Emerging research suggests environmental exposures before conception may adversely affect allergies and lung diseases in future generations. Most studies are limited as they have focused on single exposures, not considering that these diseases have a multifactorial origin in which environmental and lifestyle factors are likely to interact. Traditional exposure assessment methods fail to capture the interactions among environmental exposures and their impact on fundamental biological processes, as well as individual and temporal factors. A valid estimation of exposure preconception is difficult since the human reproductive cycle spans decades and the access to germ cells is limited. The exposome is defined as the cumulative measure of external exposures on an organism (external exposome), and the associated biological responses (endogenous exposome) throughout the lifespan, from conception and onwards. An exposome approach implies a targeted or agnostic analysis of the concurrent and temporal multiple exposures, and may, together with recent technological advances, improve the assessment of the environmental contributors to health and disease. This review describes the current knowledge on preconception environmental exposures as related to respiratory health outcomes in offspring. We discuss the usefulness and feasibility of using an exposome approach in this research, advocating for the preconception exposure window to become included in the exposome concept.
The reviewed literature strongly suggests that preconception exposures may be important for the development of asthma and lung health outcomes in future offspring. Associations with lung health outcomes of offspring are suggested for a range of single chemical exposures (smoking, occupation, and air pollution), hormonal metabolic exposures (being overweight and using oral contraceptives), and disease processes (infections, and asthmatic and allergic disease activity). In the context of preconception exposures, there is more evidence on the paternal line, and, in particular, for the childhood and early puberty exposure windows in males. The importance of these exposure windows may possibly be high; for instance, the associations between the father’s smoking starting before the age of 15 years and the offspring’s asthma risk appear to be at least as strong as for the associations with the mother’s smoking in pregnancy. Within the maternal line, associations with the asthma of a grandmother who smoked tobacco in pregnancy are reported in several studies. There is also some evidence of a maternal preconception exposure window in young adulthood.
The literature on the importance of preconception exposure for allergies and lung diseases in future offspring is supported by the evidence on preconception exposures for other health outcomes, such as obesity and growth [19][105]. Furthermore, the concept of preconception origins of health and disease is supported by mechanistic and experimental studies showing biological plausibility for the transfer of environmentally induced adverse impacts across generations. A role of the influence of germ cells, both for the female and male lines, is the most plausible pathway for the transfer of environmental effects across generations, and the mechanism most suitable for a discussion of the exposome effects, i.e., the effect of the totality of multiple concurrent or temporal exposures from all sources. One may speculate that the transfer of microbiome, or immune features influenced by the microbiome or infections, may become better documented and more relevant for future research on the preconception exposome.
The exposome concept is divided into three different domains: the general external exposome, the specific external exposome, and the internal exposome [14][105][106]. The general external exposome includes the wider social, economic, and psychological influences (e.g., socioeconomic status, education, psychological and mental stress, urban and rural environments, etc.). This domain can partly be captured by questionnaires, registry data, and geocoding, while the use of personal apps and the global positioning system (GPS) to capture these domains is likely to increase in the years to come. The specific external exposome includes exposures such as chemical agents and environmental/occupational pollutants, infectious agents, radiation, noise, diet, lifestyle factors, and medication [107]. Traditionally, this type of information has been collected by questionnaires, expert-based exposure matrices, and through measurements of the agent in question in the ambient air, drinking water, or food. Loh and coworkers (2017) reviewed the possibilities and limitations in the use of wearable sensor technology and smart technologies as a means to measure the specific external exposure domain, including the use of the GPS for the measurement of personal location, which together with activity affect all three exposome domains [108]. Finally, the internal exposome includes chemicals or their metabolites in biological fluids and tissues, as well as nongenotoxic processes (metabolome, epigenome, transcriptome, proteome, adductome, and microbiome processes). In general, the high-resolution and high-throughput technologies needed for investigating the multiple omics above are already in place. A major challenge in the field of exposome research is that the biostatistical and bioinformatical methods needed for analyzing the vast number of combined omics and exposure data are lacking. This technology and knowledge are imperative in order to facilitate the translation and interpretation of the exposome to derive new biological knowledge that can be used in prevention and that has implications for human health. Even though the complexity will be even higher with data from two generations, methodological and technological advances should aspire to be able to also include the preconception window in the exposome concept.
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. For the susceptibility window, from puberty to conception, it is possible to collect mature sperm and parts of its microenvironment from the paternal line. The sampling of egg cells (ova) from the maternal line would be excessively invasive to be feasible in large cohorts, and in relation to ovum retrieval, the microenvironment will most likely be affected by the treatment cycle prior to the procedure (e.g., hormonal and inflammatory effects).
The first obstacle for applying the exposome approach in the preconception period is the need to document the bioavailability and exposure intensities of the compounds of interest at the target cell. While the external exposome domain does not give us any information on the bioavailability of the compound, the endogenous exposome accounts for uptake from all sources (e.g., air, food, cosmetics, etc.) and routes (e.g., inhalation, oral, or dermal) of exposure. The use of the biological monitoring of exposure (chemical or its metabolites) in the assessment of health risk or prognosis requires that the biomarker is quantifiable, sufficiently correlated to the exposure of interest, and biologically relevant for the health effect or biological effect. Hence, although the internal concentrations of the environmental compounds of interest can be measured as proxies in accessible tissues (i.e., cord blood, blood, and urine) in future parents from birth and until conception, the true concentration available for the target cells or tissues (germ cells) during specific time points is not available.
