Adult Exposure Research Articles

Exposure Matching-Based Pediatric Dose Selection for Drugs with Renal Excretion - Lessons Learned from Pediatric Development of Direct Oral Anticoagulants.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

5.F. Scientific session: Staying cool: innovative solutions for an ageing population in a warming Europe

Abstract The EU is facing the dual challenge of climate change and rapid population ageing: temperatures in Europe are warming more rapidly than in the rest of the world and at the same time the number of those aged 85 years or more in the EU is projected to more than double by 2050. The increase of morbidity and mortality due to extreme heat is higher in older adults compared to the other age groups. During the workshop, we will first address the effect of heat waves and raising temperatures on older adults’ health and then present and discuss possible innovative tools and actions to minimise their impact on the EU ageing population. Objectives Emphasise the importance of addressing heat waves and raising temperatures including their impact on NCDs, with a focus on the implications for the ageing population; Present the reinforced activities of the Climate and Health Observatory, focusing on raising temperatures and heat waves; Discuss possible measures at EU level, multisectoral collaboration, the synergies and possible trade-offs between adaptation and mitigation measures; Discuss innovative solutions to minimise the impact of raising temperatures and heat waves on older adults. Speakers/Panelists • Projections of heat exposure of older adults and the consequences. • The European Climate & Health Observatory – presentation of reinforced & broadened activities. • Measures for adapting to and protecting against the effects of heat waves and warming. • Tackling the problem at the source: mitigating the contribution of the healthcare sector to GHG emissions/climate change.

A Sequential Population Pharmacokinetic Model of Zilovertamab Vedotin in Patients with Hematologic Malignancies Extrapolated to the Pediatric Population.

Recently a number of antibody-drug conjugate (ADC) pharmacometric models have been reported in the literature, describing one or two ADC-related analytes. The objective of this analysis was to build a population pharmacokinetic (popPK) three-analyte ADC model to describe efficacy and safety of zilovertamab vedotin, an ROR1-targeting ADC conjugated to monomethyl auristatin E (MMAE). Data from a phase 1 study of zilovertamab vedotin in subjects with hematologic malignancies was used in a stepwise ADC modeling strategy based on the simplified ADC popPK model proposed by Gibiansky. This choice provided opportunity to model three analytes: conjugated monomethyl auristatin E (acMMAE), total monoclonal antibody (total mAb), and free MMAE. The model was extrapolated to the pediatric population using a clearance maturation function and accounting for weight dependent pharmacokinetic (PK) changes. The simplified model provided a good structure to fit the adult acMMAE, total mAb, and free MMAE data. Analysis showed that MMAE was released through deconjugation of the payload and full proteolytic degradation of the acMMAE. Deconjugation was associated with an immediate release of MMAE, proteolytic clearance introduced a delay in the release of MMAE. Simulation of the model extrapolated to the pediatric population was the basis for pediatric dosing strategies forzilovertamab vedotinthat were approved in the United States and European Union. The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levelsthan found in adults.

Postpartum anger among low-income women with high rates of trauma exposure.

Few studies have examined anger concerns among postpartum women despite their risk of mood dysregulation. This study examined the performance of the Dimensions of Anger Reactions-5 (DAR-5) scale, a brief screen for problematic anger, in a sample of 1,383 postpartum women in Wisconsin who received perinatal home visiting services. We aimed to analyze the discriminant validity and measurement invariance of the DAR-5, the occurrence of problematic anger symptoms and their co-occurrence with mental health concerns, and the association between elevated anger levels and exposure to potentially traumatic events in childhood and adulthood. Descriptive statistics for anger symptoms and their associations with depression, anxiety, and PTSD were calculated. Psychometric properties of the DAR-5 were assessed via confirmatory factor analyses, and associations between trauma exposure and anger were evaluated as bivariate and partial correlations. Approximately 21% of the sample exhibited problematic anger based on an established DAR-5 cutoff score (≥ 12). Anger symptoms co-occurred with posttraumatic stress disorder (PTSD), depressive, and anxiety symptoms, though the DAR-5 sufficiently distinguished anger from these correlated symptom profiles. The DAR-5 also demonstrated acceptable measurement invariance across levels of trauma exposure. Higher levels of trauma exposure in childhood and adulthood significantly increased the risk of problematic anger even after controlling for PTSD, anxiety, and depressive symptoms, partial pb range:.07-.16. The findings suggest the DAR-5 is a valid brief screen for anger in postpartum women. Increased attention should be paid to elevated anger and the co-occurrence of other mental health concerns following childbirth.

