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

Abstract

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.

Keywords: Epigenetics; epigenetic epidemiology; miRNAs; overkalix; transgenerational.

Figure 1

Schematic pedigree diagram showing the main routes for biological transmission of the effects of exposure to the next generation(s). Left, female line; right, male line. The exposure can potentially affect the germline, the reproductive system and the soma more generally. The traditional pedigree lines (blue) show chromosomal transmission, which, in addition to the DNA, can potentially include exposure-induced epigenetic marks that escape erasure and impact on offspring development. The germline can potentially transmit exposure-induced non-coding RNAs (ncRNAs) that influence offspring development. Exposure induced metabolic changes can set up a ‘metabolic cascade’ such that changes in the reproductive tract influence early embryo programming of the offspring or change metabolic signals across the placenta. An additional maternal transmission route is the influence of the mother's microbiome on that of her child.