Biomarkers Of Exposure Research Articles

Associations of maternal blood biomarkers of prenatal APAP exposure with placental gene expression and child attention deficit hyperactivity disorder

Associations of maternal blood biomarkers of prenatal APAP exposure with placental gene expression and child attention deficit hyperactivity disorder

Biomarkers of Exposure to Nicotine and Selected Toxicants in Individuals Who Use Alternative Tobacco Products Sold in Japan and Canada from 2018 to 2019.

Comparisons of nicotine and toxicant exposures between people who use different alternative tobacco products remain underexplored. This cross-sectional, multicountry study analyzed urinary metabolites of nicotine, tobacco-specific nitrosamines [4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK)], and volatile organic compounds (acrolein, acrylamide, and acrylonitrile) among established users (n = 550) in Japan and Canada. Participants exclusively or concurrently used nicotine vaping products (NVP; Canada only), heated tobacco products (HTP; Japan only), and combustible cigarettes (CC; Japan and Canada) or abstained (Japan and Canada). All product groups showed substantial nicotine exposure. Both HTPs and NVPs exposed exclusive users to lower toxicant levels than exclusive CC use. Canadian participants who exclusively used NVPs exhibited lower NNK and acrolein exposure but higher acrylamide exposure than Japanese participants who exclusively used HTPs. Concurrent use of CCs alongside alternative products exposed users to higher toxicant levels compared with exclusive use of either alternative product. Exclusive use of alternative tobacco products results in significant nicotine exposure but substantially lower toxicant exposure compared with exclusive CC use. People who use HTPs in Japan may experience higher exposure to nicotine and certain toxicants (NNK and acrolein) than people who use NVPs in Canada. Concurrent use results suggest that partially substituting CCs with alternative products may reduce toxicant exposure but to a lesser extent than completely transitioning to alternative products. Exposure patterns between two popular alternative tobacco products differ. The overall toxicant exposure from these products is lower than from CCs, providing critical data for regulatory decisions and public health considerations.

Development and Validation of a Fast and Sensitive UPLC-MS/MS Method for Ethyl Glucuronide (EtG) in Hair, Application to Real Cases and Comparison with Carbohydrate-Deficient Transferrin (CDT) in Serum

Alcohol is responsible for an ever-increasing number of deaths worldwide, and many road accidents are caused by irresponsible drinking and driving. The use of biomarkers that can support a diagnosis of alcohol abuse is a very important tool that can improve the prevention of many alcohol-related diseases and serious traffic accidents. The main aim of our study was the full validation of a rapid and simple method by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to detect ethyl glucuronide in hair (hEtG). The method was successfully applied to n = 171 real hair samples collected from drivers convicted of driving while impaired by alcohol or drugs. A comparison of hEtG and serum Carbohydrate-Deficient Transferrin percentages (% CDT) was also performed to carefully evaluate the data in relation to the specific detection windows of the two different biomarkers. Most of the drivers with hEtG > 30 pg/mg were males in their thirties. None of the hEtG-positives had a serum % CDT above the cutoff (≥2%). Although some researchers suggest caution until solid data are available on the possible effects of interindividual variability that may influence EtG incorporation and metabolism, hEtG is a very useful biomarker of long-term alcohol exposure that shows greater reliability than traditional blood markers.

Biomarkers of Fumonisin Exposure in Pigs Fed the Maximum Recommended Level in Europe

This study investigated biomarkers of fumonisin exposure in pigs fed diets contaminated with fumonisins at the European Union’s maximum recommended level. Pigs were assigned to either a fumonisin (FB) diet or a fumonisin plus AlgoClay (FB + AC) diet for durations of 4, 9, and 14 days. At 14 days, the plasma Sa1P:So1P ratio increased in pigs fed the FB diet, while the Sa:So ratio remained unchanged. In the liver, FB1 was detected at four days of exposure, with the concentration tending to increase through day 14. The Sa:So and C22-24:C16 ratios of 18:1-, 18:2-, and m18:1-ceramides were elevated at 9 and 14 days, respectively. In the kidneys, FB1 was only detectable at 14 days, and the Sa:So and C22-24:C16 ratios of 18:1-ceramides were increased. In both the liver and kidneys, the increase in the C22-24:C16 ratio was attributed to a reduction of C16 ceramides. In the lungs, no FB1 was detected; however, the Sa:So and Sa1P:So1P ratios increased, and C16 ceramide concentrations decreased at 14 days. Feeding the pigs the FB + AC diet resulted in a reduction of the FB1 tissue-to-feed ratio in the liver and kidneys but did not affect the Sa:So or Sa1P:So1P ratios. Interestingly, the decreases in C16 ceramides observed in the FB diet group were no longer detectable in the FB + AC group. Overall, these findings highlight the complexity of the relationship between FB1 tissue concentrations and sphingolipid changes, suggesting that a comprehensive analysis of multiple biomarkers is required to fully understand fumonisin’s effects.

