Early life stress (ELS) is defined as an acute or chronic stressor that negatively impacts a child's development. ELS is associated with substance use and mental health problems. This narrative literature review focuses on sex and gender differences in the effects of ELS on 1) adolescent neuroendocrine development; 2) pubertal brain maturation; and 3) development of internalizing symptoms and subsequent substance use. We posit that ELS may generate larger hormonal dysregulation in females than males during puberty, increasing internalizing symptoms and substance use. Future research should consider sex and gender differences in neuroendocrine developmental processes when studying the link between ELS and negative health outcomes.

Apolipoprotein E (apoE) (299 residues) is a highly helical protein that plays a critical role in cholesterol homeostasis. It comprises a four-helix bundle N-terminal (NT) and a C-terminal (CT) domain that can exist in lipid-free and lipid-associated states. In humans, there are two major apoE isoforms, apoE3 and apoE4, which differ in a single residue in the NT domain, with apoE4 strongly increasing risk of Alzheimer's disease (AD) and cardiovascular diseases (CVD). It has been proposed that the CT domain initiates rapid lipid binding, followed by a slower NT domain helix bundle opening and lipid binding to yield discoidal reconstituted high density lipoprotein (rHDL). However, the contribution of the NT domain on the CT domain organization in HDL remains poorly understood. To understand this, we employed Cys-specific cross-linking and spatially-sensitive fluorophores in the NT and CT domains of apoE3 and apoE4, and in isolated CT domain. We noted that the helices in isolated CT domain are oriented parallel to those in the neighboring molecule in rHDL, whereas full length apoE3 and apoE4 adopt either an anti-parallel or hairpin-like organization. It appears that the bulky NT domain determines the spatial organization of its CT domain in rHDL, a finding that has significance for apoE4, which is more susceptible to proteolytic cleavage in AD brains, showing increased accumulation of neurotoxic NT and CT fragments. We envisage that the structural organization of HDL apoE would have profound functional consequences in its ability to regulate cholesterol homeostasis in AD and CVD.

Background: Adverse childhood experiences (ACEs) such as abuse (defined as emotional, physical, or sexual abuse without distinguishing type or severity) have long been linked to mental health challenges in adulthood. However, less is known about how these effects differ by sex/gender in global samples, particularly using large-scale, multi-country panel data. Objectives: To examine whether the long-term association between childhood abuse and changes in depressive symptoms during adulthood differ between men and women, after adjusting for demographic and socioeconomic factors. Methods: We conducted a secondary analysis of Waves 1 and 2 of the Global Flourishing Study (GFS), a longitudinal panel study covering 22 diverse countries. The sample included adult participants with complete data on childhood abuse (yes/no); depression at baseline and follow-up; sex/gender; and relevant covariates (age; education; marital status; immigration status; smoking status; and employment). Depression was measured using a two-item scale. Multi-group structural equation models were used to test the effect of ACE on changes in depression over time where groups were defined based on sex/gender. Results: Overall, childhood abuse was associated with a statistically significant increase in depression scores between Wave 1 and Wave 2. This association was significant among women but not among men. Conclusions: Our findings suggest that the mental health consequences of childhood abuse extend into adulthood and disproportionately affect women. These sex/gender differences may reflect variations in stress processing; coping; and social roles. Interventions addressing early adversity may need to be tailored to recognize and respond to such sex/gender-specific vulnerabilities.

Early life stress (ELS) increases the risk of substance use disorder (SUD) in adulthood. The pathway from ELS to SUD is hypothesized to be influenced by sex. We examine the impact of ELS on adolescent first substance use, a common precursor to adult SUDs, and test for sex differences in the relationship between ELS and risk of first use of alcohol, nicotine, and marijuana. Individuals from the Adolescent Brain Cognitive Development study (ABCD; N = 8608 US children aged 9-10 at baseline) were assessed for multiple measures of ELS (Environmental, Family, Trauma), covariates (race/ethnicity, age in months at baseline, pubertal development score), and first substance use. Cox proportional hazards regression was performed for total population and stratified by sex, generating adjusted hazard ratios (aHRs) of first substance use. One unit increase in ELS Total scores significantly increased aHRs of first use of all substances. Dimensional ELS analysis revealed associations with risk that differed across sex, type of ELS, and substance. Females with higher ELS Environmental scores display a significant increase in risk of first use across all substances, while males with higher ELS Trauma scores showed a significant increase in risk of first nicotine and marijuana use. Findings highlight sex differences in the association of ELS Environmental and Trauma scores with the risk of first substance use, while illustrating the consistency of the association of ELS Family scores with risk. Existing family-based prevention and intervention strategies should consider addressing sex differences in adolescent substance use risk and protection.

