Females are twice as likely as males to develop posttraumatic stress disorder (PTSD) and/or severe PTSD symptoms (PTS) following trauma exposure. Evidence suggests that this disparity may, in part, have a biological basis: trauma exposure can be biologically embedded via acquired epigenetic alterations that affect stress reactivity to even mild future stressors. Thus, sex differences in PTSD/PTS may be mediated, in part, by acquired epigenetic modifications. The long-term goal of the planned line of research is to contribute to the development of strategies to reduce sex/gender inequities associated with PTSD. The immediate objective of the proposed multidisciplinary pilot study is to collect information needed to design a full-scale R01 investigation of factors that might underlie observed sex/gender differences in PTSD/PTS. The planned R21 study would leverage the infrastructure and resources of an ongoing R01 investigation to obtain epigenetic information on a subgroup at especially high risk for PTSD/PTS, i.e., Latino survivors of serious physical injury. Building on the R01 study design, which would entail interviews with physical injury survivors within days of hospitalization and at 5-month follow-up, the planned pilot study would collect blood samples from a subsample of 100 (i.e., 50 males/50 females) at both interviews. Blood data will be linked with interview data to gather preliminary information about the likely magnitude of key epigenetic effects and to determine which of several different genes involved in stress regulation and vulnerability are most promising for further R01 study of sex/gender differences in PTSD. The planned R21 has the following specific aims: (1) To explore the magnitude and direction of cross-sectional associations between methylation at loci of four stress- and mood-related genes (PACAP, NR3C1, RORA, ESR1) and lifetime trauma history (number of events, event severity, type, and chronicity) and baseline PTS in Latino men and women. (2) To determine the degree to which methylation of PACAP, NR3C1, RORA, and ESR1 at the initial post-injury assessment can explain the link between sex and subsequent PTSD/PTS, after accounting for lifetime trauma exposure. (3) To appraise whether post-trauma changes in methylation of PACAP, NR3C1, RORA, and ESR1 can be detected at 5-month follow-up, and whether the magnitude of any change is related to sex or to PTSD/PTS. The knowledge obtained from the proposed research has the potential to accelerate efforts aimed at reducing PTSD-related sex/gender disparities. Specifically, insofar as epigenetic processes are modifiable, this line of research can lay the foundation for tailored interventions to prevent or treat PTSD/PTSS in men and women. This research may also result in identification of novel biomarkers of vulnerability to PTSD, and insights into whether these markers are sex-specific.