Discovery of Noninvasive Biomarkers for Radiation Exposure via LC-MS-Based Hair Metabolomics.

Ionizing radiation exposure from a potential nuclear energy plant leak or detonation of a nuclear weapon can cause massive casualties to both warfighters and civilians. RNA, proteins, and metabolite biomarkers in biological specimens like blood and tissue have shown potential to determine radiation dose levels. However, these biomarkers in blood and urine are short-lived, typically detectable within hours or a few days. To address the need for stable, long-term radiation exposure biomarkers, we developed two mass spectrometry-based methods using noninvasive hair samples to identify radiation-exposure biomarkers. Our results show that hippuric acid and 5-methoxy-3-indoleacetate significantly increase after higher (4 gray) doses of gamma irradiation compared to lower (1 and 2 Gy) doses or nonexposed hair samples. While 2-aminooctadec-4-ene-1,3-diol, oleoyl ethanolamide, palmitoylcarnitine, 25-hydroxy vitamin D3, vernolic acid, and azelaic acid significantly increased over time after exposure. Trimethylamine N-oxide (TMAO) was found in higher concentrations in female specimens across all time points. Further validation using a machine learning model suggested that these biomarkers can predict differences in the exposure dose and time point. Our findings highlight the potential of noninvasive hair sample analysis for assessing radiation exposure, offering a viable alternative to address critical public health concerns of unexpected radiation exposure.

Associations of Prenatal Mercury Exposure and PUFA with Telomere Length and mtDNA Copy Number in 7-Year-Old Children in the Seychelles Child Development Nutrition Cohort 2.

Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) variations are linked to age-related diseases and are associated with environmental exposure and nutritional status. Limited data, however, exist on the associations with mercury exposure, particularly early in life. We examined the association between prenatal mercury (Hg) exposure and TL and mtDNAcn in 1,145 Seychelles children, characterized by a fish-rich diet. Total mercury (THg) was determined in maternal hair at delivery and cord blood. TL and mtDNAcn were determined relative to a single-copy hemoglobin beta gene in the saliva of 7-y-old children. Linear regression models assessed associations between THg and relative TL (rTL) and relative mtDNAcn (rmtDNAcn) while controlling for maternal and cord serum polyunsaturated fatty acid (PUFA) status and sociodemographic factors. Interactions between THg and child sex, PUFA, and telomerase genotypes were evaluated for rTL and rmtDNAcn. Higher THg concentrations in maternal hair and cord blood were associated with longer rTL [; 95% confidence interval (CI): 0.002, 0.016 and ; 95% CI: 0.001, 0.003, respectively], irrespective of sex, PUFA, or telomerase genotypes. Maternal serum n-6 PUFA and n-6/n-3 ratio were associated with shorter [; 95% CI: , and ; 95% CI: , , respectively] and PUFA with longer (; 95% CI: 0.032, 0.65) rTL. Cord blood n-6 PUFA was associated with longer (; 95% CI: 0.050, 0.26) rTL. Further analyses revealed linoleic acid in maternal blood and arachidonic acid in cord blood as the main drivers of the n-6 PUFA associations. No associations were observed for THg and PUFA with rmtDNAcn. Our results indicate that prenatal THg exposure and PUFA status are associated with rTL later in childhood, although not consistently aligned with our initial hypothesis. Subsequent research is needed to confirm this finding, further evaluate the potential confounding of fish intake, and investigate the underlying molecular mechanisms to verify the use of rTL as a true biomarker of THg exposure. https://doi.org/10.1289/EHP14776.

