between the food supply of the paternal grandfather in their early childhood with the mortality rate (and diabetic deaths) of their grandsons. It also demonstrates a similar association with early life exposures (from conception to 3 years) in the paternal grandmother with respect to her granddaughters. ALSPAC data shows that commencement of smoking before 11 years of age in the father is associated with higher body mass index in his future sons but not daughters mortality rate. A Taiwanese study on paternal betel nut chewing points to the metabolic syndrome as a TGR outcome in the father?s offspring. Many of these results mirror those found in animal experiments.

This project will use ALSPAC data to test the fetal and childhood exposures of study parents to toxins such as cigarette smoking as a TGR trigger for features of the metabolic syndrome in study participants. The analysis will investigate previously observed sex differences in early childhood exposure sensitive periods as well as sex differences in offspring outcomes. In line with animal data, early life ?traumatic events? in study parents (death of a parent, divorce or separation) and paternal grandmother (onset of war) will be examined as a stressful TGR trigger in relation to behavioural and cognitive traits in the study participants. Features of the metabolic syndrome will also be included in these offspring outcomes to evaluate whether toxic and stressful TGR triggers result in a similar range of downstream outcomes or whether stressful triggers only lead to behavioural and cognitive effects in the offspring. Answers to these questions will help inform future molecular (epi)genetic studies investigating the molecular mechanisms underlying male-line TGR.