Negative feedback between PTH1R and IGF1 through the Hedgehog pathway in mediating craniofacial bone remodeling
Fan et al. report that parathyroid hormone 1 receptor (PTH1R) couples bone formation and bone resorption by negatively regulating Hedgehog signaling and IGF1 production. The cover image shows a mouse molar with colocalized Gli1+ mesenchymal stem cells (red) and Runx2+ osteoblasts (green) during development.
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Research Articles
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Abstract
Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.
Authors
Quetzalli D. Angeles-Lopez, Jhonny Rodriguez-Lopez, Paula Agudelo Garcia, Jazmin Calyeca, Diana Álvarez, Marta Bueno, Lan N. Tu, Myriam Salazar-Terreros, Natalia Vanegas-Avendaño, Jordan E. Krull, Aigul Moldobaeva, Srimathi Bogamuwa, Stephanie S. Scott, Victor Peters, Brenda F. Reader, Sruti Shiva, Michael Jurczak, Mahboobe Ghaedi, Qin Ma, Toren Finkel, Mauricio Rojas, Ana L. Mora
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Fibrosis results from excessive extracellular matrix (ECM) deposition, which causes tissue stiffening and organ dysfunction. Activated fibroblasts, central to fibrosis, exhibit increased migration, proliferation, contraction, and ECM production. However, it remains unclear if the same fibroblast performs all of the processes that fall under the umbrella term of “activation.” Owing to fibroblast heterogeneity in connective tissues, subpopulations with specific functions may operate under distinct regulatory controls. Using a transgenic mouse model of skin fibrosis, we found that Mindin (also known as spondin-2), secreted by Snail-transgenic keratinocytes, differentially regulates fibroblast subpopulations. Mindin promotes migration and inflammatory gene expression in SCA1+ dermal fibroblasts via Fyn kinase. In contrast, it enhances contractility and collagen production in papillary CD26+ fibroblasts through c-Src signaling. Moreover, in the context of the fibrotic microenvironment of the tumor stroma, we found that differential responses of resident fibroblast subpopulations to Mindin extend to the generation of functionally heterogeneous cancer-associated fibroblasts. This study identifies Mindin as a key orchestrator of dermal fibroblast heterogeneity, reshaping cellular dynamics and signaling diversity in the complex landscapes of skin fibrosis and cancer.
Authors
Sunny Kataria, Isha Rana, Krithika Badarinath, Rania F. Zaarour, Gaurav Kansagara, Sultan Ahmed, Abrar Rizvi, Dyuti Saha, Binita Dam, Abhik Dutta, Ravindra K. Zirmire, Edries Yousaf Hajam, Pankaj Kumar, Akash Gulyani, Colin Jamora
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Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.
Authors
Emilie Jaune-Pons, Xiaoyi Wang, Fatemeh Mousavi, Zachary Klassen, Abdessamad El Kaoutari, Kurt Berger, Charis Johnson, Mickenzie B. Martin, Saloni Aggarwal, Sukhman Brar, Muhammad Khalid, Joanna F. Ryan, Parisa Shooshtari, Angela J. Mathison, Nelson Dusetti, Raul Urrutia, Gwen Lomberk, Christopher L. Pin
×Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor–GLP-1 receptor (GIPR–GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist–GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil–induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity.