Phosphonylated tyrosine and cysteine disulfide adducts both generated from immunoglobulin G and human serum albumin indicate exposure to the nerve agent VX in vitro.

Pronase-catalyzed proteolysis is shown to produce single amino acid adducts of tyrosine (Tyr) and cysteine (Cys) obtained from both human serum albumin (HSA) and immunoglobulin G (IgG) after in vitro exposure of plasma to the nerve agent VX. Total plasma as well as isolated HSA and IgG yielded the Tyr residue phosphonylated with the ethyl methylphosphonic acid moiety, Tyr(-EMP). Furthermore, a Cys residue adducted with the diisopropylaminoethane thiol leaving group of the agent bound via a disulfide bridge, Cys(-DPAET), was also obtained from both proteins. Even though Tyr(-EMP) represents an internationally well-accepted biomarker of a VX-like agent its origin from plasma IgG has never been shown before. In addition, this is the first time that Cys(-DPAET) is presented as a biomarker of VX exposure clearly identifying the chemical nature of the V-type nerve agent's leaving group. Both biomarkers were detected after selective affinity-based solid-phase extraction (SPE) from plasma that yielded highly purified HSA and IgG as documented by sodium dodecyl polyamide gel electrophoresis (SDS-PAGE). Both biomarkers were found in the corresponding protein bands of HSA and IgG each after in-gel proteolysis with pronase. A micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry method (LC-ESI HR-MS/MS) was developed for the simultaneous detection of Tyr(-EMP) and Cys(-DPAET). The time for proteolysis was optimized for maximum biomarker yield. The method showed excellent selectivity and sensitivity, and the adducted proteins and biomarkers were found to be highly stable during storage. Accordingly, the presented method sheds more light on the molecular toxicology of VX and broadens the spectrum of methods suited for biomedical verification.

Integrated Computational Analysis Reveals Early Genetic and Epigenetic AML Susceptibility Biomarkers in Benzene-Exposed Workers

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) and other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading to increased oxidative stress, DNA damage, and cancer transformation. While its toxicity is well-documented, the link between genetic and epigenetic alterations and cancer susceptibility in exposed workers remains underexplored. This study aims to identify early biomarkers of benzene exposure and AML risk by analyzing gene expression and DNA methylation datasets from GEO DataSets, integrated with molecular pathway analyses, as well as miRNA-target and protein-protein network evaluations. This multi-approach led to the identification of nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) in workers exposed to benzene, with NFKB1 showing strong discriminatory potential. Also, dose-dependent DNA methylation changes were observed in CXCR6 and MELTF, while selected miRNAs such as let-7d-5p, miR-126-3p, and miR-361-5p emerged as key post-transcriptional regulators. Furthermore, functional enrichment linked these genes to immune response, inflammation, cell proliferation, and apoptosis pathways. While network analyses highlighted NFKB1, CRK, and CXCR6 as central to benzene-associated leukemogenesis. Altogether, these findings provide novel insights into an early biomarker fingerprint for benzene exposure and AML susceptibility, supporting the future development of biomolecular-based targeted occupational health monitoring and personalized preventive strategies for at-risk workers.

Identification of hub genes and pathways in mouse with cold exposure

Abstract Background Cold exposure is linked to numerous diseases, yet the changes in key genes and pathways in mice under cold exposure remain unexplored. Understanding these alterations could offer insights into the mechanisms of cold resistance and contribute valuable ideas for treating cold-related diseases. Methods The dataset GSE148361 was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the “limma” package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on DEGs. The STRING (Search Tool for the Retrieval of Interacting Genes) database was used to construct a protein-protein interaction (PPI) network. Additionally, gene set enrichment analysis (GSEA) was conducted to identify pathways associated with key genes. miRNAs and upstream transcription factors (TFs) were predicted using the miRNet database. Results A total of 208 DEGs were identified, with 137 upregulated and 71 downregulated. In biological processes, DEGs were enriched in nucleotide and purine-containing compound metabolism. For cellular components, DEGs were involved in condensed chromosomes and mitochondrial protein complexes. In molecular functions, proton transmembrane transporter activity was enriched. KEGG pathway analysis showed significant enrichment in biosynthesis of unsaturated fatty acids, fatty acids, and pyruvate metabolism. From the PPI network, 12 hub genes were identified using MCODE. Four hub genes (Col3a1, fi203, Rtp4, Vcan) demonstrated similar trends in a validation set (GSE110420) and were significantly differentially expressed. GSEA analysis indicated that these four genes were enriched in pathways such as ECM-receptor interaction and cytokinecytokine receptor interaction. The hub gene network included 93 miRNAs and one TF Conclusion This study identified four hub genes as potential diagnostic biomarkers for cold exposure, providing insights for further research on the effects of cold on gene expression and disease.

