Chronic psychosocial stressors and salivary biomarkers in emerging adults
Introduction
The stress response engages the hypothalamic pituitary adrenal axis and the sympathetic nervous system, activating or suppressing genes both centrally and in the periphery through the release of hormones at each level of the axis (Chrousos and Gold, 1998). These systems are normally under negative feedback control to respond appropriately to acute risks (flight-or-fight response), but upon chronic stimulation, these biological systems become dysregulated, leading to altered hormonal, cytokine, and metabolic states (McEwen, 2000). Exposure to chronic stressors (social and environmental toxicants) contributes to allostatic load and to disease, including behavioral, metabolic and inflammatory disorders (Cohen et al., 2007, Koob and Kreek, 2007, Miller, 2008, Epel, 2009, Rappaport and Smith, 2010). Identification of biomarkers of exposure to chronic stressors will not only facilitate identification and characterization of individuals suffering from the effects of exposure to chronic stressors, but will also elucidate the mechanisms mediating the etiologic link between chronic stressor exposure and chronic disease.
A biomarker of exposure to chronic psychosocial stressors in leukocyte RNA from adults in multiple distinct studies (Cole et al., 2007, Miller et al., 2008, Miller et al., 2009) is the gene expression signature of reduced glucocorticoid receptor (GR) regulated gene expression and increased nuclear factor kappa B (NF-κB) regulated gene expression. This signature was identified using differential gene expression analyses on DNA microarrays (Schena et al., 1995), gene ontology (GO) analyses (Ashburner et al., 2000) and transcription factor binding motif (TFBM) analyses (Cole et al., 2005). An advantage of utilizing the genomic technologies represented by the work of Cole (Cole, 2010) is the opportunity to identify functional biological elements and to leverage biomedical knowledge to hypothesize mechanisms at the pathway (Cole et al., 2007, Miller et al., 2008, Miller et al., 2009) or gene (Cole et al., 2010) level.
Our objective in this study was to evaluate how emerging adults with high or low levels of exposure to severe life events and difficulties differ in relevant clinical characteristics, salivary analyte metrics, and salivary gene expression. Emerging adulthood (ages 18–25) is a prime transitional period marked by departure from the childhood home and a decline in institutional structure and support (Arnett, 2000), potentially exposing the individual to both chronic and episodic stressors. Since substance use often peaks during emerging adulthood (Schulenberg et al., 2005), and the onset of substance abuse and dependence typically occurs at this time (Compton et al., 2005, Kessler et al., 2005), we included alcohol use disorders and tobacco use in our analyses. We analyzed behaviors and a demographic variable that might influence oral health and disease. We analyzed saliva metrics and several components of whole saliva (human DNA and RNA, bacterial DNA, and cortisol). As a specific biological hypothesis, we analyzed gene expression to observe whether the expression signature of differential exposure to a chronic stressor identified in monocytes derived from whole blood samples in adults was also present in whole saliva from emerging adults differentially exposed to chronic stressors. We chose to study whole saliva samples, as we seek to understand the potential of analyzing saliva collected in community and clinical trial settings for translation toward social genomics, health surveillance and analysis of treatment response applications. Saliva has obvious utility as a diagnostic tissue due to its ease of collection and ongoing efforts to identify salivary biomarkers of both oral cavity and non-oral cavity disease (Kaufman and Lamster, 2002, Streckfus and Bigler, 2002, Gao et al., 2009, Lee et al., 2009, Luther et al., 2010, Zhang et al., 2010).
Section snippets
Oregon Youth Substance Use Project (OYSUP) participants
The study cohort of 48 individuals was chosen based on data from the Life Events and Difficulties Schedule (LEDS) obtained at age 21–23 from 123 participants within two grade-based cohorts from the OYSUP, a 15-year ongoing longitudinal study of approximately 1000 participants examining the etiology of substance use in Oregon youth (Andrews et al., 2003). OYSUP began in the 1997–1998 school year with students in five grade cohorts in the first through fifth grade, recruited from a single school
Clinical differences between groups stratified by exposure to chronic stressors
We selected 48 participants from the first 123 individuals in Cohorts 4 and 5 of OYSUP with available saliva samples and LEDS data as the study sample (Table 1). At the time of the assessment, the 48 participants were on average 21.05 years of age (SD = 0.38), 31% female, and 94% self-identified white non-Hispanic race/ethnicity with no significant differences in age, gender or self-identified race/ethnicity between stressor exposure strata (Table 1).
We compared the stressor exposure strata for
Discussion
To explore whether whole saliva might be used to identify biomarkers of exposure to chronic stressors, we evaluated clinical features, salivary analyte metrics, and expression of a priori selected candidate genes in whole saliva samples from 48 individuals stratified by exposure to chronic stressors. These 48 individuals were selected from an ongoing assessment of five grade-based cohorts of ∼1000 participants (Andrews et al., 2003), specifically from a subset of 123 individuals from two
Role of funding source
The project described was supported by RC2DA028793 from the National Institute on Drug Abuse (JAA and AWB, co-Principal Investigators) and the core project, OYSUP, is supported by R01DA10767 (JAA, Principal Investigator). AM was supported by NIH/NCCR CTSA grant number TLI RR025742. SPD was supported by R21DA027331 and R24GM61374. The content is solely the responsibility of the authors. The funders had no role in study design, data collection, analysis and interpretation, in the writing of the
Conflict of interest
All authors state that there are no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work.
Acknowledgments
We thank the OYSUP participants, who have contributed to population-based research for over a decade. We thank personnel at ORI including Niraja Lorenz, Erika Westling, Jenel Jorgensen, Melissa Peterson, Erik Burke, Miranda Brown, Katie Geiser, Jessica Olson, Christine Lorenz, Anita Grimaldi, and Anne Kjosnes who assisted in the collection of participant clinical data. We thank David Cooper of SRI International, David Cohen, formerly of SRI International, and Amy Hamilton, of Fluidigm, whose
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