Exposure Profiles Research Articles

MBX 2109, a Once-Weekly Parathyroid Hormone Replacement Therapy Prodrug: Phase 1, First-in-Human, Randomized Trial.

Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers. This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomized 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary endpoint was safety and tolerability. Key secondary endpoints were PK and PD. Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomized (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50%-88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79-95 hours for MBX 2109 and 184-213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases. The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

Air pollution mixture exposure during pregnancy and postpartum psychological functioning: racial/ethnic- and fetal sex-specific associations.

Prenatal air pollution (AP) exposure has been linked to postpartum psychological functioning, impacting health outcomes in both women and children. Extant studies primarily focused on individual pollutants. To assess the association between prenatal exposure to a mixture of seven AP components and postpartum psychological functioning using daily exposure data and data-driven statistical methods. Analyses included 981 women recruited at 24.0 ± 9.9 weeks gestation and followed longitudinally. We estimated prenatal daily exposure levels for constituents of fine particles [elemental carbon (EC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), ammonium (NH4+)], nitrogen dioxide (NO2), and ozone (O3) using validated global 3-D chemical-transport models and satellite-based hybrid models based on residential addresses. Edinburgh Postnatal Depression Scale (EPDS) was administered to participants to derive a total EPDS score and the subconstruct scores for anhedonia and depressive symptoms. A distributed lag model (DLM) was employed within Bayesian Kernel Machine Regression (BKMR) to develop time-weighted exposure profile for each pollutant. These exposures were then input into a Weighted Quantile Sum (WQS) regression to estimate an overall mixture effect, adjusted for maternal age, education, race/ethnicity, season of delivery, and delivery year. Effect modification by race/ethnicity and fetal sex was also examined. Women were primarily Hispanic (51%) and Black (32%) reporting ≤12 years of education (58%). Prenatal exposure to an AP mixture was significantly associated with increased anhedonia subscale z-scores, particularly in Hispanics (β = 0.07, 95%CI = 0.004-0.13, per unit increase in WQS index). It was also borderline associated with increased total EPDS (β = 0.11, 95%CI = 0.00-0.22) and depressive symptom subscale (β = 0.09, 95%CI = -0.02 to 0.19) z-scores, particularly among Hispanic women who gave birth to a male infant. Sulfate (SO42-), O3 and OC were major contributors to these associations. This study utilizes an advanced data-driven approach to examine the temporally- and mixture-weighted effects of prenatal air pollution exposure on postpartum psychological functioning. We found that exposure to a prenatal air pollution mixture predicted poorer postpartum psychological functioning, particularly anhedonia symptoms in Hispanic women. Findings underscore the importance of considering both exposure mixtures as well as potential modifying factors to better help identify particular pollutants that drive effects and susceptible populations, which can inform more effective intervention strategies.

Comparison of a fixed-dose combination of Celecoxib/PG201 [Layla®] versus co-administration of individual formulations in healthy participants: A randomized trial.

Osteoarthritis (OA) is a prevalent joint disease affecting the spine, hands, hips, knees, and feet. However, definitive drugs for OA are lacking, and current treatments are limited owing to inconvenient administration, inadequate functional improvement, and long-term side effects including gastrointestinal and cardiovascular adverse events. Therefore, in this study, we aimed to assess the pharmacokinetics and safety profiles of PK101, a fixed-dose combination (FDC) comprising PG201, a 12-herb extract used in OA treatment in traditional East Asian medicine, and celecoxib, a selective cyclooxygenase-2 inhibitor, by comparing its administration as an FDC and the corresponding individual formulations in healthy subjects. A randomized, open-label, single-dose, 2 × 2 crossover design with a cohort of healthy participants. All subjects received a single FDC tablet (405.4 mg PG201 and 100 mg celecoxib) or the individual formulations, with 7-day washout period between administrations. The estimation of maximum plasma concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration of celecoxib involved determining the geometric mean ratios and 90% confidence intervals of the FDC compared to its individual formulations. Forty-six participants were enrolled; however, only 44 completed the study. The geometric mean ratios (90% confidence intervals) for the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and maximum plasma concentration of celecoxib were 1.1124 (1.0601-1.1672) and 1.2788 (1.1708-1.3969), respectively. The time of maximum plasma concentration range was 1.0 to 4.0 hours and 1.0 to 6.0 hours (minimum-maximum) for the FDC and individual formulations, respectively. Seven adverse events occurred in 6 subjects. The systemic exposure and safety profiles of the individual and FDC formulations were similar, supporting their potential as an innovative and effective therapeutic approach for OA treatment. All relevant data are within the paper and its Supporting Information files.

