Prenatal and prepubertal exposures to tobacco smoke in men may cause lower lung function in future offspring: a three-generation study using a causal modelling approach

Abstract

Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited.We investigated multi-generation causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age: 18–47; female: 52.0%) and their 274 fathers, who had participated in the ECRHS/RHINESSA generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multi-level mediation models were developed with: paternal grandmothers’ smoking in pregnancy and fathers’ smoking initiation in prepuberty as exposures; fathers’ FEV1 and FVC, or FEV1/FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); offspring's FEV1 and FVC, or FEV1/FVC z-scores as outcomes. All effects were summarised as differences in expected z-scores related to fathers’ and grandmothers’ smoking history.Fathers’ smoking initiation in prepuberty had a negative direct effect on both offspring's FEV1 (−0.36; 95% confidence interval: −0.63, −0.10) and FVC (−0.50; −0.80, −0.20) compared to fathers’ never smoking. Paternal grandmothers’ smoking in pregnancy had a negative direct effect on fathers’ FEV1/FVC (−0.57; −1.09, −0.05) and a negative indirect effect on offspring's FEV1/FVC (−0.12; −0.21, −0.03) compared to grandmothers’ not smoking before fathers’ birth nor during fathers’ childhood.Fathers’ smoking in prepuberty and paternal grandmothers’ smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations.

Maternal preconception occupational exposure to cleaning products and disinfectants and offspring asthma

“…13 Emerging evidence from human and animal models suggests that preconception parental exposures may influence the health of future generations. [14][15][16][17][18][19][20][21][22][23][24] Previous studies on maternal occupational exposure and respiratory health in offspring are scarce. [25][26][27] However, a registry study found that several parental occupations were associated with increased hospitalization for childhood asthma among offspring.…”

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

“…In addition to supporting the results on grandmother’s smoking, the role of the father’s smoking in early puberty (i.e., before age 15 years) on the respiratory health of future offspring has been demonstrated in concordant findings from three epidemiological studies: the European Community Respiratory Health Survey (ECRHS), Respiratory Health In Northern Europe (RHINE), and Respiratory Health In Northern Europe Spain and Australia (RHINESSA) cohorts [ 28 , 29 , 30 ]. In these international multigeneration cohorts, extensive offspring- and parent-reported information on respiratory diseases and preconception exposures in the previous generation (together with objective measurements of lung function) were collected in both the maternal and paternal lines.…”

“…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).…”

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

“…Statistical mediation models were used to account for the complexity in the multicenter multigeneration data, including simulation analyses showing that the impact of unmeasured confounding on the estimates was limited. State-of-the-art statistical methods for causal inference from observational data were applied in a subsequent analysis of the RHINESSA/ECRHS cohorts, finding that father's smoking before age 15 years might also have a negative impact on lung function in offspring [14]. Impact on both FEV 1 and FVC suggests detrimental causal effects on lung growth as well as on airways obstruction.…”

“…This is reflected in "First 1000 Days" programs around the world targeting the mother and child. Current multigeneration research has provided evidence that exposures during pregnancy may also impact grand offspring [8][9][10][11][12][13][14]. Thus, the focus on the pregnant woman might in some cases give triple returns-for the unborn child, for the mother beyond pregnancy, and, possibly, for the grand offspring whose germ cells are present already in the fetus in utero.…”