Long-term inhalation exposure: A model for phthalate accumulation in the respiratory tract

BackgroundInhalation is a major pathway for phthalates (PAEs), an endocrine disruptor, to enter the human body. The actual internal exposure amount that participates in metabolism cannot be estimated by calculating total inhalation intake. ObjectiveTo estimate the accumulation in each region of the respiratory tract after long-term exposure to PAEs in different populations. MethodsA mass transfer model was developed to simulate the long-term accumulation of PAEs in respiratory tract through inhalation. The model considered (1) mass transfer of PAEs in three phases across seven regions, (2) the effect of temperature differences on the mass transfer process. Based on this model, we simulated adult exposure to PAEs in a laboratory, identified key model parameters, and further simulated various scenarios for children, adults, and elders. ResultsPAEs are not completely cleared from the respiratory tract after 16 hours, following 8 hours of daily exposure. Under regular laboratory environment, accumulation after 30 days is 3.8 times higher than that after the first day. The distribution of PAEs between the gas and mucus phases has a greater impact on the results than between the gas and particle phases. Children are at the highest risk to Diethyl phthalate (DEP) exposure compared with adults and elders. Nearly 80 % of DEP is exhaled, with 14 % accumulating in the alveolar region after an hour. ConclusionThis model links indoor air PAEs to human internal exposure, showing that most PAEs are exhaled, while the remainder accumulates in the respiratory tract and may participate in human metabolism.

Development and evaluation of a questionnaire to capture environmental and occupational inhalational exposures in adults with fibrotic interstitial lung disease

BackgroundIdentification of exposures in patients with interstitial lung diseases (ILDs) is essential for diagnosis and management and can be facilitated through the use of exposure questionnaires. However, for most ILDs, a patient-focused questionnaire is lacking. Cognitive interviewing is a methodology used to evaluate sources of understanding and misunderstanding in a questionnaire and to provide evidence of content validity. We developed and refined a new exposure questionnaire for patients with fibrotic ILDs by using cognitive interviewing to establish its understandability and content validity.MethodsAn exposure assessment questionnaire was developed by a multidisciplinary team. Cognitive interviews with 24 patients with fibrosing ILDs were conducted by trained interviewers over the phone or Zoom using a semi-structured interview guide. The questionnaire was amended based on the interviewers’ interpretation of sources of misunderstanding. The revised questionnaire was tested in a second round of cognitive interviews with a different group of 24 patients.ResultsAmong the 48 patients who completed interviews, mean age was 61 years, 58.3% were male and 75.0% were white. Based on the first round of cognitive interviews, the multidisciplinary team modified the questions, organization, and instructions of the questionnaire to facilitate recall, adjust for exposures that were frequently misunderstood or required clarification, and focus on clinically relevant exposures. The revised questionnaire performed well in the second round of interviews.ConclusionAn exposure questionnaire, developed with input from patients, can be used to assess clinically relevant exposures in adults with fibrosing ILDs. This is the first questionnaire for all types of fibrosing ILD to have undergone content validation.

Exploring the Impact of Developmental Clearance Saturation on Propylene Glycol Exposure in Adults and Term Neonates Using Physiologically Based Pharmacokinetic Modeling.

