Primary cilia are sensory organelles essential for signaling and defects in formation, maintenance or structure underlie diverse ciliopathies. Here, we identify lysine demethylase 4A (KDM4A) as a previously unrecognized mediator of ciliogenesis. Using genetic depletion and pharmacologic inhibition, we show that KDM4A is required for cilia assembly and maintenance. Super-resolution imaging reveals KDM4A localization at the basal body, where it distinctively wraps around the centrioles. We uncover a direct interaction between KDM4A and Rootletin (CROCC), a structural protein mediating centriole cohesion, and demonstrate that KDM4A loss increases inter-centriolar distances, implicating basal body architecture in ciliary failure. Together, these findings define a demethylase-centrosome axis that integrates KDM4A activity with organelle biology, revealing new mechanisms underlying ciliogenesis.

Environmental toxicant exposures can induce widespread alterations in both the transcriptome and epigenome of mammals, and directly contribute to the increased risk of various diseases, including cardiovascular disorders, cancer, and neurological disorders. To evaluate how early-life toxicants produce long-term impacts on the transcriptome and epigenome in mice, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 3607 multi-omics datasets from longitudinal studies in mice. The molecular changes in responding to distinct environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), were systematically identified and visualized on an integrative platform, ToxiTaRGET, to allow quickly search and browse by researchers. ToxiTaRGET houses a rich repository of molecular signatures, including gene expression, chromatin accessibility, and DNA methylation profiles, in response to early-life toxicant exposures. These molecular signatures span multiple biologically important tissues in both male and female mice at three distinct life stages, offering a valuable resource for the environmental health and toxicogenomic research communities.

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

Renal medullary carcinoma (RMC) is defined by the loss of the SMARCB1 tumor suppressor and represents one of the most aggressive kidney cancers, predominantly affecting young individuals of African descent with the sickle cell trait. RMC exhibits rapid progression, and poor response to standard therapies, with a median survival of only 13 months following diagnosis. In pursuit of more effective treatments, we launched two clinical trials specifically for patients with RMC evaluating anti-PD1 + anti-CTLA4 immune checkpoint therapy (ICT) with nivolumab + ipilimumab (ClinicalTrials.gov identifier: NCT03274258) and anti-PD1 + anti-LAG3 ICT using nivolumab + relatlimab (ClinicalTrials.gov identifier: NCT05347212). However, both trials were terminated early for futility due to resistance and hyperprogression by the established consensus Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 radiological criteria in Matos et al. Clin Cancer Res. 2020 (PMID: 31757877). Co-clinical experiments testing the same ICT regimens in our immunocompetent somatic mosaic genetically engineered mouse model (GEMM) of RMC demonstrated similar patterns of resistance and hyperprogression with ICT compared with IgG control. The combination of anti-PD1 with either anti-CTLA4 or anti-LAG3 significantly accelerated primary tumor progression and markedly increased metastatic burdens in the lung and liver of RMC mice. Comprehensive analyses, including longitudinally collected single-cell RNA sequencing from human RMC patient samples and RNA sequencing of GEMM RMC tumors revealed significant transcriptional reprogramming, enhanced tumor proliferation, activation of oncogenic pathways, and a shift toward myeloid-specific gene expression by RMC tumor cells in response to ICT. In our RMC mouse models, tumor cells have been engineered to express green fluorescent protein (GFP), enabling us to distinguish them from non-malignant mouse cells. Accordingly, multiplex immunofluorescence (mIF) revealed that tumor tissues from mice treated with ICT showed a significant increase of tumor cells co-expressing GFP and myeloid markers such as CD68, F4/80 and S100A9. Differential patterns of resistance and hyperprogression when RMC mice were treated with monotherapies targeting PD1, CTLA4, or LAG3. To counteract ICT-induced hyperprogression, we tested the CEBPB/p300 complex inhibitor IACS16898 which successfully induced tumor responses when combined with ICT in our RMC GEMM. IACS16898 treatment significantly reduced the expression of myeloid-associated markers on GFP+ tumor cells. Our study not only elucidates a novel mechanism of resistance and hyperprogression to PD1 plus either CTLA4 or LAG3 inhibition in SMARCB1-deficient cancers but also provides a foundation for targeting oncogenic and resistance pathways in RMC treated with distinct immunotherapy regimens. Jing Qian, Melinda Soeung, Xinmiao Yan, Kai Yu, Ciro Zanca, Li Zhang, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca Slack Tidwell, Hania Khan, Fei Duan, Menuka Karki, Rong He, Courtney N. Le, Truong N.A. Lam, Nirjar Bhattacharya, Mariah N. Williams, David H. Peng, Rutvi Shah, I-Lin Ho, Ningping Feng, Niki Millward Zacharias, Rahul Anil Sheth, Tharakeswara K. Bathala, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Hsinyi Lu, Cara L. Haymaker, Ignacio I. Wistuba, Andrew Futreal, Andrea Viale, Timothy Heffernan, Giulio F. Draetta, Nazir M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Unravelling the mechanisms of resistance and hyperprogression of renal medullary carcinoma to immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 646.

