Associations Among Environmental Exposures and Physical and Psychiatric Symptoms in a Care-Seeking Sample of U.S. Military Veterans.

INTRODUCTION: Recent research and policy (e.g., the Sergeant First Class (SFC) Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act) have highlighted the potential health consequences of toxic environmental exposures. The purpose of the current study was to assess the self-reported prevalence of such exposures among a sample of U.S. military veterans seeking care at a Veterans Affairs facility and to examine associations between exposures and physical and psychiatric symptoms. MATERIALS AND METHODS: Participants were 4,647 newly enrolling post-9/11 veterans at the VA San Diego Healthcare System who completed standard clinical screening processes between January 2015 and April 2019. Electronic health screening data, including demographic information, military history, environmental exposures, and physical and psychiatric symptoms, were assessed. t-Tests for continuous variables and chi-square tests for categorical variables were used to compare exposed to unexposed veterans on demographic and military characteristics as well as physical and psychiatric symptoms. RESULTS: A total of 2,028 veterans (43.6%) reported exposure to environmental toxins during their military service. Analyses revealed a disproportionate burden of exposure on older, male, educated, combat veterans as well as Asian and Native American veterans. Exposure to any type of environmental toxin was associated with more physical symptoms, particularly pain, fatigue, and insomnia, as well as psychiatric symptoms, including moderate depressive symptomology, mild to moderate anxiety, and scores approaching the threshold for likely post-traumatic stress disorder and alcohol misuse. CONCLUSIONS: The high prevalence and detrimental health correlates of environmental exposures underscore the importance of implementing screening for exposures and providing healthcare services that address the multisystemic nature of exposure-related illness.

The Impact of COVID-19 on Health Behavior Engagement and Psychological and Physical Health Among Active Duty Military Enrolled in a Weight Management Intervention: An Exploratory Study.

INTRODUCTION: The COVID-19 pandemic profoundly affected the health and well-being of people globally. Some studies suggest individuals with overweight or obesity may have been more adversely impacted by pandemic restrictions. Additionally, military personnel may have been more vulnerable to stress during the pandemic because of job demands (e.g., work in close quarters). Our research group was conducting a randomized clinical trial of a weight management intervention in active duty military personnel with overweight or obesity when the COVID-19 pandemic struck. Thus, we collected additional pandemic-related data from participants enrolled during the COVID-19 pandemic and conducted exploratory analyses to understand how the pandemic affected their stress levels and perceived abilities to engage in health behaviors like exercise and healthy eating. The aims of this exploratory study were to: (1) assess associations between pandemic-related stress and health behaviors with body fat percentage (BF%) and psychological and physical health, and (2) explore how pandemic-related stress and health behaviors affected BF% during and after the intervention. MATERIALS AND METHODS: A total of 29 active duty Navy personnel (55% female, 69% White) were enrolled after the onset of pandemic restrictions and completed measures assessing pandemic-related stress and health behaviors as well as measures of general psychological and physical health before the intervention. BF% was collected at 5 timepoints, including baseline, during, and following the intervention. Bivariate correlations assessed associations at baseline. Linearmixed-effects longitudinal models explored how pandemic-related stress and health behaviors affected BF%. Post-hoc analyses evaluated the effects of pandemic factors on BF% at each timepoint. RESULTS: Most participants perceived of the pandemic as increasing stress and detracting from their abilities to engage in health behaviors (i.e., exercise and healthy eating). Higher pandemic stress was significantly associated with reporting exercise and healthy eating as more difficult, worse overall health, and more anxiety and general stress. Reporting exercise as harder during the pandemic also was associated with more psychological distress at baseline. A linearmixed- effects model controlling for age, sex, and number of intervention sessions attended revealed endorsing "exercise as harder" was associated with higher BF%. Post-hoc regression analyses revealed rating "exercise as harder" significantly predicted higher BF% 3 months post-intervention (B = 0.65, P = .01), whereas pandemic stress was not significantly associated with higher BF% at 3 month (B =0.14, P = .08) or 6 month (B = 0.21, P = .09) follow-up. CONCLUSIONS: As expected, most participants perceived of the pandemic as heightening stress and interfering with engagement in health behaviors. It is possible that pandemic-related stress may have exacerbated weight gain-promoting behaviors and/or interfered with achievement of desired weight management outcomes. Outside the context of the pandemic, it may be beneficial for healthcare providers to screen individuals for stress and perceptions of ease of engagement in health behaviors before enrollment in a weight management intervention. Further, tailoring interventions to mitigate stress and promote perceptions of ease in engaging in health behaviors may promote better weight management outcomes.