Propylene glycol (PG) is a pharmaceutical excipient which is generally regarded as safe (GRAS), though clinical toxicity has been reported. PG toxicity has been attributed to accumulation due to saturation of the alcohol dehydrogenase (ADH)-mediated clearance pathway. This study aims to explore the impact of the saturation of ADH-mediated PG metabolism on its developmental clearance in adults and neonates and assess the impact of a range of doses on PG clearance saturation and toxicity. Physiologically based pharmacokinetic (PBPK) models for PG in adults and term neonates were developed using maximum velocity (Vmax) and Michaelis-Menten's constant (Km) of ADH-mediated metabolism determined in vitro in human liver cytosol, published physicochemical, drug-related and ADH ontogeny parameters. The models were validated and used to determine the impact of dosing regimen on PG clearance saturation and toxicity in adults and neonates. The Vmax and Km of PG in human liver cytosol were 1.57 nmol/min/mg protein and 25.1 mM, respectively. The PG PBPK model adequately described PG PK profiles in adults and neonates. The PG dosing regimens associated with saturation and toxicity were dependent on both dose amount and cumulative in standard dosing frequencies. Doses resulting in saturation were higher than those associated with clinically observed toxicity. In individuals without impaired clearance or when PG exposure is through formulations that contain excipients with possible interaction with PG, a total daily dose of 100-200 mg/kg/day in adults and 25-50 mg/kg/day in neonates is unlikely to result in toxic PG levels or PG clearance saturation.

Effects of single and combined urinary polycyclic aromatic hydrocarbon effects on lung function in the U.S. adult population

BackgroundThe impact of polycyclic aromatic hydrocarbons (PAHs) on lung function has garnered attention, but studies mostly focus on individual effect. This study investigates urinary PAH metabolites as biomarkers of exposure and assesses the relationships between single and combined exposures to nine urinary PAH metabolites and lung function in adults.MethodsData from 4040 adults in the 2007–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Weighted generalized linear models estimated the effects of individual PAH metabolites on lung function. Additionally, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were employed to evaluate the combined impacts of multiple PAH metabolites.ResultsAnalyses of individual PAH metabolites revealed negative associations with lung function, excluding forced vital capacity (FVC). The WQS, qgcomp, and BKMR models consistently showed that exposure to multiple PAH metabolites was associated with lung function decrease. WQS indicated that 2-hydroxynaphthalene (2-NAP) was the largest contributor to the reductions in forced expiratory volume in 1 s (FEV1), FVC, peak expiratory flow (PEF), and forced expiratory flow from 25 to 75% of FVC (PEF25-75%). Additionally, 1-hydroxypyrene (1-PYR) was the primary PAH metabolite contributing to the decreases in FEV1/FVC and fractional exhaled nitric oxide (FeNO). The combined effect of urinary PAH metabolites did not affect FVC in the current smokers or FeNO in nonsmokers, but decreased FEV1/FVC in current smokers.ConclusionThis study strengthens the negative relationships between multiple PAH metabolites exposure and lung function in adults. Given the limitations of this study, including the lack of knowledge of other exposure pathways and the uncertainty of urinary metabolites, further research is necessary to explore the mechanisms underlying these associations and to address the limitations in exposure assessment.

Examining the psychometric properties of the CEFIS-AYA using item response theory.