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was halted for futility at a prespecified interim analysis as all 10 treated patients experienced rapid disease progression. 5/10 met radiological criteria for hyperprogression and median progression-free survival (secondary outcome) was 1.38 months (95% confidence interval: 1.28, 1.60). In a post-hoc single-cell RNA sequencing analysis, data from patients with RMC before and after nivolumab plus ipilimumab treatment indicated that immune checkpoint therapy (ICT) triggered an interferon-γ response that induced a "myeloid mimicry" program in tumor cells, regulated by the CEBPB / p300 axis and linked to proliferation and hyperprogression. In preclinical experiments using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, combination ICT accelerated tumor growth while activating myeloid-affiliated transcriptional circuits. Selective pharmacologic inhibition of p300 suppressed this program and restored sensitivity to ICT. These findings reveal an adaptive mechanism of resistance to ICT in RMC and support targeting master myeloid regulators to enable therapeutic benefit.

Environmental exposures during early life are increasingly recognized as key determinants of health and disease in adulthood (1) but how they durably shape disease risk across the lifecourse remains poorly understood. Here, we show early-life toxicants reprogram the epigenome and redirect age-associated transcriptional trajectories-polarizing cell-specific gene expression and predisposing to liver disease. The TaRGET II Consortium (2) exposed mice to diverse toxicants from pre-conception through weaning and followed individual animals though adulthood with multi-omic profiling. Analysis of >800 liver epigenomic and transcriptomic profiles from male and female mice revealed that despite differing chemical classes and mechanisms of action, multiple toxicants - BPA, TBT, TCDD, and PM2.5 - produced exposure signatures that converged on genes normally differentially expressed in the liver as animals aged. Histone modifications at enhancers emerged as key targets for epigenomic reprogramming of these liver aging-associated plasticity genes (LAAsP genes). Reprogrammed LAAsP genes exhibited a striking, bidirectional signature. In hepatocytes LAAsP genes that typically increase with age, such as those involved in metabolism, were repressed. Conversely, in non-parenchymal cells, LAAsP genes that normally decline with age, including those for extracellular matrix production, remained elevated. An attenuated LAAsP gene signature and polarized transcriptional states were mirrored in human liver disease and hepatocellular carcinoma and could effectively distinguished healthy from diseased human liver transcriptomes. Together, these findings demonstrate that early-life environmental exposures can hijack the plasticity of epigenomic aging, durably reprogram expression trajectories, and lock in polarized states that foreshadow chronic liver disease and cancer.

Centrosomes play a fundamental role in nucleating and organizing microtubules in the cell and are vital for faithful chromosome segregation and maintenance of genomic stability. Loss of structural or functional integrity of centrosomes causes genomic instability and is a driver of oncogenesis. Here we identify lysine demethylase 4A (KDM4A), an epigenetic 'eraser' of chromatin methyl marks, as a centrosome-localized protein, visualized at the nanometer-scale resolution. We additionally uncovered that KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis and integrity; a previously unknown functionality unlinked to altered expression of genes regulating centrosome number. We find that KDM4A interacts with and localizes to the centrosome in all stages of mitosis, where it maintains centrosome numbers and centriole engagement during mitosis. Loss of KDM4A results in supernumerary centrosomes and accrual of chromosome segregation errors including chromatin bridges and micronuclei, markers of genomic instability. In summary, these data highlight a previously unknown role for an epigenetic 'eraser' regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.