Associations Among Stress, Internalized Weight Stigma, Emotional Eating, and Body Composition in Active-Duty Service Members Enrolling in a Randomized Controlled Trial of a Weight Management Program.

BACKGROUND: Obesity is a critical public health concern with particular relevance to US military personnel. Stress and internalized weight stigma ("stigma") may contribute to and maintain obesogenic processes and behaviors, including emotional eating. In this secondary cross-sectional analysis, we examined (1) associations among stress and stigma with emotional eating and body fat percentage (BF%), (2) whether stress explains the association between stigma and emotional eating, and (3) whether emotional eating explains associations between stress and stigma with BF%. METHOD: Active-duty military service members (N = 178) completed BF% assessment and questionnaires assessing stress, stigma, and emotional eating. RESULTS: Structural equation modeling path analyses showed that stress and stigma were both significantly associated with emotional eating (b = 0.35, p < 0.001 and b = 0.23, p < 0.001, respectively) and with BF% (b = 0.38, p < 0.001 and b = 0.29, p < 0.001, respectively) such that individuals who reported higher stress and stigma tended to report more emotional eating and had higher BF%. Stress partially explained the association between internalized weight stigma and emotional eating, and emotional eating partially explained the relationship between stress and BF% but did not significantly mediate the association between stigma and BF%. CONCLUSION: Greater stress and internalized weight stigma were associated with more emotional eating and higher BF%; however, emotional eating only partially explained the association between stress and BF%. Results highlight the importance of interventions targeting stress management skills, but additional research is needed to identify mechanisms that explain the association between stigma and BF%.

Examining the Association Between Objective Physical Activity and Momentary Pain: A Systematic Review of Studies Using Ambulatory Assessment.

Chronic pain (CP) is a debilitating and increasingly common health condition that adversely impacts function, including physical activity (PA). Research using ambulatory assessment (AA) methods (eg, ecological momentary assessment, actigraphy) offers promise for elucidating the relationship between momentary pain and objective PA in CP populations. This study aimed to systematically review articles assessing the association between momentary pain and PA in adults with CP as measured using AA and to make recommendations for the measurement and study of this relationship. Five databases were systematically searched, and 13 unique records (N = 768) met the inclusion criteria. CP conditions included mixed/nonspecific CP (k = 3), low back pain (k = 2), fibromyalgia (k = 1), unspecified arthritis (k = 1), and hip/knee osteoarthritis (k = 6). The average age of participants across studies was 55.29 years, and the majority identified as women (60.68%) and White (83.16%). All studies measured objective PA via actigraphy, and momentary pain with either a diary/log or ratings on an actigraph. Studies varied in the quantification of PA (ie, activity counts, step count, moderate-vigorous PA), statistical method (ie, correlation, regression, multilevel modeling), and inclusion of moderators (eg, pain acceptance). Studies reported mixed results for the pain-PA relationship. This heterogeneity suggests that no summarizing conclusions can be drawn about the pain-PA relationship without further investigation into its complex nuances. More within-person and exploratory examinations that maximize the richness of AA data are needed. A greater understanding of this relationship can inform psychotherapeutic and behavioral recommendations to improve CP outcomes. PERSPECTIVE: This article presents a systematic review of the literature on the association between momentary pain and PA in adults with CP as measured using AA methods. A better understanding of this nuanced relationship could help elucidate areas for timely intervention and may inform clinical recommendations to improve CP outcomes. PROSPERO REGISTRATION NUMBER: CRD42023389913.

Disentangling trait and daily experiences of uncertainty and meaning in life: implications for daily anxiety, negative affect, and somatic symptoms.