Background: Social determinants of health—including both adversity and socioeconomic position—are known to shape physical health, health-related behaviors, and overall well-being. However, the psychological mechanisms that link these determinants to diverse outcomes remain insufficiently explored across international contexts. Objective: The objective of this study is to test whether sense of mastery and control over one’s life mediates the associations between key stressors (childhood abuse, financial insecurity) and socioeconomic resources (education, employment, and marital status) with a wide range of outcomes spanning health, behaviors, and well-being. Methods: Using cross-sectional data from Wave 1 of the Global Flourishing Study (GFS), we analyzed responses from more than 200,000 adults in 23 countries. Predictors included exposure to childhood abuse, perceived financial insecurity, and indicators of socioeconomic position (education, employment, and marital status). Outcomes included self-rated physical and mental health, depression, anxiety, smoking, drinking, physical activity, life satisfaction, and happiness. Structural equation modeling (SEM) was used to evaluate both direct and indirect (mediated) effects through sense of mastery and control over life. Results: Stressors were associated with poorer health, higher engagement in risk behaviors, and lower well-being. In contrast, higher levels of education, employment, and being married were linked to more favorable outcomes. In all tested models, sense of mastery and control over life significantly mediated the effects of both stressors and socioeconomic resources on health, behaviors, and well-being outcomes. Conclusions: Sense of mastery and control over life may represent key psychological pathways linking both adversity and social advantage to diverse health-related outcomes. Interventions that enhance individuals’ perceived control may offer cross-cutting benefits to improve health, promote well-being, and reduce behavioral risk factors globally.

Background:Delinquent behaviors during early adolescence reflect complex interactions between individual traits, family context, neighborhood conditions, and neurobiological responses to emotional stimuli. Despite extensive research on each domain, few studies have integrated psychological, socioeconomic, and neural data to examine correlations of delinquent behavior in a large, population-based cohort. Objective: This exploratory study examined demographic, psychological, socioeconomic, and neural correlates of parent-reported delinquent behaviors in pre-adolescents participating in the Adolescent Brain Cognitive Development (ABCD) Study. Methods:Data (n = 7,879) were drawn from ABCD participants with available demographic, psychological, socioeconomic, and task-based fMRI data during the n-back facial emotion task. Correlation analyses (Spearman’s ρ) assessed associations between delinquent behavior and measures of impulsivity and behavioral control (UPPS, BIS/BAS), family socioeconomic indicators (parental education, household income, financial difficulty), neighborhood characteristics (area deprivation, local crime rates), and mean beta weights representing activation to emotional faces versus places. Results:Delinquent behavior was positively correlated with impulsivity-related traits including positive urgency (ρ = 0.13, p < 0.001), lack of perseverance (ρ = 0.10, p < 0.001), and BAS fun-seeking (ρ = 0.06, p = 0.02). Higher BIS punishment sensitivity (ρ = 0.10, p < 0.001) and BAS reward responsiveness (ρ = 0.09, p < 0.001) were also linked to greater delinquent behavior. Socioeconomic disadvantages lower parental education (ρ = −0.07, p < 0.001) and greater financial difficulty (ρ = 0.09, p < 0.001)—showed small but consistent associations with delinquency. Neural activation of across prefrontal and salience-related regions during emotional face processing were positively correlated with delinquent behavior (ρ ≈ 0.09–0.13, p < 0.001). Conclusions:Findings suggest that youth delinquent behaviors are linked to impulsivity, socioeconomic adversity, and greater neural reactivity to emotional cues. These multilevel associations underscore the value of integrating behavioral, contextual, and neuroimaging data to understand early externalizing tendencies. Future longitudinal analyses should examine whether these correlates predict escalation or resilience in later adolescence.