Exposure to toxic substances, particularly early in life, can perturb epigenomic marks linked to disease susceptibility. Human studies of environmental exposures often rely on surrogate tissues such as blood, but toxicant accumulation differs across organs and results in tissue-specific responses. Thus, understanding whether exposure-induced epigenomic alterations in surrogate tissues such as blood reflect changes in toxicant target tissues, such as liver, is essential for designing and interpreting environmental epigenetic studies. To address this knowledge gap, we systematically analyzed 1,013 multi-omics data from the TaRGET II Consortium, comparing molecular responses in mouse liver and blood following perinatal exposure to arsenic, lead, bisphenol A, tributyltin, di-2-ethylhexyl phthalate, tetrachlorodibenzo-p-dioxin, or air pollution in the form of particulate matter < 2.5μm (PM2.5). Most toxicant-induced molecular changes were tissue-specific, yet we identified a subset of co-regulated genes and regulatory elements in liver and blood in response to early-life exposure to toxicants. Moreover, we discovered that specific pathways, such as immune-related processes, were commonly affected by exposures in both tissues, and transcription factors, including Klf, Jun, Ets1, and Cebp, emerged as shared regulators. While molecular alterations are infrequently conserved between tissues following toxicant exposure, the shared alterations in transcription factors and biological pathways may provide a strategy to link effects in surrogate tissues to target tissues.

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 2,570 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser. This resource from target (liver, brain, lung, heart) and surrogate (blood) tissues at weaning (3 weeks) and two adult time-points (5 and 10 months) characterized the molecular response to arsenic (As), lead (Pb), bisphenol-A (BPA), di-2-ethylhexyl phthalate(DEHP), tributyltin (TBT), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter with a diameter of <2.5μm (PM2.5). The findings revealed persistent, toxicant-specific, sex-dependent epigenomic and transcriptomic perturbations, resulting in disrupted expression of 14,908 genes, altered chromatin accessibility at 87,409 regulatory elements, DNA methylation changes at 113,186 genomic regions, and chromatin state switching of histone modifications. The resulting high-resolution map of how environmental exposures reprogram the epigenome and transcriptome is broadly accessible via ToxiTaRGET database, offering unparalleled opportunities for the scientific community to investigate the molecular underpinnings of environmental toxicant exposures and their contributions to disease pathogenesis.

Environmental toxicant exposures can induce widespread alterations in both the transcriptome and epigenome of mammals, and directly contribute to the increased risk of various diseases, including cardiovascular disorders, cancer, and neurological disorders. To evaluate how early-life toxicants produce long-term impacts on the transcriptome and epigenome in mice, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 3,607 multi-omics from longitudinal studies in mice. The molecular changes in responding to distinct environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), were systematically identified and visualized on an integrative platform, ToxiTaRGET, to allow quickly search and browse by researchers. ToxiTaRGET houses a rich repository of molecular signatures, including gene expression, chromatin accessibility, and DNA methylation profiles, in response to early-life toxicant exposures. These molecular signatures span multiple biologically important tissues in both male and female mice at three distinct life stages, offering a valuable resource for the environmental health and toxicogenomic research communities.

Environmental exposures to toxic chemicals can profoundly alter the transcriptome and epigenome in both humans and animals, contributing to disease development across the lifespan. To elucidate how early-life exposure to toxicants exerts such persistent effects, the Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription II (TaRGET II) Consortium generated a landmark resource comprising 2,564 epigenomes and 1,043 transcriptomes from longitudinal studies in mice. All data are publicly available through the TaRGET II data portal and the WashU Epigenome Browser. This resource from target (liver, brain, lung, heart) and surrogate (blood) tissues at weaning (3 weeks) and two adult time-points (5 and 10 months) characterized the molecular response to arsenic (As), lead (Pb), bisphenol-A (BPA), di-2-ethylhexyl phthalate(DEHP), tributyltin (TBT), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter with a diameter of <2.5μm (PM2.5). The findings revealed persistent, toxicant-specific, sex-dependent epigenomic and transcriptomic perturbations, resulting in disrupted expression of 14,908 genes, altered chromatin accessibility at 87,409 regulatory elements, DNA methylation changes at 113,186 genomic regions, and chromatin state switching of histone modifications. The resulting high-resolution map of how environmental exposures reprogram the epigenome and transcriptome is broadly accessible via ToxiTaRGET database, offering unparalleled opportunities for the scientific community to investigate the molecular underpinnings of environmental toxicant exposures and their contributions to disease pathogenesis.