BACKGROUND: Although there is growing evidence supporting the association between intolerance of uncertainty (IU) and psychopathology, little is known about the covariation of IU and psychological distress day-to-day. The purpose of this ecological momentary assessment (EMA) study was to examine negative emotional and somatic correlates of trait IU and daily uncertainty, while investigating how a source of stability, meaning in life (MIL), might buffer against deleterious effects of IU and uncertainty. DESIGN AND METHODS: Adult community members (n = 62) from a mid-size town in the Rocky Mountain region completed baseline measures of IU and MIL and ecological momentary assessments (EMA) of meaning, uncertainty, affect, and somatic symptoms over the course of one week. RESULTS: Results indicate individuals high in trait IU experience more uncertainty day-to-day and greater distress when they feel uncertain compared to individuals lower in trait IU; however, MIL plays a stronger protective role for high IU compared to low IU individuals. CONCLUSIONS: These findings support and extend previous research showing IU is associated with psychological distress and that MIL may be a critical resource to cultivate. Interventions promoting meaning day-to-day may reduce the effects of uncertainty on the well-being of those highly intolerant of uncertainty.

Functional decline during the COVID-19 pandemic among U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

OBJECTIVES: The coronavirus disease-2019 pandemic has contributed to widespread social and economic stressors, along with substantial health problems, including loss of life. To date, however, relatively few studies have examined the prevalence and correlates of declines in mental and physical functioning in U.S. military veterans, an older and potentially vulnerable segment of the U.S. adult population. METHODS: Data were analyzed from the 2019-2020 National Health and Resilience in Veterans Study, a nationally representative, longitudinal study of 3078 veterans. Veterans were surveyed prior to the pandemic (pre-pandemic) and 1 year later during the height of the pandemic (peri-pandemic). Multivariable analyses were conducted to identify risk and protective variables associated with pre-to-peri pandemic declines in self-reported physical and mental functioning. RESULTS: The prevalence of veterans who experienced functional decline (≥0.5 standard deviation reductions) pre-to-peri-pandemic was 18.1% (N = 541) for physical functioning and 18.3% (N = 547) for mental functioning. Older age, greater adverse childhood experiences (ACEs), and pandemic-related posttraumatic stress symptoms were the strongest correlates of physical functional decline, while greater ACEs, loneliness, pandemic-related posttraumatic and social restriction stress symptoms, and lower protective psychosocial characteristics were the strongest correlates of mental functional decline. CONCLUSIONS: Although the majority of U.S. Veterans showed functional maintenance or improvement 1 year into the pandemic, nearly one-in-five experienced a decline in physical or mental functioning. Results could help inform identification of veterans who may be at risk for functional decline during large-magnitude stressors, such as national or global pandemics.

Daily Functioning of Veterans With Type 2 Diabetes: Protocol for an Ambulatory Assessment Study.

BACKGROUND: Diabetes impacts nearly 25% of veterans. Many veterans do not engage in recommended physical activity and other diabetes self-management behaviors. Type 2 diabetes is generally asymptomatic; as such, the long-term consequences of inadequate self-management and benefits of consistent self-management are not salient in the short term. Furthermore, self-management behaviors typically take place outside of medical visits; however, self-management-related factors are only assessed during medical visits, likely missing large amounts of variability. Thus, ambulatory assessment methods such as ecological momentary assessment (EMA), accelerometry, and continuous glucose monitoring are needed to understand the dynamics of daily self-management and identify potential intervention targets. OBJECTIVE: The overarching goal of this study is to understand daily, time-varying factors (comorbid affective symptoms and social context) that influence physical activity, diabetes self-management, glycemic management, daily functioning, and quality of life in participants' natural environments. METHODS: We are recruiting veterans with type 2 diabetes (target N=100). Participants are required to complete a battery of baseline assessments related to mental health, psychosocial factors, and self-management behaviors. Participants then receive 5 momentary EMA surveys and 1 daily EMA survey per day, in which veterans report comorbid affective symptoms (mood, stress, and pain), social support, social interactions, physical activity, and other self-management behaviors. Momentary surveys are delivered randomly during daily preprogrammed intervals over a 14-day sampling period. Accelerometry and continuous glucose monitoring are also used to assess physical activity and blood glucose, respectively. The first 6 participants also completed interviews assessing their experience in the study and barriers to participation. These test participants informed modifications to the protocol for the remaining participants. RESULTS: The project received funding in April of 2023. Enrollment began in March of 2023 and is planned to be completed in April 2025. Among the 6 test participants, the overall EMA response rate was 87% (range 74%-95%). The response rate for the EMA survey including daily items (67%, range 21%-93%) was lower than the earlier shorter EMA surveys (89%, range 81%-96%). The mean rate of valid accelerometer wear of at least 20 hours per day was 93% (SD 11%), and continuous glucose monitoring data were available for 91% (SD 17%) of days on average. Participants reported few barriers to completing EMA surveys but noted the random timing of questions made it difficult to plan around, and the end-of-day survey was long. Two participants reported survey items reminded or motivated them to engage in diabetes self-management behaviors. CONCLUSIONS: Assessment tools developed from this study can inform clinical decision-making by considering barriers to self-management that occur in daily life. Clinical applications include tailored, adaptive technology-supported interventions to improve self-management that provide the right type and amount of support at the right time by adapting to an individual's changing internal and contextual state. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53874.

