The role of epigenetics in multi-generational transmission of asthma: An NIAID workshop report-based narrative review

Abstract

There is mounting evidence that environmental exposures can result in effects on health that can be transmitted across generations, without the need for a direct exposure to the original factor, for example, the effect of grandparental smoking on grandchildren. Hence, an individual's health should be investigated with the knowledge of cross-generational influences. Epigenetic factors are molecular factors or processes that regulate genome activity and may impact cross-generational effects. Epigenetic transgenerational inheritance has been demonstrated in plants and animals, but the presence and extent of this process in humans are currently being investigated. Experimental data in animals support transmission of asthma risk across generations from a single exposure to the deleterious factor and suggest that the nature of this transmission is in part due to changes in DNA methylation, the most studied epigenetic process. The association of father's prepuberty exposure with offspring risk of asthma and lung function deficit may also be mediated by epigenetic processes. Multi-generational birth cohorts are ideal to investigate the presence and impact of transfer of disease susceptibility across generations and underlying mechanisms. However, multi-generational studies require recruitment and assessment of participants over several decades. Investigation of adult multi-generation cohorts is less resource intensive but run the risk of recall bias. Statistical analysis is challenging given varying degrees of longitudinal and hierarchical data but path analyses, structural equation modelling and multilevel modelling can be employed, and directed networks addressing longitudinal effects deserve exploration as an effort to study causal pathways.

FIGURE 1

Transgenerational inheritance of disease risk: evidence from animal models. Gestational exposure of mice to an environmental trigger, in this case, diesel exhaust particles (DEP) or concentrated urban air particles (CAP), leads to increased asthma risk in up to 3 generations of offspring. It is important to distinguish intergenerational inheritance from transgenerational because in a gestational exposure model not only the pregnant F0 ancestor is directly exposed to the trigger, but also the fetus; moreover inside the F1 fetus there are predecessors of gametes that will give rise to F2 progeny which are theoretically also directly exposed. In the paternal line only the predecessors of gametes that form the F1 are directly exposed and effects that persist to the F2 can be considered transgenerational

FIGURE 2

Vertical and induced epigenetic transmission models. (A) Vertical epigenetic transmission model proposes direct transfer of epigenetic information from parents to child in successive generations. (B) The alternative model, induced epigenetic transmission, proposes that maternal disease is an essential element in the chain of epigenetic transmission of information. DNA‐M, DNA methylation. Adapted from Arshad et al.

FIGURE 3

Models of multi‐generation cohorts. (A) In three generational cross‐sectional cohorts, grandparents (F0) and parents (F1) are recruited in their adult life while grandchildren (F2) could be children or adult. They may be assessed once or followed up longitudinally. (B) Some three generational cohorts include a birth cohort, where two generations (grandparents and parents) are recruited in adult life, while grandchildren are recruited at birth and followed up longitudinally. (C) Transgenerational cohorts will have at least two birth cohorts so that both F1 and F2 are recruited at birth.