Exposome Study to Understand Effects of Environmental Exposure on Health Outcomes

Abstract

The exposome describes the totality of exposure during the life-course of people, and aims to comprehend the causal association between exposure and health risks, mediated by multi-layered biological mechanisms. Compared to the conventional risks assessment, the concept of exposome has expanded its paradigm. Firstly, environmental exposure is not restricted to high-dose effects specifically through accidents or occupations. Exposome study attempts to understand the long-term effects of small amounts of the exposure consistently introduced to us throughout our lives, resulting in chronic health risks or diseases. Secondly, there are complex biological regulations in multi-layered levels that mediate causality. Association analyses have been performed between values representing exposure levels and health states. Additionally, genomic variations, gene expressions, and epigenomic regulations could be taken into account for discovering their contributions and how they mediate health outcomes when affected by exposure. Nucleic acids are essential for understanding molecular mechanisms. Various types of biological samples could yield nucleic acids. Exposome studies that target the normal population generally utilize blood, because it is easily accessible compared to other solid tissues. However, biological samples start to degrade rapidly once extracted from the body, which makes it challenging to obtain the materials with the desirable qualities. As an alternative, samples are required to be properly processed by recognizing their structural or componential characteristics. For example, whole blood can be damaged upon freezing due to its fluidic property, causing cell bursts; this destroys the integrity of the sample and several molecular materials cannot be obtained. The limited utility of blood is a common challenge that many cohorts aiming at exposome studies face. In this study, I incorporated two research categories within the topic of exposome. First, I have discussed blood handling strategies which can be utilized for exposome study. By mimicking possible situations in the actual fields, such as types of sample collection tube, time and temperature before freezing, and long-term freezing, I compared the RNA qualities isolated from each blood sample and their applicability to omics analyses. As I hypothesized, unfavorable handling conditions significantly damaged sample integrity. The damaged RNA was unavailable for downstream applications, and even if it were technically applicable, the results fluctuated. As the variabilities are critical obstacles for reliable data interpretation, I emphasized the importance of establishing proper sample handling strategies to minimize unnecessary confounding effects caused by improper sample management. Second, I studied the prenatal exposome using two independent birth cohorts, MOCEH and GREEN, which deal with how the maternal environmental exposure during pregnancy affects fetal development and its life-long health effects after birth. I assessed the correlations between maternal exposure levels to heavy metals and perfluoroalkyl substances, which were measured in the maternal blood and cord blood, and between exposure levels and health outcomes such as atopic dermatitis and birth outcomes were assessed, respectively. Furthermore, by obtaining nucleic acids from the subjects, I have generated various omics data using either microarray or next-generation sequencing techniques. The omics data were integrated with information of exposure levels and health outcomes to explore insightful mediating effects between the exposure and health outcomes. Specifically, I identified that an increase in maternal Cd exposure elevated the methylation levels at a specific CpG site (cg21010642) involved in embryonic development, to increase the risks of reduced gestational age. I further identified that an increase in maternal Pb exposure increased the expression of certain genes (TIRAP, PSMD11, and TAP2) in mothers, which are involved in inflammatory and immune responses, and increase in prenatal Pb exposure delivered from the mother decreased the expression of certain genes (FOSL1 and LOXL2) in the fetuses, which are involved in early development and placentation. This alteration of gene expression resulted in low birth weight of fetuses. In addition, I observed that the toxicity of maternal Pb or As exposure could be delivered to the fetus, and lower the DNA methylation levels of both mothers and fetuses in specific regions; for example, near the genes involved in uterine contraction. Referring to inverse association of DNA methylation and gene expression, the genes would be up-regulated abnormally promoting delivery which is related to preterm birth. Using the multi-layered approach to understand the prenatal exposome, I concluded that while the toxicity is delivered from mother to fetus to directly affect fetal molecular regulations, it could also exert the effect by facilitating unfavorable in utero environment through affected mothers. The word “environmental exposure” reminds us of obvious polluted sceneries such as smoke or waste water. However, environmental exposure continuously harms us through invisible permeation. As the effects are not immediately recognizable, we prone to overlook the severity of the effects. However, it would eventually disrupt our lives through chronic health risks or disease. By perceiving the potential severities of the exposure, particular population- or nation-wide risks assessment strategies ought to be developed for protecting public health. Hence, this study provides meaningful insights on exposome approaches. There are apparent limitations, which can, however, be overcome by expanding the sample size and visibility of omics levels. It is expected that exposome studies would play a critical role in developing bio monitoring systems for advanced risk assessments by providing systematic insights for understanding environmental exposure and its consequences.