Persistent Metabolic Changes Are Induced by 24 h Low-Dose Lead (Pb) Exposure in Zebrafish Embryos

Lead (Pb) is a heavy metal associated with a range of toxic effects. Relatively few studies attempt to understand the impact of lead on development from a mechanistic perspective. Danio rerio (zebrafish) embryos are a model organism for studying the developmental consequences of exposure to chemical agents. This study examined the metabolome of developing zebrafish embryos exposed to 5 ppb, 15 ppb, 150 ppb, and 1500 ppb Pb concentrations during the first 24 h post fertilization, followed by 24 h of unexposed development and harvest at 48 h. Untargeted metabolomics and multivariate analysis revealed that various Pb exposures differentially affected the embryonic metabolome. Pathway analyses showed the dysregulation of biopterin, purine, alanine, and aspartate metabolism. Inductively coupled plasma mass spectrometry demonstrated Pb accumulation in embryos. Additionally, decreases in oxidation–reduction ratios were observed in 5–150 ppb groups but not in the 1500 ppb exposure group. This finding, along with several metabolite abundances, suggests a hormetic effect of Pb concentrations on the developing zebrafish metabolome. Together, these data reveal persistent global changes in the embryonic metabolome, pin-point biomarkers for Pb exposure, unveil dose-dependent relationships, and reflect Pb-induced changes in cellular energy. This work highlights aberrant processes and persistent changes underlying low-dose heavy metal exposure during early development.

Long-term effects of combined exposures to simulated microgravity and galactic cosmic radiation on the mouse lung: sex-specific epigenetic reprogramming.

Most studies on the effects of galactic cosmic rays (GCR) have relied on terrestrial irradiation using spatially homogeneous dose distributions of mono-energetic beams comprised of one ion species. Here, we exposed mice to novel beams that more closely mimic GCR, namely, comprising poly-energetic ions of multiple species. Six-month-old male and female C57BL/6J mice were exposed to 0 Gy, 0.5 Gy, or 1.5 Gy simplified simulated 5 ion GCR (GCRsim). Exposure to microgravity was simulated using hindlimb unloading (HLU). At nine months post exposure, the mice were terminated to assess for the presence of exposure-induced epigenetic alterations. DNA hypermethylation in the 5'-untranslated regions of Lx_III, MdFanc_I, and MdMus_II families of the Long Interspersed Nucleotide Element 1 (LINE-1) was observed in the lungs of male mice. These effects were accompanied by increases in the expression of DNA methyltransferases Dnmt1 and Dnmt3a, and methyl-binding protein, MecP2. Trends towards DNA hypomethylation, although insignificant, were observed in the lungs of female mice in the HLU + 1.5Gy GCRsim group. Altogether, our findings suggest persistent and sex-specific epigenetic reprogramming in the mouse lung and suggests that the DNA methylation status of LINE-1 can serve as a robust and reliable biomarker of previous radiation exposure.

The role of exosomal hsa-miR-125b-5p and hsa-miR-320c as non-invasive biomarkers in high-radon areas of Kazakhstan

ABSTRACT Background Radon, a radioactive gas, is a significant risk factor for lung cancer, especially in non-smokers. This study examines the expression of exosomal microRNAs (miRNAs) as potential biomarkers for radon-induced effects. Methods A total of 109 participants from high- and low-radon areas in Kazakhstan were included. Exosomal hsa-miR-125b-5p and hsa-miR-320c levels were quantified using real-time PCR. Results Results revealed a 25.4-fold increase in hsa-miR-125b-5p and a 12.5-fold decrease in hsa-miR-320c in participants exposed to high radon levels compared to controls. Bioinformatic analysis identified key target genes, such as PRDM1 and IRF4, which are implicated in cancer development. Conclusion These findings suggest that exosomal miRNAs could serve as non-invasive biomarkers for radon exposure, offering potential for early diagnosis and monitoring of radon-induced lung cancer. The study underscores the need for further research to validate these miRNAs as reliable diagnostic tools.