Authors
Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker
×Highly multiplexed imaging reveals prognostic immune and stromal spatial biomarkers in breast cancer
Abstract
Spatial profiling of tissues promises to elucidate tumor-microenvironment interactions and generate prognostic and predictive biomarkers. We analyzed single-cell spatial data from 3 multiplex imaging technologies: cyclic immunofluorescence (CycIF) data we generated from 102 patients with breast cancer with clinical follow-up as well as publicly available mass cytometry and multiplex ion-beam imaging datasets. Similar single-cell phenotyping results across imaging platforms enabled combined analysis of epithelial phenotypes to delineate prognostic subtypes among patients who are estrogen-receptor+ (ER+). We utilized discovery and validation cohorts to identify biomarkers with prognostic value. Increased lymphocyte infiltration was independently associated with longer survival in triple-negative (TN) and high-proliferation ER+ breast tumors. An assessment of 10 spatial analysis methods revealed robust spatial biomarkers. In ER+ disease, quiescent stromal cells close to tumor were abundant in tumors with good prognoses, while tumor cell neighborhoods containing mixed fibroblast phenotypes were enriched in poor-prognosis tumors. In TN disease, macrophage/tumor and B/T lymphocyte neighbors were enriched, and lymphocytes were dispersed in good-prognosis tumors, while tumor cell neighborhoods containing vimentin+ fibroblasts were enriched in poor-prognosis tumors. In conclusion, we generated comparable single-cell spatial proteomic data from several clinical cohorts to enable prognostic spatial biomarker identification and validation.
Authors
Jennifer R. Eng, Elmar Bucher, Zhi Hu, Cameron R. Walker, Tyler Risom, Michael Angelo, Paula Gonzalez-Ericsson, Melinda E. Sanders, A. Bapsi Chakravarthy, Jennifer A. Pietenpol, Summer L. Gibbs, Rosalie C. Sears, Koei Chin
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In systemic lupus erythematosus (lupus), environmental effects acting within a permissive genetic background lead to autoimmune dysregulation. Dysfunction of CD4+ T cells contributes to pathology by providing help to autoreactive B and T cells, and CD4+ T cell dysfunction coincides with altered DNA methylation and histone modifications of select gene loci. However, chromatin accessibility states of distinct T cell subsets and mechanisms driving heterogeneous chromatin states across patients remain poorly understood. We defined the transcriptome and epigenome of multiple CD4+ T cell populations from patients with lupus and healthy individuals. Most patients with lupus, regardless of disease activity, had enhanced chromatin accessibility bearing hallmarks of inflammatory cytokine signals. Single-cell approaches revealed that chromatin changes extended to naive CD4+ T cells, uniformly affecting naive subpopulations. Transcriptional data and cellular and protein analyses suggested that the TNF family members, TNF-α, LIGHT, and TWEAK, were linked to observed molecular changes and the altered lupus chromatin state. However, we identified a patient subgroup prescribed angiotensin receptor blockers (ARBs), which lacked TNF-linked lupus chromatin accessibility features. These data raise questions about the role of lupus-associated chromatin changes in naive CD4+ T cell activation and differentiation and implicate ARBs in the regulation of disease-driven epigenetic states.
Authors
Andrew P. Hart, Jonathan J. Kotzin, Steffan W. Schulz, Jonathan S. Dunham, Alison L. Keenan, Joshua F. Baker, Andrew D. Wells, Daniel P. Beiting, Terri M. Laufer
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The high-temperature requirement A1 (HTRA1), a serine protease, has been demonstrated to play a pivotal role in the extracellular matrix (ECM) and has been reported to be associated with the pathogenesis of age-related macular degeneration (AMD). To delineate its role in the retina, the phenotype of homozygous Htra1-KO (Htra1–/–) mice was characterized to examine the effect of Htra1 loss on the retina and retinal pigment epithelium (RPE) with age. The ablation of Htra1 led to a significant reduction in rod and cone photoreceptor function, primary cone abnormalities followed by rods, and atrophy in the RPE compared with WT mice. Ultrastructural analysis of Htra1–/– mice revealed RPE and Bruch’s membrane (BM) abnormalities, including the presence of sub-RPE deposits at 5 months (m) that progressed with age accompanied by increased severity of pathology. Htra1–/– mice also displayed alterations in key markers for inflammation, autophagy, and lipid metabolism in the retina. These results highlight the crucial role of HTRA1 in the retina and RPE. Furthermore, this study allows for the Htra1–/– mouse model to be utilized for deciphering mechanisms that lead to sub-RPE deposit phenotypes including AMD.
