Altered extracellular matrix-related pathways accelerate the transition from normal to prefibroid myometrium in Black women.

BACKGROUND: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive. OBJECTIVE: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women. STUDY DESIGN: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5-12), western blot (sample size range=5-6), and immunohistochemistry techniques (sample size range=9-16). RESULTS: The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix-related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women. CONCLUSION: These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

Neurodevelopment and Metabolism in the Maternal-Placental-Fetal Unit.

Importance: Disturbances in maternal, placental, and fetal metabolism are associated with developmental outcomes. Associations of maternal, placental, and fetal metabolism with subsequent neurodevelopmental outcomes in the child are understudied. Objective: To investigate the metabolic associations within the maternal-placental-fetal unit and subsequent neurodevelopmental outcomes in younger siblings of children with autism spectrum disorder (ASD). Design, Setting, and Participants: This cohort study was conducted within a subset of the Markers of Autism Risk in Babies, Learning Early Signs (MARBLES) cohort. MARBLES is a prospective birth cohort of younger siblings of children with ASD assessed for neurodevelopmental outcomes at approximately age 36 months. Participants in MARBLES were recruited through the UC Davis MIND Institute. This subset of the MARBLES cohort included younger siblings born between 2009 and 2015. Maternal third trimester serum, placental tissue, and umbilical cord serum samples were collected from participants. Only pregnancies with at least 2 of these sample types were included in this analysis. Data analysis was conducted from March 1, 2023, to March 15, 2024. Exposures: Quantitative metabolomics analysis was conducted on maternal third trimester serum, as well as placental tissue and umbilical cord serum collected at delivery. Main Outcomes and Measures: Using the Autism Diagnostic Observation Schedule and Mullen Scales of Early Learning, outcomes were classified as ASD, other nontypical development (non-TD), and typical development (TD). Results: This analysis included 100 maternal serum samples, 141 placental samples, and 124 umbilical cord serum samples from 152 pregnancies (median [IQR] maternal age, 34.6 [30.8-38.3] years; median [IQR] gestational age, 39.0 [38.6-39.7] weeks; 87 [57.2%] male infants). There was no evidence that the maternal third trimester serum metabolome was significantly associated with the other metabolomes. The placental and cord serum metabolomes were highly correlated (first latent variate pair: R2 = 0.75; P < .001) and the variate scores for each tissue were significantly associated with reduced risk of non-TD (placenta: relative risk [RR], 0.13; 95% CI, 0.02-0.71; cord: RR, 0.13; 95% CI, 0.03-0.70) but not ASD (placenta: RR, 1.09; 95% CI, 0.42-2.81; cord: RR, 0.63; 95% CI, 0.23-1.73) compared with the TD reference group. Conclusions and Relevance: In this cohort study of children with high familial risk of ASD, placental and cord serum metabolism at delivery were highly correlated. Furthermore, placental and cord serum metabolic profiles were associated with risk of non-TD.

"Holy cow, where do I sign up?" Attitudes of Military Veterans toward Epigenomic Biomarker Toxic Exposure Testing.

Background: With 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. Objectives: Explore Veterans' attitudes toward epigenomic biomarker research and the potential to test for past exposures that could pose intergenerational risk. Methods: Semi-structured interviews with Veterans (n=22) who experienced potentially harmful exposures during their military service. 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 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. Discussion: Results suggest that Veterans might welcome benefits of epigenomic research related to military exposures yet have some concerns about potential negative impacts.

The Maternal and Infant Environmental Health Riskscape study of perinatal disparities in greater Houston: rationale, study design and participant profiles.

Introduction: The 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. Methods: The 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. Results: Between 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. Discussion: Our 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.

Lysine Demethylase 4A is a Centrosome Associated Protein Required for Centrosome Integrity and Genomic Stability.

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. The lysine demethylase 4A (KDM4A) is an epigenetic 'eraser' of chromatin methyl marks, which we show also localizes to the centrosome with single molecule resolution. We additionally discovered KDM4A demethylase enzymatic activity is required to maintain centrosome homeostasis, and is required for centrosome integrity, a new functionality unlinked to altered expression of genes regulating centrosome number. We find rather, that KDM4A interacts with both mother and daughter centriolar proteins to localize to the centrosome in all stages of 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 novel role for an epigenetic 'eraser' regulating centrosome integrity, mitotic fidelity, and genomic stability at the centrosome.

TGFß signaling links early life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

SETD2 safeguards the genome against isochromosome formation.

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are likely due to faulty homologous recombination by RAD52. These data provide a mechanism for isochromosome generation and demonstrate that SETD2 and H3K36me3 are essential to prevent the formation of this common mutable chromatin structure known to initiate a cascade of genomic instability in cancer.

