Exposome: Time for Transformative Research

Life expectancy is an overall measure of population health, and has reflected a positive trajectory for several decades in the United States when estimated either at birth or 65 years of age [1]. Despite such improvements, life expectancy varies by socio-demographic characteristics and the availability of adequate medical care. Concerns about the continual sustainability for improving life expectancy have grown in light of the obesity epidemic currently occurring in the United States and in other countries across the globe [2, 3]. For example in 2010, all 50 States comprising the United States reported an obesity prevalence of 20% or more, with 12 states reporting a prevalence of 30% or more [2]. Overall, approximately 33% of adults and 17% of children in the United States are currently estimated to be obese [4]. Other notable changes in population health include the marked reduction in fertility rates over time [5], which has partially but not entirely been attributed to changes in cultural norms and behaviors regarding childbearing practices. In fact, an evolving body of evidence is suggestive of temporal declines in human fecundity, which is defined as the biologic capacity of men and women for reproduction irrespective of pregnancy intentions [6]. The body of evidence supporting a decline in male fecundity over the past few decades includes diminished semen quality and increasing rates of genital-urinary malformations and testicular cancer, all of which are hypothesized to originate in utero or the so-called TDS or testicular dysgenesis syndrome [7]. This conceptual framework has recently been extended to women. Specifically, the ovarian dysgenesis syndrome (ODS) posits that female fecundity is established at conception or in utero with early impairments arising during prepubertal or reproductive years as manifested by alterations in the onset or progression of puberty or gynecologic and gravid disorders, respectively [8]. Assuming that human fecundity may be positively associated with survival as recently reported for semen quality [9], its decline may be at a ‘critical tipping point’ for human health as recently suggested [10] underscoring the importance of new research pardigms such as the exposome for assessing the early origins of fecundity and its implications for health across the lifespan. How might researchers further impact the health and well being of populations across the globe? Certainly, new research paradigms are needed for transforming how we think about health and disease and design research, acordingly. Novel paradigm changes are already underway (e.g., genome and epigenome), though noticeably absent is a paradigm that captures the multitude of environmental exposures that impact human health and disease. This data gap prompted the development of the exposome paradigm, which compliments the (epi)genome while providing a multitude of opportunities for intervention if exposures can be eliminated or minimized. The exposome paradigm focuses on the simultaneous measurement of a multitude of biomarkers including those that originate from external and internal sources. External environmental exposures may include chemicals or physical agents such as radiation among many other types of exposures, while internal environmental exposures arise from bodily functions and processes that govern homeostasis. Internal exposures may include chemicals or biomarkers generated via inflammation or stress along with various other pathways. Of note is the absence of biomarkers for some external environmental exposures (e.g., noise or vibration) resulting in missing data or the need for proxy biomarkers. These issues are further discussed below along with the unique aspects of the exposome such as the longitudinal and high dimensional nature of biomarkers across the lifespan. This paper provides a brief overview of the exposome paradigm along with the resources needed for getting started, research hurdles and challenges to overcome and opportunities for discovery. The overview is organized as responses to five questions: 1) What is the exposome? 2) Why is the timing right for exposome research? 3) What resources are needed for moving forward? 4) What research hurdles and challenges need to be overcome? and 5) What impact might the exposome have for transforming population health? We use human fecundity to illustrate how the exposome might be implemented, though the issues pertain to most (non-Mendelian) health outcomes.