Associations among meaning in life, coping, and distress in trauma-exposed U.S. military veterans.

Experiencing meaning in life may be particularly relevant following traumatic experiences as individuals who report meaning post trauma report less psychological distress. Engaging in avoidant coping, however, may be a sign of underlying psychological distress in the aftermath of traumatic experiences. We sought to examine associations among meaning in life, avoidant coping, and psychological distress in a sample of trauma-exposed veterans. Secondary cross-sectional analyses were conducted on data from veterans exposed to a traumatic event(s) who experienced clinically meaningful guilt (N = 145). Questionnaires on meaning in life, avoidant coping, and psychological distress were administered, and structural equation modeling was used to test direct effects. Path analysis revealed that greater meaning was associated with lower depression, anxiety, and posttraumatic stress symptomatology, while higher avoidant coping was associated with greater depression, anxiety, posttraumatic stress, and somatization symptomatology. Participants who report more meaning in life and report lower avoidant coping post trauma may experience less psychological distress. If replicated longitudinally, results could suggest cultivating meaning in life and reducing avoidant coping may decrease psychological distress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prevalence, characteristics, and health burden of rheumatoid arthritis in the U.S. veteran population.

OBJECTIVE: To examine the prevalence, characteristics, and physical and mental health burden of rheumatoid arthritis (RA) in a nationally representative sample of U.S. military veterans. METHODS: Data were analyzed from the 2019-2020 National Health and Resilience in Veterans Study (NHRVS), which surveyed a contemporary, nationally representative sample of 4,069 U.S. veterans. Veterans with RA (n = 227) were compared to veterans with any other medical condition(s) (n = 3,444) on measures of sociodemographic, military, trauma, medical and psychiatric characteristics. Multivariable analyses were then conducted to examine independent associations between RA and health conditions. RESULTS: A total of 5.3% (95% confidence interval = 4.5-6.2%) of primarily male U.S. veterans reported having been diagnosed with RA. Relative to controls, veterans with RA were older, and more likely to be racial/ethnic minorities, unpartnered, lower income, and combat veterans. They also reported greater cumulative trauma burden, more medical conditions (i.e., osteoarthritis, chronic pain, respiratory and cardiovascular conditions), and greater severity of somatic symptoms, and were more likely to screen positive for current insomnia and subthreshold posttraumatic stress disorder (PTSD), and lifetime alcohol use disorder (AUD). In adjusted analyses, RA remained associated with number of medical conditions, more severe somatic symptoms, insomnia, subthreshold PTSD, and AUD. CONCLUSIONS: One of 20 U.S. veterans has RA, which is more prevalent among certain sociodemographic subsets, and is associated with elevated physical and mental health burden. Results provide insight into risk correlates of RA and underscore the importance of assessing, monitoring, and treating medical and psychiatric conditions/symptoms that co-occur with RA in this population.

Valuing Negative Affect Weakens Affect-Health Linkages: Similarities and Differences Across Affect Valuation Measures.