TGFß signaling links early-life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-months old Eker rats exposed neonatally to Diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. METHODS: We evaluated the IC50 concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naïve and platinum-experienced patient-derived xenograft (PDX) models of RMC. RESULTS: The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naïve and platinum-experienced PDX models of RMC (p < .01). CONCLUSIONS: Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.

Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

Background: Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development. Methods: A total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods. Results: Gestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test. Conclusions: Although the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

SMARCB1 regulates the hypoxic stress response in sickle cell trait.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

A precision environmental health approach to prevention of human disease.

Human health is determined by the interaction of our environment with the genome, epigenome, and microbiome, which shape the transcriptomic, proteomic, and metabolomic landscape of cells and tissues. Precision environmental health is an emerging field leveraging environmental and system-level ('omic) data to understand underlying environmental causes of disease, identify biomarkers of exposure and response, and develop new prevention and intervention strategies. In this article we provide real-life illustrations of the utility of precision environmental health approaches, identify current challenges in the field, and outline new opportunities to promote health through a precision environmental health framework.

Maternal Serum and Placental Metabolomes in Association with Prenatal Phthalate Exposure and Neurodevelopmental Outcomes in the MARBLES Cohort.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using 1H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. We conclude that in this model, maternal obesity was associated with changes in the infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic factors.

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques.

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors.

Placental morphology in association with autism-related traits in the EARLI study.

BACKGROUND: In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. METHODS: Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). RESULTS: In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. CONCLUSIONS: Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism.

BACKGROUND: Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. RESULTS: We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085, renamed NHIP. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP-associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence. CONCLUSIONS: Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.

Responding to Natural and Industrial Disasters: Partnerships and Lessons Learned.

OBJECTIVES: The aim of this study was to provide insights learned from disaster research response (DR2) efforts following Hurricane Harvey in 2017 to launch DR2 activities following the Intercontinental Terminals Company (ITC) fire in Deer Park, Texas, in 2019. METHODS: A multidisciplinary group of academic, community, and government partners launched a myriad of DR2 activities. RESULTS: The DR2 response to Hurricane Harvey focused on enhancing environmental health literacy around clean-up efforts, measuring environmental contaminants in soil and water in impacted neighborhoods, and launching studies to evaluate the health impact of the disaster. The lessons learned after Harvey enabled rapid DR2 activities following the ITC fire, including air monitoring and administering surveys and in-depth interviews with affected residents. CONCLUSIONS: Embedding DR2 activities at academic institutions can enable rapid deployment of lessons learned from one disaster to enhance the response to subsequent disasters, even when those disasters are different. Our experience demonstrates the importance of academic institutions working with governmental and community partners to support timely disaster response efforts. Efforts enabled by such experience include providing health and safety training and consistent and reliable messaging, collecting time-sensitive and critical data in the wake of the event, and launching research to understand health impacts and improve resiliency.

Goals for Reaching Optimal Wellness (GROWell): A clinical trial protocol of a digital dietary intervention for pregnant and postpartum people with prenatal overweight or obesity.

BACKGROUND: Excess gestational weight gain (EGWG) is associated with multiple pregnancy complications and health risks for birthing people and their infants. Likewise, postpartum weight retention (PPWR), or not losing all pregnancy weight, has long-term health consequences. EGWG among people who enter pregnancy with overweight or obesity have worse obstetric outcomes and increased PPWR compared to women who gain within Institute of Medicine guidelines. METHODS: This study protocol describes the details of a blinded, randomized clinical trial of GROWell: Goals for Reaching Optimal Wellness, a mHealth tool designed to improve diet quality among people who enter pregnancy with overweight or obese BMIs to help them achieve appropriate GWG and safe postpartum pregnancy weight loss. Individuals with overweight and obesity will be randomly assigned to an attention control or intervention arm. The intervention group will receive personalized, goal-oriented text messages regarding dietary choices, while the attention control group will receive text messages about healthy pregnancy, labor, delivery, and early infancy. Both groups will complete online surveys at baseline, follow up, 3 and 6 months postpartum. RESULTS AND DISCUSSION: Currently, 162 subjects have been enrolled. Outcomes associated with GWG and pregnancy are expected in late 2023, while outcomes on postpartum weight retention GROWell adherence are expected in late 2024. The results of this trial will support the use of an evidence-based mHealth tool to be integrated into clinical practice to reduce EGWG and PPWR among pregnant people with overweight and obese BMIs, a resource that is currently lacking. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04449432. Registered on June 26, 2020.