Associations Between Mosaic Loss of Sex Chromosomes and Incident Hospitalization for Atrial Fibrillation in the United Kingdom.

Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190 613 men and 224 853 women with genotyping data from the UK Biobank. Among these participants, there were 37 037 men with mLOY and 13 978 women with mLOX detected using the Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization was conducted to estimate causal associations. Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR, 1.06 [95% CI, 1.03-1.11]). The associations were apparent in both never smokers (HR, 1.07 [95% CI, 1.01-1.14]) and ever smokers (HR, 1.05 [95% CI, 1.01-1.11]) as well as men aged >60 and ≤60 years. Mendelian randomization analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO, 1.15 [95% CI, 1.13-1.18]). Among postmenopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR, 0.90 [95% CI, 0.83-0.98]). However, associations with mLOY and mLOX were not found for other heart diseases. Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Whole body vibration and rider comfort determination of an electric two-wheeler test rig

Background Two-wheeled vehicles are the major mode of transportation in India. Such vehicles are exposed to excessive vibration on the road when compared to four-wheeled vehicles. However, the research on the reduction of whole body vibration in the case of two-wheelers is not explored in detail. The present study predicts rider comfort in the case of an electric two-wheeler as per ISO 2631-1, by obtaining the finding the weighted acceleration at the strategic locations of vibration at the test rig. Methods An electric two-wheeler test rig is used in the study. The values of acceleration from the test rig in running conditions are obtained by using NI LabVIEW 2019. The drive cycle of the electric vehicle (EV) test rig is controlled by Sync sols’ EV lab software. Obtaining the weighted root mean square (RMS) acceleration from running the test setup, it is compared with the ISO 2631-1 standard to obtain the rider comfort. Results Loading area, traction motor, base mount, and suspension were found to be the strategic points of vibration. Frequency weighted RMS acceleration of 0.3 to 0.4 m/s2 obtained at these points are prone to cause discomfort for the rider. Vehicle speed, road profile, and duration of exposure were found to be important parameters affecting the rider’s comfort. A maximum of 4.6 m/s2 amplitude was observed. The loading area, which corresponds to a rider’s seat in actual vehicle, is important and reduction of these vibrations make the ride comfortable for the rider. Suspension and base mount of the test rig are found to be uncomfortable observing the weighted RMS acceleration. Conclusions A suitable damping technique design is very much essential in reducing these vibrations and improve the rider comfort, as many more non-deterministic vibrations are prone to cause dis-comfort in case of actual on road riding conditions.

Association of chronic arsenic exposure with cellular immune profile in MINIMat adolescents: A birth cohort in Bangladesh

Chronic arsenic exposure is known to affect the immune system. We aimed to evaluate the association between arsenic exposure and immune cell profile in 15 years old adolescents (n=389) in rural Bangladesh, with chronic exposure to groundwater arsenic. Single blood and urine were collected. Urinary arsenic (U-As) concentration was measured using atomic absorption spectrometry. Peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry. Non-linear association was found between U-As (median, 24.9 µg/L) and immune cells with a cut-off at U-As 20 µg/L. U-As (<20 µg/L) were significantly associated with increases in CD8+T (21 %), naïve CD8+T (42 %) and early B cells (40 %), and classical monocytes (55 %), but reduction in CD3+T cells (37%) and intermediate-monocytes (56 %). U-As (>20 µg/L) were associated with a 3 % reduction in memory B cells. Arsenic exposure was associated with altered immune cell profile in adolescents likely rendering them vulnerable to adverse health effects in later life.

