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

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

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.

Technical Summary

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.

Publications

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Borghol N (2012) Associations with early-life socio-economic position in adult DNA methylation. in International journal of epidemiology

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Golding J (2014) The anthropometry of children and adolescents may be influenced by the prenatal smoking habits of their grandmothers: a longitudinal cohort study. in American journal of human biology : the official journal of the Human Biology Council

 
Description SAPEA Science Advice for Policy by European Academies - Authorisation processes of plant protection products in Europe. Results presented by Paul Nurse to the European Parliament in 2019
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
URL https://ec.europa.eu/research/sam/index.cfm?pg=pesticides
 
Description Diet in Pregnancy Neurodevelopmental Phenome Scan: Family Adversity Interactions. Diet in Childhood/Adolescence and Substance Abuse Risks
Amount $190,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 06/2019 
End 11/2021
 
Description Escher Family Fund Grandmaternal smoking and risk of autism
Amount $25,000 (USD)
Funding ID 2015-139645 (3923) 
Organisation Silicon Valley Community Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2015 
End 10/2016
 
Description Exploration of personality and cognitive phenotypes in regard to grandmaternal prenatal smoking.
Amount $25,000 (USD)
Organisation Silicon Valley Community Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2017 
End 12/2017
 
Description Religious belief, health and disease: a family prospective. Phase 1 Data collection
Amount $234,800 (USD)
Funding ID 61356 
Organisation The John Templeton Foundation 
Sector Academic/University
Country United States
Start 08/2019 
End 07/2021
 
Description Transgenerational non-genetic pathways to human development.
Amount £995,615 (GBP)
Funding ID 60828 
Organisation The John Templeton Foundation 
Sector Academic/University
Country United States
Start 01/2018 
End 09/2020
 
Title ALSPAC autistic traits 
Description 4 different traits independently related to autistic spectrum disorders 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2009 
Provided To Others? Yes  
Impact Publications ongoing - being used by other scientists 
 
Title Exposome technique 
Description Development of a hypothesis-free method to analyse different environmental exposures, including trans-generational exposures, in relation to outcomes. In particular this uses data from the Avon Longitudinal Study of Parents and Children (ALSPAC). 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2014 
Provided To Others? Yes  
Impact This has highlighted the importance of the mother's childhood in influencing the motor development of the child, and has focused attention on the possible mechanisms. 
 
Description 9th UK/Ireland Conference on Occupational & Environmental Epidemiology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation given to the 9th UK/Ireland Conference on Occupational and Environmental Epidemiology, in Oxford on 16th April 2015. Epidemiological evidence of early effects of fetal exposure on later outcomes, including the next generation.
Year(s) Of Engagement Activity 2015
 
Description British Toxicology Society Annual Congress 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited Speaker: Symposium 1 MRC Integrative Toxicology Training Partnership: Epidemiological evidence of early effects of fetal exposure on later outcomes including into the next generation.
Year(s) Of Engagement Activity 2015
 
Description CCAH presentation Oct 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Presentation by Jean Golding on initial findings from this grant funded work. At monthly meeting of Centre for Child & Adolescent Health. Comprising support staff, academic staff and lecturers, research fellows, and postgraduate students. Everyone was fascinated by the topic and put forward ideas. There was much discussion.

None
Year(s) Of Engagement Activity 2012
 
Description Marcus Pembrey Invited speaker at 2017 Latsis Foundation Zurich, Symposium on Transgenerational Epigenetic Inheritance: Impact for Biology and Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk by Professor Marcus Pembrey
Year(s) Of Engagement Activity 2017
URL https://www.latsis2017.ethz.ch/
 
Description Oral presentation DOHad 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact DOHaD 2012 Conference (Developmental origins of health and disease), Rotterdam 6-7 December 2012.
Transgenerational effects of maternal smoking habits in pregnancy on fetal growth. Authors: L Miller, J Golding, K Northstone, M Pembrey


Much interest from other scientists
Year(s) Of Engagement Activity 2012
 
Description Presentation at "@Bristol" for ALSPAC 21st Birthday 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact 200 participants, Bristol academics and academic collaborators and media celebrating ALSPAC's 21 years and its research achievements. Talk title: ALSPAC-The Beginning.

The journal 'Nature' commissioned an article. There was a lot of press coverage both locally and nationally.
Year(s) Of Engagement Activity 2012
 
Description Presentation to JGI 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Jean Golding presented: "A life in data" to the Jean Golding Institute Showcase, University of Bristol 3rd July 2018
Year(s) Of Engagement Activity 2018
 
Description Round table discussion - European Medicines Agency 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact European Medicines Agency, Canary Wharf, London. Scientific meeting on long-term pregnancy outcomes. 28th-29th June 2018. Jean Golding presentation and discussion: Long-term effects of prenatal exposure to over-the-counter medications including paracetamol as an example
Year(s) Of Engagement Activity 2018
 
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Seminar given at University of Oxford, 8th May 2018: Environmental impact on child health and development: Have we been looking at the wrong generation?
Year(s) Of Engagement Activity 2018
 
Description UK Independent Advisory Committee on Toxicity, Carcinogenicity and Mutagenicity of Chemicals in Food, Consumer Products and the Environment (Didcot) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Jean Golding was invited to join this workshop and present a 30 minute plenary talk on epigenetics and disease as one of the thought-starter presentations. She then had to facilitate one of the discussion groups (10-12 people). Her talk was entitled "Evidence of human responses to environmental exposures".
Year(s) Of Engagement Activity 2017