Epigenetics: Prenatal roots of asthma, allergies and lung function

Research findings indicate that exposure years before conception can have a relevant effect on the health of subsequent generations.

The influence of previous generations on the respiratory health of our children

There is now growing evidence that respiratory health is influenced by parental exposures that occur long before conception.1 The authors of a review in the Journal of Internal Medicine see a clear evidence in the literature that for many influencing factors, the primary issue is not exposure to a specific factor, but its timing. We already know this from other contexts: for example, an exposure can be of little consequence in adulthood, but it can have devastating effects if it occurs in utero. However, most studies focus on the dosage and the (relatively) short-term consequences of exposure to risk factors such as smoking and obesity.

Given the very different development of germ cells into mature oocytes and sperm, there are different vulnerable time windows for men and women. In the context of the transmission of environmental influences via the gametes, which depends on the developmental stage of the gametes, pre-puberty in boys is potentially a particularly important period for the health of future offspring. Exposures that begin before the age of 15 or between childhood and voice change in boys show surprisingly strong associations in studies with effects on future offspring, comparable to exposures in utero, the researchers emphasise.1

Does parenthood begin in childhood?

The best-documented pre-conceptual risk factor for respiratory health or disease in human studies to date is paternal smoking, which begins in early adolescence. This is associated with low lung function and asthma in future offspring. In girls, no such effect is seen for pre-puberty, but exposure in the womb (e.g. even grandmother's smoking during this period) was consistently associated with asthma in offspring.

The data also shows that paternal obesity in childhood/adolescence appears to be an important risk factor (probably a causative factor) for asthma and reduced lung function. The review emphasises the astonishing consistency of the results across different studies and evaluation methods. No such effect was found on the maternal side. 

The literature is sparse on the possible role of other preconceptional hormonal-metabolic factors in respiratory health. Two mother-child studies came to somewhat different conclusions: in a Japanese cohort, earlier use of oral contraceptives by the mother was associated with more wheezing, asthma and rhinitis in the offspring at the age of 5 years. A Norwegian study, which analysed the use of contraceptives only in the year before pregnancy in over 60,000 mother-child pairs, was unable to establish any such association for combination pills (oestrogen and progestogen) until the children were three years old; however, progestogen-only pills were weakly associated with increased wheezing in the 6-8 month old infants.

There is only very limited evidence to date in favour of the hypothesis that pronounced immune reactions to certain infections can influence immunity across generations.

Translating prenatal disease development into cross-generational prevention

This is a very crucial field for prevention, but difficult to study in humans because our life cycle spans decades and, unlike experimental animal models (such as rodents, fish, and invertebrates) the human environment is much more complex and subject to change over time. To investigate pre-conceptual risk factors in human studies, we need accurate data on exposures, effects, and important covariates for two or more generations. And ideally these would include prospectively collected biosamples (including gametes), to enable mechanistic studies.

Epigenetic inheritance of changes in germline cells caused by external factors opens up a new prevention paradigm: to identify potentially vulnerable groups and promote healthier choices in children approaching puberty to improve the lifelong health of the affected individuals themselves as well as their future offspring and possibly further generations. This could counteract a vicious cycle of transmission of predispositions and health inequalities in the population across generations, the review concludes.1

  1. Svanes, C., Holloway, J. W. & Krauss-Etschmann, S. Preconception origins of asthma, allergies and lung function: The influence of previous generations on the respiratory health of our children. Journal of Internal Medicine 293, 531–549 (2023).