Contaminant Exposure Profiles Demonstrate Similar Physiological Effects Across Environments Despite Unique Profile Composition in Formosa, Argentina, and Connecticut, USA.

Exposure to environmental contaminants is globally universal. However, communities vary in the specific combination of contaminants to which they are exposed, potentially contributing to variation in human health and creating "locally situated biologies." We investigated how environmental exposures differ across environments by comparing exposure profiles between two contexts that differ markedly across political, economic, and sociocultural factors-Namqom, Formosa, Argentina, and New Haven, Connecticut, United States. We collected infant urine, maternal urine, and human milk samples from mother-infant dyads in Formosa (n = 13) and New Haven (n = 21). We used untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS) to annotate environmental contaminants and endogenous metabolites in these samples, and we analyzed the data using exposome-wide association studies (EWAS) followed by pathway enrichment. We found statistically significant differences between the chemical exposure profiles of the Argentinian and US mothers, mostly involving pesticides; however, we observed similarities in the infant urine and human milk environmental contaminant profiles, suggesting that the maternal body may buffer infant exposure through human milk. We also found that infants and mothers were exposed to contaminants that were associated with alterations in amino acid and carbohydrate metabolism. Infants additionally showed alterations in vitamin metabolism, including vitamins B1, B3, and B6. Differences in chemical exposure profiles may be related to structural factors. Despite variation in the composition of exposure profiles between the two study sites, environmental contaminant exposure was associated with similar patterns in human physiology when we considered contaminants comprehensively rather than individually, with implications for metabolic and cardiovascular disease risk as well as infant cognitive development.

The potential of including the microbiome as biomarker in population-based health studies: methods and benefits.

The key role of our microbiome in influencing our health status, and its relationship with our environment and lifestyle or health behaviors, have been shown in the last decades. Therefore, the human microbiome has the potential to act as a biomarker or indicator of health or exposure to health risks in the general population, if information on the microbiome can be collected in population-based health surveys or cohorts. It could then be associated with epidemiological participant data such as demographic, clinical or exposure profiles. However, to our knowledge, microbiome sampling has not yet been included as biological evidence of health or exposure to health risks in large population-based studies representative of the general population. In this mini-review, we first highlight some practical considerations for microbiome sampling and analysis that need to be considered in the context of a population study. We then present some examples of topics where the microbiome could be included as biological evidence in population-based health studies for the benefit of public health, and how this could be developed in the future. In doing so, we aim to highlight the benefits of having microbiome data available at the level of the general population, combined with epidemiological data from health surveys, and hence how microbiological data could be used in the future to assess human health. We also stress the challenges that remain to be overcome to allow the use of this microbiome data in order to improve proactive public health policies.

Profiles of refugee-related trauma exposure and depression among North Korean refugees in South Korea: A latent class analysis.

North Korean refugees (NKRs) exhibit alarmingly high levels of depression prior to or immediately after entering South Korean society, which is likely attributable to their pre-migration traumatic experiences. However, prior research on NKRs has simply examined the cumulative effect of trauma on depression. Despite calls for research identifying trauma exposure patterns that co-occur among refugees, to date, no study has investigated distinct profiles of NKRs' pre-migration trauma exposure and their associations with depression in this high-risk population. To better understand the unique mental health needs of NKRs and provide them with tailored care, it is imperative to identify meaningful subgroups of NKRs with distinct profiles of trauma exposure. Using latent class analysis (LCA), which is a person-centered approach, this study aimed to identify subgroups of NKRs based on trauma exposure and their associations with sociodemographic characteristics and depression levels. A sample of NKRs (N = 405) in South Korea were assessed for depression, pre-migration trauma, and sociodemographic covariates through a self-administered survey. LCA was conducted to identify trauma exposure classes and multivariate ordinary least squares regression analysis was performed to examine associations between trauma exposure classes and depression. The prevalence of clinically significant depression was 47.2% for our study sample. Three classes of trauma were identified: deprivation trauma and witnessing death (59.3%), complex and pervasive trauma (23.7%), and low exposure (17.0%). Members in the complex and pervasive trauma class demonstrated very high probabilities of exposure to all traumatic events and had the strongest association with elevated depression. Our findings underscore the importance of identifying subgroups of NKRs to unravel heterogeneity in trauma exposure and provide more nuanced explanations for different risk profiles regarding depression. These findings also provide evidence for a framework for clinicians to provide individualized resources and trauma-informed services to NKRs.

Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

Spatio-temporal mapping of urban noise exposure: insights from the agent-based transport model of the Nantes metropolitan area

Beyond the estimation of daily exposure profiles of agents, agent-based models can be used to investigate the role of different urban areas in noise exposure. This study explores this potential by proposing a new approach to spatio-temporal mapping of the accessibility to quiet areas in agglomerations, integrating mobility into the analysis of place effects. Using an agent and activity-based framework, composed of EQASim, MATSim and NoiseModelling, the Nantes Metropolitan Area (France) is modeled. The definition of the quiet areas conditions and the accessibility metric are analyzed in order to understand the influence of these parameters on the identification of critical urban areas where agents don't have their access to quiet areas assured. The results show a great variability of accessibility according to its definition and emphasize the need to include new variables in the assessment.

Associations of pre- and postnatal per- and polyfluoroalkyl substance exposure with adolescents' eating behaviors.

Per- and polyfluoroalkyl substances (PFAS), persistent environmental chemicals, may act as obesogens by interacting with neuroendocrine pathways regulating energy homeostasis and satiety signals influencing adolescent eating behaviors. In 211 HOME Study adolescents (Cincinnati, OH; recruited 2003-2006), we measured PFAS concentrations in serum collected during pregnancy, at delivery, and at ages 3, 8, and 12 years. Caregivers completed the Child Eating Behavior Questionnaire (CEBQ) at age 12, and we calculated food approach and food avoidance scores. Using quantile-based g-computation, we estimated covariate-adjusted associations between a mixture of four gestational PFAS and CEBQ scores. We identified high (n = 76, 36%) and low (n = 135, 64%) longitudinal PFAS mixture exposure profiles between delivery and age 12 years using latent profile analysis and related these to CEBQ scores. We examined whether child sex or physical activity modified these associations. We observed no association of gestational PFAS mixture with food approach or food avoidance scores. Children in the higher longitudinal PFAS mixture profile had slightly higher food approach scores (β: 0.47, 95% CI: -0.27, 1.23) and similar food avoidance scores (β: -0.15, 95% CI: -0.75, 0.46) compared with children in the lower profile. We found some evidence that higher physical activity favorably modified the association between longitudinal PFAS mixture profiles and emotional overeating (interaction P value = 0.13). Child sex did not consistently modify any associations. Serum PFAS concentrations were not consistently linked to adolescent eating behaviors in this study, suggesting alternative pathways, such as metabolic rate, may underlie previously observed associations between PFAS exposure and childhood obesity.

Development of an LC-HRMS non-targeted method for comprehensive profiling of the exposome of nicotine and tobacco product users – A showcase for cigarette smokers

The global prevalence of electronic cigarettes, heated tobacco products, and other smokeless alternatives has grown significantly in the last ten years. These products have been suggested as combustion-free alternatives for conventional tobacco products like cigarettes, aiming to reduce the negative health impacts associated with smoking. However, the impact of those products on the health and safety of the general population are still unclear, as the absolute exposure from those products has not been thoroughly studied, yet. In this project, a non-targeted LC-HRMS method was developed comprising four different analytical modes for the investigation of the exposure profile in urine of the product users. The method is characterized by its high sensitivity and reproducibility, as shown during method validation. As a proof of concept, we first applied this method to detect significant differences in biomarkers of exposure (BoEs) between smokers and non-smokers. We observed a total of 171 BoEs significantly elevated in smokers, including several well-known biomarkers of smoke exposure like nicotine and its metabolites, mercapturic acid derivatives, and phenolic compounds. Some of the detected biomarkers are present at low ng/mL concentrations in urine, proving the high sensitivity needed for a holistic exploration of the exposome. Moreover, we were able to identify BoEs that have not been reported previously for smoking, such as 2,6-dimethoxyphenol and 7-methyl-1-naphthol glucuronide.