Relationship between butyrylcholinesterase activity and hepatic transaminases: a cross-sectional study in agricultural workers from Peru

IntroductionChronic exposure to pesticides causes various adverse health effects, mainly at a neurological level. However, there is little evidence focused on liver tissue injury and transaminase activity as indicators of effect.MethodsA cross-sectional study was designed based on medical-occupational records of workers from an agro-export company in Peru to associate the levels of butyrylcholinesterase (BChE) transaminases (ALT and AST). Occupational medical records were reviewed to obtain demographic and occupational information and laboratory values of BChE activity and transaminases.ResultsWe evaluated 459 records, and 69.9% were men. The mean age was 34.9 ± 11.5 years. BChE, ALT, and AST levels were 6238.8 ± 709.1 U/l, 34.4 ± 12.5 U/l, and 22.4 ± 8.5 U/l, respectively. The proportion of inhibited BCHE and elevated transaminase levels was 15.3% and 21.6%, respectively. We found a significant association between BChE inhibition and elevation of transaminases (AST: PR = 0.798, 95%CI: 0.716–0.889; ALT: PR = 0.419, 95%CI: 0.239–0.736).ConclusionThe potential usefulness of transaminases is shown as a biomarker of exposure and monitoring in occupational health programs for the agro-industry.

Urinary Fluoride Levels Among Youth in the National Health and Nutrition Examination Survey (NHANES) 2015-2016: Potential Differences According to Race.

Urinary fluoride (UF) is the most well-established biomarker for fluoride exposure, and understanding its distribution can inform risk assessment for potential adverse systemic health effects. To our knowledge, this study is the first to report distributions of UF among youth according to sociodemographic factors in a nationally representative United States (US) sample. The study included 1191 children aged 6-11 years and 1217 adolescents aged 12-19 years from the National Health and Nutrition Examination Survey (NHANES) 2015-2016. We examined UF according to sociodemographic variables as well as Spearman correlations between UF and plasma fluoride. Survey-weighted quantile regression examined associations between tap water fluoride and UF levels adjusted for covariates. The average age of participants was 12.5 years. The median (IQR) UF and water fluoride concentrations were 0.52 (0.50) mg/L and 0.39 (0.54) mg/L, respectively. Children had higher UF levels than adolescents and males had higher UF levels than females. UF differed according to race/ethnicity among both children and adolescents. Specifically, non-Hispanic Black youth tended to have higher UF levels than all participants except for those classified as other race/multiracial. UF and plasma fluoride were moderately correlated for children and adolescents. Higher water fluoride levels were associated with higher UF levels, and the magnitudes of association were larger at higher quantiles of UF (β = 0.14, p < 0.001; β = 0.20, p< 0.001 at the 25th and 50th quantiles, respectively). The magnitude of association between water fluoride and UF was the largest for non-Hispanic Black participants (predictive margin = 0.3, p < 0.001). Non-Hispanic Black youth in the US may have greater fluoride exposure and receive more of their fluoride intake from tap water than youth of other races/ethnicities. Factors contributing to potential racial/ethnic disparities in fluoride exposure within the US warrant further investigation so that they can be mitigated to reduce the potential for harm.

Dispersion-based cognitive intra-individual variability in former American football players: Association with traumatic encephalopathy syndrome, repetitive head impacts, and biomarkers