The COVID-19 Exposure and Family Impact Scale, Adolescent and Young Adult Version (CEFIS-AYA; Schwartz, L. A., Lewis, A. M., Alderfer, M. A., Vega, G., Barakat, L. P., King-Dowling, S., Psihogios, A. M., Canter, K. S., Crosby, L., Arasteh, K., Enlow, P., Hildenbrand, A. K., Kassam-Adams, N., Pai, A., Phan, T. L., Price, J., Schultz, C. L., Sood, E., Wood, J., & Kazak, A. (2022). COVID-19 exposure and family impact scales for adolescents and young adults. Journal of Pediatric Psychology, 47, 631-640. https://doi.org/10.1093/jpepsy/jsac036) was developed to assess the pandemic's effects on adolescents and young adults (AYA). Via principal component analysis, measure developers examined the structure and reliability of the CEFIS-AYA and identified seven exposure and five impact components. This study built upon prior work through use of item response theory (IRT) models to characterize the dimensionality of the CEFIS-AYA, determine the strength of relations between items and underlying trait(s), and examine associations between trait scores and pandemic-related distress. This was a secondary analysis of data collected between July 2020 and July 2021 from three studies of emerging adults (ages 18-29; N = 834). The CEFIS-AYA structure was multidimensional, with the strongest support for five traits. Trait 1 represented pandemic impact on social/emotional functioning and self-care. Trait 2 reflected other pandemic disruptions. Trait 3 represented pandemic disruptions to education and/or other milestones. Trait 4 represented pandemic impact on physical well-being. Trait 5 assessed pandemic disruptions to work/financial circumstances. Item loadings and parameters indicated variability in how consistently trait level was associated with item endorsement. Trait scores did not predict distress, except that increases in Trait 3 were associated with lower distress. The present study examined the psychometric properties of the CEFIS-AYA among emerging adults using a statistical framework better suited for modeling categorical data. The identified dimensional structure was relatively consistent with the initial psychometric evaluation of the CEFIS-AYA, albeit more parsimonious. However, replication is critical in light of sample demographic characteristics.

Passive smoking and risk of pancreatic cancer: an updated systematic review and meta-analysis.

Previous meta-analysis has demonstrated that no association was validated between passive smoking and pancreatic cancer. However, there is growing evidence on this issue recently. This study aimed to confirm this association. PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to April 2024 for retrieval of full articles. Studies with the exposure of passive smoking and outcome of pancreatic cancer were eligible for the analysis. We generated pooled relative risks (RRs) and 95% confidence intervals (CIs) using DerSimonian-Laird random-effects models. Quality of evidence was assessed using the GRADE system. Fourteen studies were included, with 5,560 pancreatic cancer patients. Passive smoking was associated with a moderate increased risk of pancreatic cancer (RR = 1.20, 95% CI: 1.11-1.30, p<0.001). The results were consistent in both case-control (p=0.013) and cohort studies (p<0.001) and in studies with high (p=0.007) and moderate quality (p<0.001). In subgroup analysis, the risk was significant for both current (RR=1.91, 95% CI: 1.45-2.51, p<0.001) and non-current smokers (RR = 1.17, 95% CI: 1.01-1.36, p=0.037), for exposure both in adulthood (RR = 1.18, 95% CI: 1.06-1.31, p=0.002) and childhood (RR = 1.20, 95% CI: 1.08-1.34, p=0.001). However, only regular or daily exposure (RR=1.28, 95% CI: 1.08-1.50, p=0.003), rather than exposing occasionally, seldom or few times per week (p=0.421), to passive smoking could increase the risk of pancreatic cancer. Passive smoking exposure confers a significant increased risk for pancreatic cancer. The risk was valid in both case-control and cohort, high and moderate quality studies, in current and non-current smokers, and for both childhood and adulthood exposure. Regular or daily exposure rather than exposing occasionally, seldom or few times per week could exert a detrimental effect on pancreatic cancer.

Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling.

The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii. The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii. A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices. The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population. The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

The association between patterns of exposure to adverse life events and the risk of chronic kidney disease: a prospective cohort study of 140,997 individuals