Transcriptomic and functional effects from a chemical mixture based on the exposure profile in Baltic Sea salmon, on metabolic and immune functions in zebrafish embryo

The Baltic Sea is one of the world’s most contaminated seas with long-standing adverse health status of its wildlife such as the Baltic Sea salmon, resulting in reduced fecundity and increased mortality. While adverse health effects have been reported among wild fish from the Baltic Sea, the toxicity mechanisms underlying these adversities, and the chemical effect drivers mediating them are poorly understood. To address this knowledge gap, we utilized the zebrafish (Danio rerio) embryo model to determine molecular and functional effects brought on by exposure to a technical mixture including 9 organohalogen compounds detected in serum from wild-caught Baltic Sea salmon. To align with the salmon exposure scenario, an internal dose regimen was opted to establish same relative proportions of the compounds in the zebrafish (whole body) as observed in the salmon serum. Through transcriptomic profiling, we identified dose-dependent effects on immune system and metabolism as two critical functions overlapping with adverse effects observed in wild fish from the Baltic Sea. We then determined likely effect drivers by comparing gene responses of the mixture with those of individual mixture components. Aligned with our transcriptome results, the number of total macrophages was reduced and the zebrafish’s ability to respond to a tissue damage suppressed in a dose-dependent manner. This study brings forth a key advancement in delineating the impact of chemical pollutants on the health of wild fish in the Baltic Sea.

Associations between avoidant/restrictive food intake disorder profiles and trauma exposure in veteran men and women.

Trauma exposure, particularly interpersonal trauma, is prevalent among individuals with eating disorders (EDs), and trauma exposure and the subsequent development of posttraumatic stress disorder have been associated with poorer outcomes for ED treatment. To our knowledge, there are no published investigations of trauma exposure among individuals with avoidant/restrictive food intake disorder (ARFID), a new diagnosis introduced by the Diagnostic and Statistical Manual of Mental Disorders-5. We investigated associations between trauma exposure and ARFID profiles in a sample of U.S. military veteran men and women. Participants in this cross-sectional study included 1494 veterans randomly selected from the population of post-9/11 veterans who had separated from military service within the previous 18 months. They completed a survey assessing EDs, including the Nine Item ARFID Screen and trauma exposure. Results revealed that 9.8% of the sample exceeded cutoffs for any ARFID profile, with the picky eating profile being the most common. Trauma exposure was prevalent among participants who exceeded cutoffs for ARFID, particularly the picky eating profile. Findings highlight the importance of addressing EDs, including ARFID, in veterans. It will be important to examine the extent to which trauma and trauma-related disorders impact treatment outcomes for individuals with ARFID.

Impact of Skin Care Products on Phthalates and Phthalate Replacements in Children: the ECHO-FGS.

