Exposures during the prepuberty period and future offspring’s health: evidence from human cohort studies†

Abstract

Emerging evidence suggests that exposures in pre-puberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father’s exposed to tobacco smoking or overweight that started in pre-puberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of pre-puberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during pre-puberty play a role for grand-offspring health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multi-generation data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male pre-puberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research and biological plausibility, all support the notion that exposures in the pre-puberty of males may influence the phenotype of future offspring.

Human transgenerational observations of regular smoking before puberty on fat mass in grandchildren and great-grandchildren

“…A subsequent detailed study of antecedents associated with fat mass at age 24 showed that a similar association remained with paternal onset of smoking < 11 years, which increased in size on adjustment for confounders 9 . There is support for these findings since the association of fathers’ prepubertal onset of smoking with fat mass in sons but not daughters was also found in the RHINESSA study 4 .…”

“…The most recent population studies to investigate this have largely focussed on asthma as the outcome of interest. The authors have shown paternal exposures to smoking of cigarettes prepuberty to be associated with increased risk of asthma and reduced lung function as well as of increased fat mass in the offspring 4 .…”

The Exposome Approach in Allergies and Lung Diseases: Is It Time to Define a Preconception Exposome?

“…To have a beneficial or adverse effect on human health, the environmental exposure in question must interact with the biological system at some level, i.e., it must be bioavailable for the target cell at the right time and be able to interact with biomolecules. An optimal assessment of the exposome during the preconception period would require access to the germ cells of the parent and, perhaps, of previous generations, as well as (surrogate) target tissues in the next generation [ 6 ]. The human germ cells and the microenvironments of these in the ovaries/testes are unavailable for research in the prepuberty window, in both males and females.…”

“…Validation analyses from the same cohorts on information reported across two generations showed that recall bias is likely to have a limited impact on these results [ 33 , 34 ]. Three-generation causal associations of the smoking of grandmothers and grandfathers on the lung function of offspring within the paternal line were assessed in the ECRHS and RHINESSA cohorts [ 30 ], using a causal modeling approach [ 6 , 32 , 35 ]. The father’s smoking in prepuberty appeared to cause lower lung function in offspring, with a negative direct effect on the offspring’s forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC).…”

“…There is growing awareness that the traditional methods of exposure assessment fail to capture the full extent of environmental exposures and their impact on fundamental biological processes [ 5 ]. The human reproductive cycle spans decades, and germline precursor cells undergo important developmental stages from the early intrauterine period to maturation and reproductive capacity [ 6 , 7 , 8 , 9 , 10 ]. Hence, shortcomings related to assessing concurrent exposures and their temporal aspects might be even more challenging when addressing exposures occurring during the preconception period, as there is a long lag time between the exposures and the manifestation of health and disease in the offspring.…”