Exposure to adverse life events is linked to somatic disorders. The study aims to evaluate the association between adverse events at varying life stages and the risk of chronic kidney disease (CKD), a condition affecting about 10% population worldwide. This prospective cohort study included 140,997 participants from the UK Biobank. Using survey items related to childhood maltreatment, adulthood adversity and catastrophic trauma, we performed latent class analysis to summarize five distinct patterns of exposure to adverse life events, namely “low-level exposure”, “childhood exposure”, “adulthood exposure”, “sexual abuse” and “child-to-adulthood exposure”. We used Cox proportional hazard regression to evaluate the association of patterns of exposure to adverse life events with CKD, regression-based mediation analysis to decompose the total effect, and gene-environment-wide interaction study (GEWIS) to identify interactions between genetic loci and adverse life events. During a median follow-up of 5.98 years, 2734 cases of incident CKD were identified. Compared with the “low-level exposure” pattern, “child-to-adulthood exposure” was associated with increased risk of CKD (hazard ratio 1.37, 95% CI 1.14 to 1.65). BMI, smoking and hypertension mediated 11.45%, 9.79%, and 4.50% of this total effect, respectively. Other patterns did not show significant results. GEWIS and subsequent analyses indicated that the magnitude of the association between adverse life events and CKD differed according to genetic polymorphisms, and identified potential underlying pathways (e.g., interleukin 1 receptor activity). These findings underscore the importance of incorporating an individual’s psychological encounters and genetic profiles into the precision prevention of CKD.

Lifetime chronic stress Exposures, stress Hormones, and biological Aging: Results from the midlife in the United States (MIDUS) study

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26–78 years (Mage = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life.

Exposure of young German adults to the anti-dandruff agent climbazole from 2002 to 2022: Analysis of specific biomarkers in urinary samples

The fungicide climbazole is mainly used as an anti-dandruff (AD) agent in cosmetics, such as shampoos or other hair care products. Consequently, an exposure of the general population seems likely because many people suffer from dandruff. We have analyzed urine samples from the German Environmental Specimen Bank (ESB) for two specific climbazole biomarkers, namely (OH)2-climbazole and cx-OH-climbazole, in samples collected in the years 2002, 2007, 2012, 2017 and 2022. (OH)2-Climbazole was determined diastereoselectively, hence three analytes are discussed ((OH)2-climbazole 1, (OH)2-climbazole 2 and cx-OH-climbazole). The study population consisted of 300 students (150 male, 150 female) aged between 20 and 29 at the time of sampling from Halle/Saale in Germany. Most samples under scrutiny did not contain any climbazole metabolites in levels above the limit of quantification (LOQ, 0.5 μg/L for either analyte), only in 16 samples at least one analyte could be quantitated. Even the sample with the highest metabolite concentrations (10.23 μg/L (OH)2-climbazole and 2.53 μg/L cx-OH-climbazole) barely reached the urinary concentrations found in an excretion kinetics study after the typical application of a climbazole-containing shampoo in three volunteers. As a result, estimated daily intakes (max. 1.8 μg/kg bw/d) lay below the subchronic NOAEL (15 mg/kg bw/d) and NOEL (5 mg/kg bw/d) by a factor of more than 8300 and 2700, respectively. The evaluation of the climbazole burden of the general population gives valuable insights for the authorities on the effect of legal restrictions.

Blood Biomarkers of Trans-Fatty Acid Intake among Nigerian Adults in the Federal Capital Territory: A Cross-Sectional Study

BackgroundIntake of trans-fatty acids (TFAs) is an established risk factor for cardiovascular disease. In April 2023, Nigeria passed regulations limiting TFA content in foods, fats, and oils, but the current level of TFA exposure in the Nigerian population is unknown. We assessed TFA biomarkers in dried blood spots from Nigerian adults in the Federal Capital Territory before policy enforcement to establish a baseline for future evaluation. MethodsWe used gas chromatography to measure TFA content in dried blood spots from adults participating in a cross-sectional household survey using a representative sampling frame. Individual TFA (t-16:1, t-18:1, and t- 18:2) and their total, were expressed as % of total fatty acids. We assessed differences in TFA levels between subgroups based on sex, age, body mass index (BMI), education, income, and local government area using multivariable-adjusted linear regression models. Mean TFA levels were compared to samples from individuals in 30 countries. ResultsIn 213 adults (62% females; mean age: 36 years, mean BMI: 25.9 kg/m2), the mean TFA level in dried blood spots was 0.61% of total fatty acids (range: 0.23-1.31%). In multivariable-adjusted models, TFA levels were higher in younger adults (<30 years compared with ≥42 years, 0.07% [95% confidence interval (CI): 0.00,0.15], p=0.047), those without a high school degree (compared with higher education, 0.08% [95% CI: 0.01,0.16], p=0.023;), and residents of Abuja Municipal Area Council (compared with residents in Gwagwalada, 0.12% [95% CI: 0.05,0.20], p=0.001). Total TFA levels were comparable to international samples, but t-16:1 and t-18:1 appeared lower, whereas t-18:2 appeared greater (52% of all TFA), in the Nigerian samples. ConclusionsThese results provide a baseline assessment of TFA exposure in Nigerian adults to evaluate implementation and effect of national regulation passed in 2023. The observed subgroup differences may help identify subpopulations for targeted interventions to reduce TFA intake.