Background: Exposure to repetitive head impacts (RHI), such as those experienced in American football, is linked to cognitive dysfunction later in life. Traumatic encephalopathy syndrome (TES) is a proposed clinical syndrome thought to be linked to neuropath­ology of chronic traumatic encephalopathy (CTE), a condition associated with RHI from football. Cognitive intra-individual variability (d-CIIV) measures test-score dispersion, indicating cognitive dysfunction. This study examined d-CIIV in former football players and its associations with TES diagnosis, RHI exposure, and DTI and CSF biomarkers. Methods: Data included 237 males (45–74 years) from DIAGNOSE CTE Research Project, including former professional and college football players (COL) (n = 173) and asymptomatic men without RHI or TBI (n = 55). Participants completed neuropsychological tests. TES diagnosis was based on 2021 NINDS TES criteria. Years of football play and a cumulative head impact index (CHII) measured RHI exposure. Lumipulse technology was used for CSF assays. DTI fractional anisotropy assessed white matter integrity. Coefficient of variation (CoV) measured d-CIIV. ANCOVA compared d-CIIV among groups (football versus control; TES-status). Pearson correlations and linear regressions tested associations between d-CIIV, RHI exposure, and CSF and DTI biomarkers. Results: Former professional players had higher d-CIIV than controls (F(7, 194) = 2.87, p = .007). d-CIIV was associated with TES diagnosis (F(8, 146) = 9.063, p < .001), with highest d-CIIV in TES Possible/Probable-CTE. Higher d-CIIV correlated with higher CHII scores (r = 0.19), reduced CSF Aβ1–42 (β = −0.302), increased p-tau181 (β = 0.374), and reduced DTI FA (β = −0.202). Conclusion: d-CIIV is linked to RHI exposure and TES diagnosis in former football players, with associated changes in CSF biomarkers and white matter integrity.

Uncovering the Metabolic Footprint of New Psychoactive Substances by Metabolomics: A Systematic Review.

New psychoactive substances (NPSs) emerged in the 2000s as legal alternatives to illicit drugs and quickly became a huge public health threat due to their easy accessibility online, limited information, and misleading labels. Synthetic cannabinoids and synthetic cathinones are the most reported groups of NPSs. Despite NPSs being widely studied, due to their structural diversity and the constant emergence of novel compounds with unknown properties, the development of new techniques is required to clarify their mode of action and evaluate their toxicological effects. Metabolomics has been a useful tool to evaluate the metabolic effects of several xenobiotics. Herein, a systematic review was performed, following PRISMA guidelines, regarding metabolomic studies on synthetic cathinones and synthetic cannabinoids to evaluate their effects in cellular metabolism. In the studies, in vivo models were the most employed (86%) and the analysis mostly followed untargeted approaches (75%) using LC-MS techniques (67%). Both groups of NPSs seem to primarily interfere with energy metabolism-related pathways. Even though this type of study is still limited, metabolomics holds great promise as a tool to clarify mechanisms of actions, identify biomarkers of exposure, and explain the toxicological effects of NPSs.

Species Differences in the Biotransformation of Aflatoxin B1: Primary Determinants of Relative Carcinogenic Potency in Different Animal Species.

It has been known since the early days of the discovery of aflatoxin B1 (AFB1) that there were large species differences in susceptibility to AFB1. It was also evident early on that AFB1 itself was not toxic but required bioactivation to a reactive form. Over the past 60 years there have been thousands of studies to delineate the role of ~10 specific biotransformation pathways of AFB1, both phase I (oxidation, reduction) and phase II (hydrolysis, conjugation, secondary oxidations, and reductions of phase I metabolites). This review provides a historical context and substantive analysis of each of these pathways as contributors to species differences in AFB1 hepatoxicity and carcinogenicity. Since the discovery of AFB1 as the toxic contaminant in groundnut meal that led to Turkey X diseases in 1960, there have been over 15,000 publications related to aflatoxins, of which nearly 8000 have addressed the significance of biotransformation (metabolism, in the older literature) of AFB1. While it is impossible to give justice to all of these studies, this review provides a historical perspective on the major discoveries related to species differences in the biotransformation of AFB1 and sets the stage for discussion of other papers in this Special Issue of the important role that AFB1 metabolites have played as biomarkers of exposure and effect in thousands of human studies on the toxic effects of aflatoxins. Dr. John Groopman has played a leading role in every step of the way-from initial laboratory studies on specific AFB1 metabolites to the application of molecular biomarkers in epidemiological studies associating dietary AFB1 exposure with liver cancer, and the design and conduct of chemoprevention clinical trials to reduce cancer risk from unavoidable aflatoxin exposures by alteration of specific AFB1 biotransformation pathways. This article is written in honor of Dr. Groopman's many contributions in this area.

Biomonitoring PhIP, a Potential Prostatic Carcinogen, in the Hair of Healthy Men of African and European Ancestry.