For the same reasons described for bioavailability above, when judging whether it is biologically plausible that the human germ cells may be affected by preconception environmental exposures that also affect the immune and respiratory systems of future generations, we must rely on proxies of both exposures and effects, from existing and future human cohorts, combined with data from mechanistic and animal studies. The latter provides, for example, the possibility to gain detailed knowledge on how, and at what stages during testicular development and epididymal maturation, environmental information is transferred to the spermatozoa, and how the transfer of spermatozoan epigenetic information to the oocyte regulates transcriptional programs in the early embryo and the resulting later phenotypes. The experimental manipulation of epigenetic information, e.g., by injecting noncoding RNAs of interest into the early zygote, may potentially establish a cause–effect relationship.
In parallel with the increased use of exposome technologies and the collection of high-resolution and high-dimensional data in health sciences, there is also a continuing need to address the ethical, legal, and social issues related to biobanking, archiving, and analysis of the large amount of biological material and data generated. These issues apply to all types of health research, but future offspring is a particularly vulnerable population. A main concern for discussion in large-scale epigenetic and genetic studies is the procedures for reporting pertinent and incidental findings back to the participants. This issue also applies to exposome research. At present, there seems to be a consensus that at least three requirements should be fulfilled prior to reporting research results: the results must be analytically valid, clinically significant, and actionable [109][110]. However, the criteria for what is valid, clinically significant, and actionable are not established for many of the exposures and outcomes that are being investigated nowadays, and must, hence, often be decided after a discretionary assessment.
For studies that investigate how the exposome at the preconception time window may affect future offspring, informed consent is provided by the parents or previous generations, but not by the subject at risk. This raises several ethical considerations for reporting back research results to the study participants and their offspring. How can we ensure that the offspring want to know whether he or she has an increased susceptibility to respiratory diseases in adult life, and how will this information affect future choices with respect to education and occupation, family life, or leisure time? Moreover, will his or her future employer or insurance company have the right to obtain this information before employment or before accepting him or her as a customer?
Finally, although there are analytical methods that allow examinations of thousands of chemicals in biological samples among the general population, the health risk for most of these chemicals cannot yet be determined. This hinders a liable risk communication back to the participants and, consequently, the biomonitoring of these chemicals is not performed. However, if we do not start collecting this type of biological material and information in ongoing and planned cohort studies for use in later agnostic and untargeted analysis, there will be important limitations in understanding exposure effects and interactions in the future.
There are considerable challenges related to addressing the preconception environmental impact on the health of offspring in studies of humans, for whom the reproductive cycle spans over decades. Few cohorts have exposure data from parental prepubertal and pubertal years. Statistical methods for the optimal analyses of complex multigeneration data, with multiple mediators, confounders, exposures, and outcomes, in several generations, are becoming available, but there is a need for statistical expertise and methodology that also combine omics and exposure data representing the exposome across generations. Even with advanced methodology, the interpretation of negative results may pose a particular challenge, as they may reflect truly negative findings or a sum of limitations in complex data. Two partly negative papers have been published, showing an attention to publishing negative papers, but the publication bias of the statistically significant and stronger results is likely, as in other areas with less complexity.
Overall, the literature is sufficient to justify major research efforts on the preconception origins of asthma, allergies, and lung health. The research may have wide public health implications, indicating the potential benefit of interventions—or harm from negative exposures—for not only the exposed person, but also for future generations. Thus, it is urgent to bring this research forward. We argue that the benefits of an exposome approach in addressing complex, multiple, and concurrent lifestyles, behaviors, and exposures that interplay with each other may be equally important when considering the preconception environment as when addressing exposures during the life span. An exposome approach may be particularly useful to elucidating the germ cell environment at different developmental stages, from intrauterine life until the reproductive age of the parents. Exposure information from the preconception time window will, however, often be far more limited than for other life-stages, and the biomaterial from the preconception stages is generally not available, except for sperm, rarely available in humans and, if so, sampled after the offspring were born. This underscores the need for the close integration of epidemiological and mechanistic studies. Still, obtaining valid information about the preconception period should be kept in mind when planning questionnaires, the collection of biomaterials, the use of novel technologies, and data for validation analyses, in future inter- and transgenerational studies. We advocate for explicitly including the preconception period in the exposome concept in the quest to identify the environmental contributors to health and disease (Table 1).
Table 1. Summary of multigeneration human studies associating preconception environmental exposures to asthma, allergies, and lung function.
1 Study cohort: CHS: Children’s Health study in southern California; ALSPAC: Avon Longitudinal Study of Parents and Children; MoBa: Norwegian Mother and Child Cohort Study; RHINE: Respiratory Health In Northern Europe; ECRHS: European Community Respiratory Health Survey; NSC: Nationwide Swedish Cohort; RHINESSA: Respiratory Health In Northern Europe Spain and Australia; CCHH: China-Children-Homes-Health epidemiology study; T-CHILD: Tokyo-Children’s Health, Illness and Development Study; TAHS: Tasmanian Longitudinal Health Study.
This entry is adapted from the peer-reviewed paper 10.3390/ijerph182312684