Fertility loss and recovery dynamics after repeated heat stress across life stages in male Drosophila melanogaster: patterns and processes.

Frequent and extreme temperatures associated with climate change pose a major threat to biodiversity, particularly for organisms whose metabolism is strictly linked to ambient temperatures. Many studies have explored thermal effects on survival, but heat-induced fertility loss is emerging as a greater threat to population persistence. However, while evidence is accumulating that both juvenile and adult stages heat exposure can impair fertility in their own ways, much less is known about the immediate and longer-term fitness consequences of repeated heat stress across life stages. To address this knowledge gap, we used male Drosophila melanogaster to investigate (i) the cumulative fitness effects of repeated heat stress across life stages, (ii) the potential of recovery from these heat exposures, and (iii) the underlying mechanisms. We found individual and combined effects of chronic juvenile and acute adult heat stress on male fitness traits. These effects tended to exacerbate over several days after brief heat exposure, indicating a substantial fertility loss for these short-lived organisms. Our findings highlight the cumulative and persistent effects of heat stress on fitness. Such combined effects could accelerate population declines, particularly in more vulnerable species, emphasizing the importance of considering reproduction and its recovery for more accurate models of species persistence.

Determination of Bisphenol A and its analogues in crayfish by UPLC-MS/MS and the assessment of dietary exposure of adults in Tianjin

Bisphenol A (BPA), an identified environmental endocrine disruptor, is under strict control due to its biotoxic effects. Alternatives to BPA, including Bisphenol F (BPF) and Bisphenol S (BPS), are progressively being developed and extensively utilized, with their potential health risks attracting heightened scrutiny. The objective of this study was to assess the exposure levels of BPA and its analogues (BPs) in crayfish and to evaluate the health effects related to crayfish consumption. Consequently, a robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the identification and quantification of BPs in crayfish. Furthermore, 96 crayfish samples purchased in Tianjin were obtained for analysis. The detection rate of BPA was 86.5 % in crayfish, with the maximum concentration of 31.3 µg/kg. BPS was found in 26.0 % of the samples, with the highest concentration at 33.1 μg/kg. Additionally, the levels of BPs in both abdominal muscle and hepatopancreas of the crayfish were determined. The results revealed a significantly higher concentration of BPA in the hepatopancreas compared to the abdominal muscle (P < 0.05). The total dietary intake of BPA through crayfish consumption was far below the tolerable daily intake (TDI) of 4 μg/kg body weight/day, suggesting minimal health risk associated with BPs exposure from crayfish consumption.

Prenatal immune activation in rats and adult exposure to inescapable shocks reveal sex-dependent effects on fear conditioning that might be relevant for schizophrenia

Prenatal infection is considered a relevant factor for neurodevelopmental alterations and psychiatric diseases. Administration of bacterial and viral components during pregnancy in rodents results in maternal immune activation (MIA), leading to schizophrenia-like neurochemical and behavioral changes. Despite some evidence for abnormal fear conditioning in schizophrenia, only a few animal studies have focused on this issue. Therefore, we addressed the impact of the administration of the viral mimetic polyI:C to pregnant Long-Evans rats on the adult offspring response to inescapable shocks (IS) and contextual fear conditioning. In males, polyI:C induced a greater endocrine (plasma ACTH) response to IS and both polyI:C and IS enhanced fear conditioning and generalization to a completely different novel environment (hole-board), with no additive effects, probably due to a ceiling effect. In contrast, a modest impact of polyI:C and a lower impact of IS on contextual fear conditioning and generalization was observed in females. Thus, the present results demonstrate that polyI:C dramatically affected fear response to IS in adult males and support the hypothesis that males are more sensitive than females to this treatment. This model might allow to explore neurobiological mechanisms underlying abnormal responsiveness to fear conditioning and stressors in schizophrenia.