Heterocyclic aromatic amines (HAAs), formed during the cooking of meat, are potential human carcinogens, underscoring the need for long-lived biomarkers to assess exposure and cancer risk. Frequent consumption of well-done meats containing 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a prevalent HAA that is a prostatic carcinogen in rodents and DNA-damaging agent in human prostate cells, has been linked to aggressive prostate cancer (PC) pathology. African American (AA) men face nearly twice the risk for developing and dying from PC compared to White men. We previously demonstrated that scalp hair is a reliable biospecimen for measuring PhIP intake using liquid chromatography-mass spectrometry. This study aimed to determine whether PhIP dietary intake is higher in AA men, potentially contributing to this health disparity. Healthy AA men were found to have a significantly higher mean hair PhIP level (2.12-fold) than White men on free-choice diets. However, this difference was not statistically significant after adjusting for melanin content. Further research is needed to understand how hair pigmentation, follicular density, and other morphological features of hair influence PhIP accumulation. These insights can improve the accuracy of using hair PhIP levels as a biomarker for exposure and its potential associations with cancer risk.

Comparative glucocorticoid receptor agonism: In silico, in vitro, and in vivo and identification of potential biomarkers for synthetic glucocorticoid exposure

Abstract The glucocorticoid receptor (GR) is present in almost every vertebrate cell and is utilized in many biological processes. Despite an abundance of mammalian data, the structural conservation of the receptor and cross-species susceptibility, particularly for aquatic species, has not been well defined. Efforts to reduce, refine, and/or replace animal testing have increased, driving the impetus to advance development of new approach methodologies (NAMs). Here we used in silico, in vitro, and in vivo methods to elucidate a greater understanding of receptor-mediated effects of synthetic glucocorticoid exposure in teleost fish. Evolutionary conservation of amino acid residues critical for transcriptional activation was confirmed in silico using sequence alignment to predict across species susceptibility. Subsequent in vitro assays using zebrafish and human GR provided evidence of physiological congruence of GR agonism. Finally, adult fathead minnows (Pimephales promelas) were exposed in vivo to the synthetic glucocorticoids, dexamethasone (0.04, 400, 4,000 µg/L) and beclomethasone dipropionate (130 µg/L), and GR agonism confirmed via digital polymerase chain reaction; in addition, EcoToxChip analyses identified potential mRNA biomarkers following glucocorticoid exposure. These findings support the use of NAMs to potentially reduce multispecies in vivo experimentation while providing empirical evidence that expands the taxonomic domain of applicability for the GR agonism molecular initiating event within the broader GR agonism adverse outcome pathway network.

Benzo[a]pyrene and phenanthrene hemoglobin adducts as biomarkers of longer-term air pollution exposure.

Urinary hydroxylated-polycyclic aromatic hydrocarbons (PAHs), with half-life less than 2 days, are established biomarkers of short-term exposure to PAHs, a ubiquitous constituent of air pollution mixture. In this study, we explore the use of PAHs-hemoglobin adducts as biomarkers of longer-term exposure to air pollution by leveraging an extant resource of blood samples collected from 235 pregnant women residing in Rochester, NY. We measured red blood cells for benzo[a]pyrene-tetrols (BaPT) and phenanthrene-tetrols (PHET), both of which are hydrolysis products of PAH-hemoglobin adduct. We utilized previously estimated PM2.5 and NO2 concentrations within the 1 km2 grid surrounding each participant's residence, calculated for up to 20 weeks before the blood collection date. Associations between PAHs tetrols and cumulative exposures to ambient PM2.5 or NO2 over different time periods were examined using a linear mixed-effects model with participant-specific random intercepts adjusting for season, gestation age, maternal age, maternal income level, and pre-pregnancy BMI. We observed positive associations between PHET concentration and cumulative PM2.5 exposure over gestational weeks 12-17, and between BaPT concentration and cumulative PM2.5 exposure over gestational weeks 3-16 prior to sample collection. Each interquartile range (IQR) increase in 14 week PM2.5 exposure (1.26 μg m-3) was associated with a 9.02% (95% CI: 0.30%, 17.7%) increase in PHET and a 12.8% (95% CI: 1.09%, 23.5%) increase in BaPT levels. In contrast, no associations were observed between either biomarker and cumulative NO2 exposures. These findings underscore the potential of PAH-hemoglobin adducts as longer-term (weeks to 4 months) exposure biomarkers of ambient PM2.5.