Early-life exposome and lung function in children in Europe: an analysis of data from the longitudinal, population-based HELIX cohort

Abstract

Background Several single-exposure studies have documented possible effects of environmental factors on lung function, but none has relied on an exposome approach. We aimed to evaluate the association between a broad range of prenatal and postnatal lifestyle and environmental exposures and lung function in children. MethodsIn this analysis, we used data from 1033 mother-child pairs from the European Human Early-Life Exposome (HELIX) cohort (consisting of six existing longitudinal birth cohorts in France, Greece, Lithuania, Norway, Spain, and the UK of children born between 2003 and 2009) for whom a valid spirometry test was recorded for the child. 85 prenatal and 125 postnatal exposures relating to outdoor, indoor, chemical, and lifestyle factors were assessed, and lung function was measured by spirometry in children at age 6-12 years. Two agnostic linear regression methods, a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering exposures independently, were applied to test the association with forced expiratory volume in 1 s percent predicted values (FEV₁%). We tested for two-way interaction between exposures and corrected for confounding by co-exposures. Findings In the 1033 children (median age 8•1 years, IQR 6•5-9•0), mean FEV₁% was 98•8% (SD 13•2). In the ExWAS, prenatal perfluorononanoate (p=0•034) and perfluorooctanoate (p=0•030) exposures were associated with lower FEV₁%, and inverse distance to nearest road during pregnancy (p=0•030) was associated with higher FEV₁%. Nine postnatal exposures were associated with lower FEV₁%: copper (p=0•041), ethyl-paraben (p=0•029), five phthalate metabolites (mono-2-ethyl 5-carboxypentyl phthalate [p=0•016], mono-2-ethyl-5-hydroxyhexyl phthalate [p=0•023], mono-2-ethyl-5-oxohexyl phthalate [p=0•0085], mono-4-methyl-7-oxooctyl phthalate [p=0•040], and the sum of di-ethylhexyl phthalate metabolites [p=0•014]), house crowding (p=0•015), and facility density around schools (p=0•027). However, no exposure passed the significance threshold when corrected for multiple testing in ExWAS, and none was selected with the DSA algorithm, including when testing for exposure interactions.Interpretation Our systematic exposome approach identified several environmental exposures, mainly chemicals, that might be associated with lung function. Reducing exposure to these ubiquitous chemicals could help to prevent the development of chronic respiratory disease.

Applying the exposome concept in birth cohort research: a review of statistical approaches

“…The selection of exposures to consider in the study depends on the research question and issues of feasibility and data accessibility. Previous studies have included a wide range of external environmental exposures from various families, or have been specifically focused on certain components of the exposome, such as the urban or the chemical exposome, assessed at various developmental periods [13][14][15][16][17][18][19]. Socioand public health exposome conceptual frameworks have also been proposed and can guide the selection of exposures [20,21].…”

“…The DSA algorithm was used, for instance, in recent studies within the HELIX project looking at the associations between the early-life exposome and childhood lung function and between the urban pregnancy exposome and birth weight [13,16]. The DSA algorithm is an iterative model search algorithm that relies on deletion (removing one variable from the model), substitution (replacing one variable from the model by one that was not yet included in the model) or addition (adding one new variable to the model) moves to find the optimal set of variables that minimizes the root mean square error.…”

A Scoping Review on the Characteristics of Human Exposome Studies

“…Approximately a third of the retained exposome studies had a prospective longitudinal design (n = 30, 37%), of which 26 were based on nine large population-based cohorts; the rest four longitudinal studies were relatively small in size, including between 6 and 378 subjects [46][47][48][49]. Out of the 26 studies, eleven were published as part of the Human Early-Life Exposome (HELIX) project using data from six European birth cohorts ( [50][51][52][53][54][55][56]), and among these studies, four belonged to the Spanish INMA (INfancia y Medio Ambiente) [57][58][59][60][61]. Four studies (of the 26) were published as part of the Avon Longitudinal Study of Parents and Children (ALSPAC), a 20-year population-based cohort designed to determine the influence of environmental (physical and psychological) and genetic factors on the health status and development of the offspring.…”

“…Novel agnostic tools of the exposome characterization were extensively used in 16 studies (20%), where 9 exposome studies (11%) employed the EWAS approach [50,63,73,61,67,69,79,86,107]; 3(4%) studies used the GWAS approach [71,78,92] and 2 (3%) used the so-called MWAS approach [84,88]; another publication (1%) [59] reported the use of an exposome-metabolome wide association study, and another one (1%) [108] employed both an EWAS and a GWAS approach.…”

“…48,50,63,67,70,95,97,100,103,104,106,[118][119][120][121][122][123]. Environmental factors were examined in association with gene expression profiling in four studies (5%)[65,71,78,108].…”