Negative affect (NA) has been robustly linked to poorer psychological health, including greater depressive symptoms, personal burnout, and perceived stress. These associations, known as affect-health links, have been postulated by our research team to vary with different levels of negative affect valuation (NAV), such that people who evaluate NA states as more pleasant, helpful, appropriate, and/or meaningful may show weaker affect-health links. Another affect valuation construct is ideal NA, which is the degree to which people ideally want to experience NA states (i.e., desirability of affective states). The current study extends previous research by examining these two different measures of affect valuation (NAV and ideal NA) and comparing the extent to which they moderate affect-health links for psychological health and functioning. Participants from the Health and Daily Experiences (HEADE) study (N = 162 comprising of 56 younger adults and 106 older adults) completed questionnaires in a laboratory setting and ecological momentary assessments of NA 6 times a day for 7 consecutive days (i.e., trait NA). The results demonstrated that the two affect valuation constructs were distinct and showed different patterns of buffering effects. NAV attenuated the association between trait NA and depressive symptoms, personal burnout, and intolerance of uncertainty. Ideal NA attenuated affect-health links for depressive symptoms and perceived stress. These findings point to the importance of sharpening the distinctions between various affect valuation constructs to elucidate their unique contributions to attenuating affect-health links.

Baseline Characteristics and Their Associations with Body Composition of Active-Duty Service Members Enrolling in a Randomized Controlled Trial of a Weight Management Program.

INTRODUCTION: Increasing rates of overweight and obesity among military service members (SMs) necessitate the implementation of weight management interventions. Evidence for the effectiveness of military weight management interventions is mixed. Effectiveness may be impacted by individual sociodemographic, psychiatric, psychological, and behavioral factors. Baseline data from SMs who were overweight/obese or at risk of failing body composition or physical fitness tests and enrolling in a weight management randomized controlled trial were used to examine (1) individual characteristics of this sample as a whole and by gender and (2) relationships between those characteristics and body composition metrics that are targeted by military weight management interventions. Understanding these relationships may inform intervention approaches. MATERIALS AND METHODS: Active duty SMs (N = 178) who enrolled in a randomized clinical trial of the Navy's weight management program "ShipShape" at a large military hospital provided data at their baseline visit. Because of gender differences in average body fat percentage (BF%) and underrepresentation of women SMs in research, independent samples t-tests and chi-square analyses were used to examine differences between male and female SMs across study variables. Multiple regression analyses were used to examine relationships of sociodemographic, psychiatric, psychological, and behavioral variables with body composition metrics, including weight, body mass index (BMI), BF%, and waist circumference (WC). RESULTS: Participants (61% female; Mage = 29.66 ± 6.92 years; 59.60% White) had an average BMI in the "obese" range (MBMI = 33.1 ± 3.9 kg/m2). Female participants had significantly higher BF% and significantly lower weight and WC than male participants. Compared to male participants, females reported significantly higher rates of pain and headache diagnoses, lifetime diagnosis of an anxiety disorder, lifetime treatment for a mental health concern, lifetime experiences of sexual trauma/harassment and military sexual trauma, and higher current anxiety and post-traumatic stress disorder symptoms. Across all SMs, body composition metrics were significantly associated with several demographic variables, including gender, age, marital status, Asian race, and Black race. Higher weight-related stigma was significantly associated with higher weight, BMI, BF%, and WC. Additionally, more emotional eating was significantly associated with higher BF%, and higher weight-loss confidence was significantly associated with higher BMI. Sociodemographic, psychiatric, psychological, and behavioral variables predicted the greatest variance in BF% compared to other body composition metrics evaluated. CONCLUSIONS: Participants in this study were more likely to be female, relatively young members of the Navy with overweight/obesity, who endorsed pain-related medical conditions, probable mental health conditions, and traumatic experiences at relatively high rates. Despite high endorsement of anxiety, depression, and post-traumatic stress disorder symptoms in this group, only weight-related stigma consistently emerged as significantly associated with body composition metrics. Regression results varied by body composition metric, with the most variance explained in BF%, suggesting that BF% may relate most strongly to sociodemographic, psychiatric, psychological, and behavioral variables associated with weight management. These results highlight the need for weight management programs that address weight-related stigma and mental health concerns of SMs to maximize the effectiveness of intervention efforts.