Transposable elements (TEs) are mobile DNA sequences that constitute a significant portion of mammalian genomes. While typically silenced by epigenetic mechanisms, mounting evidence indicates TEs can regulate gene expression and chromatin architecture. However, their regulatory roles under various environmental exposures remain largely unexplored. In this study, we investigate the regulatory functions of TEs in mouse liver tissue following early-life exposure to environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di-2-ethylhexyl phthalate (DEHP), tetrachlorodibenzo-p-dioxin (TCDD), and particulate matter less than 2.5 micrometers (PM2.5). These toxicants are linked to various health issues, including neurodevelopmental deficits, metabolic and immune dysfunction, and increased cancer risks. Integrative analysis of 351 multi-omics datasets from liver tissues of 5-month-old mice indicated that early-life environmental exposures significantly altered chromatin accessibility and expression of TEs in later life stage, revealing distinct exposure-specific signatures and sex-dependent responses. 6,699 TEs were identified with altered chromatin accessibility, mostly in non-coding regions, suggesting potential impact on gene regulation. Within these TEs, LINE elements were enriched in genes involved in metabolic pathways, while LTR elements, particularly the ORR1E subfamily, were predominantly associated with immune-related genes. Additionally, we identified 140 TE-gene chimeric transcripts with TE-derived novel transcription start sites, highlighting TE-contributed transcriptional plasticity. Our findings depict a comprehensive landscape of TE regulation under early-life toxicant exposures, offering insights into TEs biology and their impact on health and disease.

PURPOSE:Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC. EXPERIMENTAL DESIGN:Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA sequencing and histone chromatin immunoprecipitation sequencing. The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 reexpression. RESULTS:MUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) patients with RMC and correlated significantly with metastatic tumor burden (P = 0.03). Functional studies in RMC cell lines demonstrated that SMARCB1 reexpression significantly reduced MUC16 expression. CONCLUSIONS:The correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.

INTRODUCTION:After the Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics Promise to Address Comprehensive Toxics (PACT) Act in 2022, there has been a great interest in studying toxic exposures encountered during military service. Development of epigenomic biomarkers for exposures could facilitate understanding of exposure-related health effects, but such testing could also provide unwanted information. MATERIALS AND METHODS:We explored attitudes toward epigenomic biomarker research and the potential to test for past exposures using semistructured interviews with Veterans (n = 22) who experienced potentially harmful exposures. RESULTS:Twenty Veterans said they would hypothetically want to receive epigenomic information related to their toxic exposures and potential health impacts as part of a research study. Veterans identified 9 potential benefits, including promoting insights concerning intergenerational health, identification of early health interventions, and additional knowledge or explanation for their experiences. Sixteen participants noted potential risks, including psychological distress, receiving nonactionable, uncertain, or inaccurate results, and privacy and discrimination risks. Ten participants identified at least 1 condition in their children that they thought could be related to their exposure and most said they would be interested in receiving research results related to their children's and grandchildren's risk. CONCLUSION:Results suggest that Veterans might welcome benefits of epigenomic research related to military exposures, yet have some concerns about potential negative impacts.

The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, Environmental Health Perspectives, 128 (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver tissue from mice that developed tumors (i.e., "high-risk") and equivalently exposed mice did not (i.e., "low-risk"). Blood transcriptomic signatures separated TBT-exposed from vehicle controls but did not discriminate between animals that developed tumors versus those that did not. However, uninvolved liver tissue of mice with tumors exhibited transcriptomic and epigenomic signatures distinct from liver tissue of mice without tumors and had many features in common with tumors. These high-risk transcriptomic and epigenomic features were also found in 10/26 TBT-exposed mice at 5 months, indicating that this risk signature preceded tumor development. Thus, while early life exposure to TBT exhibits variable penetrance for hepatic tumor development, indicating TBT exposure is not sufficient for liver tumorigenesis, increased risk for hepatic tumor development is linked to epigenomic and transcriptomic reprogramming of the liver induced by this EDC.