Phthalates and their replacements have been implicated as developmental toxicants. Young children may be exposed to phthalates/replacements when using skin care products (SCPs). Our objective is to assess the associations between use of SCPs and children's urinary phthalate/replacement metabolite concentrations. Children (4-8 years old) from the Environmental Influences on Child Health Outcomes-Fetal Growth Study (ECHO-FGS) cohort provided spot urine samples from 2017 to 2019, and mothers were queried about children's SCP use in the past 24 h (). Concentrations of 16 urinary phthalate/replacement metabolites were determined by liquid chromatography-tandem mass spectrometry (). We used linear regression to estimate the child's use of different SCPs as individual predictors of urinary phthalate/replacement metabolites, adjusted for urinary specific gravity, age, sex assigned at birth, body mass index, and self-reported race/ethnic identity, as well as maternal education, and season of specimen collection. We created self-organizing maps (SOM) to group children into "exposure profiles" that reflect discovered patterns of use for multiple SCPs. Children had lotions applied (43.0%) frequently, but "2-in-1" hair-care products (7.5%), sunscreens (5.9%), and oils (4.3%) infrequently. Use of lotions was associated with 1.17-fold [95% confidence interval (CI): 1.00, 1.34] greater mono-benzyl phthalate and oils with 2.86-fold (95% CI: 1.89, 4.31) greater monoethyl phthalate (MEP), 1.43-fold (95% CI: 1.09, 1.90) greater monobutyl phthalate (MBP), and 1.40-fold (95% CI: 1.22, 1.61) greater low-molecular-weight phthalates (LMW). Use of 2-in-1 haircare products was associated with 0.84-fold (95% CI: 0.72, 0.97) and 0.78-fold (95% CI: 0.62, 0.98) lesser mono(3-carboxypropyl) phthalate (MCPP) and MBP, respectively. Child's race/ethnic identity modified the associations of lotions with LMW, oils with MEP and LMW, sunscreen with MCPP, ointments with MEP, and hair conditioner with MCPP. SOM identified four distinct SCP-use exposure scenarios (i.e., profiles) within our population that predicted 1.09-fold (95% CI: 1.03, 1.15) greater mono-carboxy isononyl phthalate, 1.31-fold (95% CI: 0.98, 1.77) greater mono-2-ethyl-5-hydroxyhexyl terephthalate, 1.13-fold (95% CI: 0.99, 1.29) greater monoethylhexyl phthalate, and 1.04-fold (95% CI: 1.00, 1.09) greater diethylhexyl phthalate. We found that reported SCP use was associated with urinary phthalate/replacement metabolites in young children. These results may inform policymakers, clinicians, and parents to help limit children's exposure to developmental toxicants. https://doi.org/10.1289/EHP13937.

53695 Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe chronic hand eczema in the Phase 3 DELTA-2 trial

53695 Systemic exposure and safety profile of delgocitinib cream in adults with moderate to severe chronic hand eczema in the Phase 3 DELTA-2 trial

Abstract P150: Epigenetic Mechanisms Linking Early-Life Stress to Hypertension Development: Implications for Prevention and Treatment

Purpose: Adverse childhood experiences (ACEs) and early-life stress (ELS) have been identified as significant risk factors for the development of hypertension later in life. This review synthesizes current evidence on how ELS induces epigenetic modifications, particularly DNA methylation and histone modifications, that predispose individuals to hypertension and discusses the implications for prevention and treatment strategies. Methods: A comprehensive literature review was conducted to identify studies examining the relationship between ELS, epigenetic modifications, and hypertension development. The search included studies investigating specific genes involved in stress response, inflammation, and cardiovascular regulation, such as NR3C1, SLC6A4, BDNF, OXTR, and FKBP5. Results: Studies have shown that ELS exposure can lead to persistent epigenetic alterations in genes involved in stress response, inflammation, and cardiovascular regulation. These modifications may contribute to impaired stress reactivity, heightened inflammation, and dysregulation of the renin-angiotensin system and endothelial function, potentially leading to the development of hypertension. The identification of ELS-induced epigenetic signatures opens up new avenues for early detection and intervention. DNA methylation biomarkers could be used to identify individuals at increased risk for hypertension due to ELS exposure, allowing for targeted prevention strategies. Moreover, the reversibility of epigenetic modifications presents an opportunity for novel treatment approaches, such as the use of epigenetic drugs and lifestyle interventions to mitigate the adverse cardiovascular effects of ELS. Conclusion: Understanding the epigenetic mechanisms linking ELS to hypertension development provides valuable insights for designing targeted prevention and treatment strategies. Future research should focus on translating these findings into clinical practice and developing personalized interventions based on an individual's ELS exposure and epigenetic profile. A multidisciplinary approach integrating epigenetics, stress neurobiology, and preventive medicine is required to address the long-term cardiovascular consequences of ELS effectively.

Comparison of Systemic Exposure Between Epinephrine Delivered via Metered-Dose Inhalation and Intramuscular Injection.

Background: Primatene® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The Cmax in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator.

As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood-brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F's pharmacokinetics, warranting further clinical drug-drug interaction (DDI) studies.