Exposure assessment and semi-quantitative risk analysis of histamine in tuna and tuna-like fish from Indonesia

This study aimed to investigate histamine exposure associated with consumption of fresh tuna and tuna-like species in West Java, and to estimate risk of Scombroid Fish Poisoning (SFP) in Indonesia. A range of species, including tuna (Thunnus spp.), bullet tuna ( Auxis sp.), and skipjack ( Katsuwonus pelamis ) were collected from local markets and fish landing sites. Subsequently, histamine concentrations were determined using NMR analysis and exposure was calculated in mg/day for toddlers, children, and adults. The results showed that skipjack had the highest histamine exposure for all age groups, followed by bullet and regular tuna. The highest EDI for histamine was from skipjack consumption, accounting for 38.67; 37.77 and 20.74 percentage of exposure for toddlers, children and adults, respectively. These values are below the defined thresholds levels (ARfD), indicating no potential risk of acute health effect. Cooked bullet tuna and skipjack were estimated to cause similar illnesses, accounting for 6–7 cases per 100,000 individuals, which was higher than cooked tuna at 1–2 cases per 100,000 individuals. Considering the preparation of raw tuna in restaurants following Good Hygienic Practices (GHP), the predicted annual cases decreased significantly to 4–5 cases per million individuals. This risk estimation only considered histamine levels in fresh fish, without including data from fish preparation. Therefore, further studies were recommended to estimate the risk level in raw/fresh tuna and similar species before consumption.

Relationship between phthalate exposure and kidney function in Taiwanese adults as determined through covariate-adjusted standardization and cumulative risk assessment

Few studies have investigated the associations between phthalate exposure and kidney function indicators in adults by simultaneously performing covariate-adjusted creatinine standardization, cumulative risk assessment, and mixture analysis. Thus, we applied these methods simultaneously to investigate the aforementioned associations in an adult population. This cross-sectional study analyzed data (N = 839) from a community-based arm of the Taiwan Biobank. The levels of 10 urinary phthalate metabolites were measured and calculated as the sum of the molar concentrations of the dibutyl phthalate metabolite (ΣDBPm) and di(2-ethylhexyl) phthalate (DEHP) metabolite (ΣDEHPm). The hazard index (HI) and daily intake (DI) were estimated by measuring the urinary levels of the phthalate metabolite. Kidney function biomarkers were assessed by measuring the following: blood urea nitrogen (BUN), uric acid, the albumin-to-creatinine ratio (ACR), and the estimated glomerular filtration rate (eGFR). Generalized linear models were implemented to examine the associations between exposure to individual phthalates, HI scores, and kidney function biomarkers. We also employed Bayesian kernel machine regression (BKMR) to analyze the relationships between exposure to various combinations of phthalates and kidney function. ΣDEHPm levels were significantly and positively associated with BUN and ACR levels, and ΣDBPm levels were positively associated with ACR levels. In addition, eGFR was negatively associated with ΣDBPm and ΣDEHPm levels. In the BKMR model, a mixture of 10 phthalate metabolites was significantly associated with BUN, uric acid, ACR, and eGFR results. Higher DIDEHP and higher DIDnBP values were significantly associated with lower eGFRs and higher ACRs, respectively. Higher DIDiBP and DIDEP values were significantly associated with higher uric acid levels. A higher HI was significantly associated with lower eGFRs and higher ACRs. Our results suggest that exposure to environmental phthalates is associated with impaired kidney function in Taiwanese adults.