IntroductionThe Maternal and Infant Environmental Health Riskscape (MIEHR) Center was established to address the interplay among chemical and non-chemical stressors in the biological, physical, social, and built environments that disproportionately impact perinatal health among Black pregnant people in a large and diverse urban area with documented disparities in the U.S.MethodsThe MIEHR cohort is recruiting non-Hispanic Black and non-Hispanic white pregnant people who deliver their infants at major obstetric hospitals in Houston, Texas. At enrollment, all participants are asked to provide urine samples for chemical [metals, cotinine, and polycyclic aromatic hydrocarbons (PAHs)] analyses and blood samples. A subset of the cohort is asked to provide oral and vaginal swabs, and fecal samples. Questionnaire and electronic health record data gather information about residential address history during pregnancy, pregnancy history and prenatal care, sociodemographic and lifestyle factors, experiences of discrimination and stress, and sources of social support. Using information on where a participant lived during their pregnancy, features of their neighborhood environment are characterized. We provide summaries of key individual- and neighborhood-level features of the entire cohort, as well as for Black and white participants separately.ResultsBetween April 2021 and February 2023, 1,244 pregnant people were recruited. Nearly all participants provided urine samples and slightly less than half provided blood samples. PAH exposure patterns as assessed on 47% of participants thus far showed varying levels depending on metabolite as compared to previous studies. Additionally, analyses suggest differences between Black and white pregnant people in experiences of discrimination, stress, and levels of social support, as well as in neighborhood characteristics.DiscussionOur findings to date highlight racial differences in experiences of discrimination, stress, and levels of support, as well as neighborhood characteristics. Recruitment of the cohort is ongoing and additional neighborhood metrics are being constructed. Biospecimens will be analyzed for metals and PAH metabolites (urine samples), miRNAs (plasma samples) and the microbiome (oral swabs). Once enrollment ends, formal assessments are planned to elucidate individual- and neighborhood-level features in the environmental riskscape that contribute to Black-White disparities in perinatal health.

BackgroundGestational nutrition can protect against adverse neurodevelopmental outcomes.ObjectivesWe developed a short tool for collecting maternal nutritional intake during pregnancy to facilitate research in this area and compared its retrospective use to prospectively-collected food frequency questionnaires (FFQ).MethodsMaternal nutritional intake was retrospectively assessed using three versions (full interview, full self-administered online, and shortened interview) of the Early Life Exposure Assessment Tool (ELEAT) among participants of the MARBLES pregnancy cohort study of younger siblings of autistic children. Retrospective responses were compared with responses to supplement questions and the validated 2005 Block FFQ prospectively collected in MARBLES during pregnancies 2–7 years prior. ELEAT nutrient values were calculated using reported food intake frequencies and nutrient values from the USDA nutrient database. Correlations between retrospectively- and prospectively-reported intake were evaluated using Kappa coefficients, Youden's J, and Spearman Rank Correlation Coefficients (rs).ResultsMARBLES FFQ dietary intakes were compared among 54 women who completed the ELEAT full form including 12 online, and among 23 who completed the ELEAT short form. Correlations across most foods were fair to moderate. Most ELEAT quantified nutrient values were moderately correlated (rs = 0.3–0.6) with those on the Block FFQ. Supplement questions in both MARBLES and the ELEAT were completed by 114 women. Kappas were moderate for whether or not supplements were taken, but modest for timing. Correlations varied by version and child diagnosis or concerns, and were higher when mothers completed the ELEAT when their child was 4 years old or younger.ConclusionsWith recall up to several years, ELEAT dietary and supplement module responses were modestly to moderately reliable and produced nutrient values moderately correlated with prospectively-collected measures. The ELEAT dietary and vitamin supplements modules can be used to rank participants in terms of intake of several nutrients relevant for neurodevelopment.

AbstractBackgroundWith the signing of the PACT Act in 2022, there is great interest and investment in studying toxic exposures encountered during military service. One way to address this is through the identification of epigenomic biomarkers associated with exposures. There is increasing evidence suggesting that exposure to toxic substances may result in alterations to DNA methylation and resultant gene expression. These epigenomic changes may lead to adverse health effects for exposed individuals and their offspring. While the development of epigenomic biomarkers for exposures could facilitate understanding of these exposure-related health effects, such testing could also provide unwanted information.ObjectivesExplore Veterans’ attitudes toward epigenomic biomarker research and the potential to test for past exposures that could pose intergenerational risk.MethodsSemi-structured interviews with Veterans (n=22) who experienced potentially harmful exposures during their military service.ResultsTwenty Veterans said they would hypothetically want to receive epigenomic information related to their toxic exposures and potential health impacts as part of a research study. Veterans identified nine potential benefits of this research, including promoting insights concerning intergenerational health, identification of early health interventions to mitigate the impact of exposures, and additional knowledge or explanation for their experiences. At the same time, 16 participants noted potential risks, including psychological distress in response to results, concerns about receiving non-actionable, uncertain, or inaccurate results, and issues related to privacy and discrimination. Ten participants also identified at least one condition in their children that they thought could be related to their exposure and most said they would be interested in receiving research results related to their children’s and grandchildren’s risk of developing a health condition associated with their exposure.DiscussionResults suggest that Veterans might welcome benefits of epigenomic research related to military exposures yet have some concerns about potential negative impacts.