Meaning in Life Moderates Relations between Personality and Temperament and Nonsuicidal Self-Injury in Hospitalized Adolescents.

Previous research indicates that sensation seeking, emotion dysregulation, and impulsivity are predictive of non-suicidal self-injury (NSSI). A body of research supports that meaning in life predicts improved mental health and well-being, including fewer suicidal thoughts and attempts, yet no research has examined the moderating effects of meaning in life on the relations between personality and temperament and NSSI. Given the growing incidence rates of NSSI among adolescents and the potential lifelong consequences of NSSI, it is imperative to better understand the factors that reduce the rates at which adolescents in a clinical sample engage in NSSI. The present study investigates if the protective factors of meaning in life moderate the relation between personality and temperament variables and NSSI among 126 adolescents (71% female, Mage = 16.1, SD = 1.1, range 13-18, 80% White) residing in an inpatient psychiatric hospital who endorsed NSSI in the last 12 months. Results from hurdle modeling indicate that two subtypes of meaning in life, presence of meaning in life and search for meaning of life, may serve as robust protective factors against engagement in NSSI among a clinical sample of adolescents. Additionally, results suggest that search for meaning, but not presence of meaning in life, variables moderate the relations between personality and temperament and NSSI. Results provide evidence that meaning in life is an understudied variable of importance in understanding how to prevent or treat NSSI. It also underscores the need to develop, refine, and test meaning-making interventions.

Uptake, p53 pathway activation, and cytotoxic responses for Co(II) and Ni(II) in human lung cells: implications for carcinogenicity.

Cobalt(II) and nickel(II) ions display similar chemical properties and act as hypoxia mimics in cells. However, only soluble Co(II) but not soluble Ni(II) is carcinogenic by inhalation. To explore potential reasons for these differences, we examined responses of human lung cells to both metals. We found that Co(II) showed almost 8 times higher accumulation than Ni(II) in H460 cells but caused a less efficient activation of the transcriptional factor p53 as measured by its accumulation, Ser15 phosphorylation, and target gene expression. Unlike Ni(II), Co(II) was ineffective in downregulating the p53 inhibitor MDM4 (HDMX). Co(II)-treated cells continued DNA replication at internal doses that caused massive apoptosis by Ni(II). Apoptosis and the overall cell death by Co(II) were delayed and weaker than by Ni(II). Inhibition of caspases but not programmed necrosis pathways suppressed Co(II)-induced cell death. Knockdown of p53 produced 50%-60% decreases in activation of caspases 3/7 and expression of 2 most highly upregulated proapoptotic genes PUMA and NOXA by Co(II). Overall, p53-mediated apoptosis accounted for 55% cell death by Co(II), p53-independent apoptosis for 20%, and p53/caspase-independent mechanisms for 25%. Similar to H460, normal human lung fibroblasts and primary human bronchial epithelial cells had several times higher accumulation of Co(II) than Ni(II) and showed a delayed and weaker caspase activation by Co(II). Thus, carcinogenicity of soluble Co(II) could be related to high survival of metal-loaded cells, which permits accumulation of genetic and epigenetic abnormalities. High cytotoxicity of soluble Ni(II) causes early elimination of damaged cells and is expected to be cancer suppressive.

Chromium(VI) causes interstrand DNA cross-linking in vitro but shows no hypersensitivity in cross-link repair-deficient human cells.

Hexavalent chromium is a human carcinogen activated primarily by direct reduction with cellular ascorbate and to a lesser extent, by glutathione. Cr(III), the final product of Cr(VI) reduction, forms six bonds allowing intermolecular cross-linking. In this work, we investigated the ability of Cr(VI) to cause interstrand DNA cross-links (ICLs) whose formation mechanisms and presence in human cells are currently uncertain. We found that in vitro reduction of Cr(VI) with glutathione showed a sublinear production of ICLs, the yield of which was less than 1% of total Cr-DNA adducts at the optimal conditions. Formation of ICLs in fast ascorbate-Cr(VI) reactions occurred during a short reduction interval and displayed a linear dose dependence with the average yield of 1.3% of total adducts. In vitro production of ICLs was strongly suppressed by increasing buffer molarity, indicating inhibitory effects of ligand-Cr(III) binding on the formation of cross-linking species. The presence of ICLs in human cells was assessed from the impact of ICL repair deficiencies on Cr(VI) responses. We found that ascorbate-restored FANCD2-null and isogenic FANCD2-complemented cells showed similar cell cycle inhibition and toxicity by Cr(VI). XPA-null cells are defective in the repair of Cr-DNA monoadducts, but stable knockdowns of ERCC1 or XPF in these cells with extended time for the completion of cross-linking reactions did not produce any sensitization to Cr(VI). Our results together with chemical and steric considerations of Cr(III) reactivity suggest that ICL generation by chromate is probably an in vitro phenomenon occurring at conditions permitting the formation of Cr(III) oligomers.

p53 activation by Ni(II) is a HIF-1α independent response causing caspases 9/3-mediated apoptosis in human lung cells.

Hypoxia mimic nickel(II) is a human respiratory carcinogen with a suspected epigenetic mode of action. We examined whether Ni(II) elicits a toxicologically significant activation of the tumor suppressor p53, which is typically associated with genotoxic responses. We found that treatments of H460 human lung epithelial cells with NiCl2 caused activating phosphorylation at p53-Ser15, accumulation of p53 protein and depletion of its inhibitor MDM4 (HDMX). Confirming the activation of p53, its knockdown suppressed the ability of Ni(II) to upregulate MDM2 and p21 (CDKN1A). Unlike DNA damage, induction of GADD45A by Ni(II) was p53-independent. Ni(II) also increased p53-Ser15 phosphorylation and p21 expression in normal human lung fibroblasts. Although Ni(II)-induced stabilization of HIF-1α occurred earlier, it had no effect on p53 accumulation and Ser15 phosphorylation. Ni(II)-treated H460 cells showed no evidence of necrosis and their apoptosis and clonogenic death were suppressed by p53 knockdown. The apoptotic role of p53 involved a transcription-dependent program triggering the initiator caspase 9 and its downstream executioner caspase 3. Two most prominently upregulated proapoptotic genes by Ni(II) were PUMA and NOXA but only PUMA induction required p53. Knockdown of p53 also led to derepression of antiapoptotic MCL1 in Ni(II)-treated cells. Overall, our results indicate that p53 plays a major role in apoptotic death of human lung cells by Ni(II). Chronic exposure to Ni(II) may promote selection of resistant cells with inactivated p53, providing an explanation for the origin of p53 mutations by this epigenetic carcinogen.

S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde.

We examined genotoxic signaling and cell fate decisions in response to a potent DNA-protein crosslinker formaldehyde (FA). DNA-protein crosslinks (DPC) are poorly understood lesions produced by bifunctional carcinogens and several cancer drugs. FA-treated human cells showed a rapid activation of ATR kinase that preferentially targeted the p53 transcription factor at low doses and CHK1 kinase at more severe damage, producing bell-shaped and sublinear responses, respectively. CHK1 phosphorylation was transient, and its loss was accompanied by increased p53 accumulation and Ser15 phosphorylation. Activation of p53 was insensitive to inhibition of mismatch repair and nucleotide and base excision repair, excluding the role of small DNA adducts in this response. The p53-targeted signaling was transcription-independent, absent in quiescent cells and specific to S-phase in cycling populations. Unlike other S-phase stressors, FA-activated p53 was functional transcriptionally, promoted apoptosis in lung epithelial cells and caused senescence in normal lung fibroblasts. FA did not induce ATR, RAD1 or RPA foci, and p53 phosphorylation was TopBP1-independent, indicating a noncanonical mode of ATR activation. Replication arrest by FA caused a dissociation of ATR from a chromatin-loaded MCM helicase but no PCNA monoubiquitination associated with stalled polymerases. These results suggest that unlike typical DNA adducts that stall DNA polymerases, replication inhibition by bulkier DPC largely results from blocking upstream MCM helicase, which prevents accumulation of ssDNA. Overall, our findings indicate that S-phase-specific, TopBP1-independent activation of the ATR-p53 axis is a critical stress response to FA-DPC, which has implications for understanding of FA carcinogenesis.