Authors
Pooja Biswas, DaNae R. Woodard, T.J. Hollingsworth, Naheed W. Khan, Danielle R. Lazaro, Anne Marie Berry, Manisha Dagar, Yang Pan, Donita Garland, Peter X. Shaw, Chio Oka, Takeshi Iwata, Monica M. Jablonski, Radha Ayyagari
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Crohn’s disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here, we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In noninflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extraintestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in patients with CD. Our findings highlight MUC17 as an essential region-specific line of defense in the small intestine with relevance for early epithelial defects in CD.
Authors
Elena Layunta, Sofia Jäverfelt, Fleur C. van de Koolwijk, Molly Sivertsson, Brendan Dolan, Liisa Arike, Sara I.M. Thulin, Bruce A. Vallance, Thaher Pelaseyed
×Abstract
Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence–associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a nonredundant role in calcium signaling in chondrocytes. Trpc1–/– mice subjected to destabilization of the medial meniscus–induced OA developed a more severe OA phenotype than WT controls. During early OA development, Trpc1–/– mice displayed an increased chondrocyte survival rate; however, remaining cells displayed features of senescence including p16INK4a expression and decreased Sox9. RNA-Seq identified differentially expressed genes related to cell number, apoptosis, and extracellular matrix organization. Trpc1–/– chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of TRPC1 activation may be a promising therapeutic strategy in OA prevention.
Authors
Meike Sambale, Starlee Lively, Osvaldo Espin-Garcia, Pratibha Potla, Chiara Pastrello, Sarah Bödecker, Linda Wessendorf, Simon Kleimann, Peter Paruzel, Rojiar Asgarian, Alexandra Tosun, Johanna Intemann, Jessica Bertrand, Francesco Dell’Accio, Mohit Kapoor, Thomas Pap, Joanna Sherwood
×Abstract
Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.
Authors
Enyong Su, Xiaoyue Song, Lili Wei, Junqiang Xue, Xuelin Cheng, Shiyao Xie, Hong Jiang, Ming Liu
×Abstract
Rhabdomyosarcoma (RMS) is one of the most common solid tumors in children and adolescents. Patients with relapsed/refractory RMS have limited treatment options, highlighting the urgency for the identification of novel therapeutic targets for RMS. In the present study, aurora kinase B (AURKB) was found to be highly expressed in RMS and associated with unfavorable prognosis of patients. Functional experiments indicated that inhibition of AURKB significantly reduced RMS cell proliferation, induced apoptosis and ferroptosis, and suppressed RMS growth in vivo. The highly expressed AURKB in RMS contributes to the apoptosis and ferroptosis resistance of tumor cells through the nucleophosmin 1 (NPM1)/Sp1 transcription factor (SP1)/acyl-CoA synthetase long-chain family member 5 (ACSL5) axis. Furthermore, inhibition of AURKB exerted an anti-RMS effect together with vincristine both in vitro and in vivo, with tolerable toxicity. The above findings provide insights we believe are new into the tumorigenesis of RMS, especially with regard to apoptosis or ferroptosis resistance, indicating that AURKB may be a potential target for clinical intervention in patients with RMS.
Authors
Huimou Chen, Mengzhen Li, Yu Zhang, Mengjia Song, Yi Que, Juan Wang, Feifei Sun, Jia Zhu, Junting Huang, Juan Liu, Jiaqian Xu, Suying Lu, Yizhuo Zhang
×Abstract
Specialized memory CD4 T cells that reside long-term within tissues are critical components of immunity at portals of pathogen entry. In the lung, such tissue-resident memory (Trm) cells are activated rapidly after infection and promote local inflammation to control pathogen levels before circulating T cells can respond. However, optimal clearance of Influenza A virus can require Trm and responses by other virus-specific T cells that reach the lung only several days after their activation in secondary lymphoid organs. Whether local CD4 Trm sentinel activity can affect the efficiency of T cell activation in secondary lymphoid organs is not clear. Here, we found that recognition of antigen by influenza-primed Trm in the airways promoted more rapid migration of highly activated antigen-bearing DC to the draining lymph nodes. This in turn accelerated the priming of naive T cells recognizing the same antigen, resulting in newly activated effector T cells reaching the lungs earlier than in mice not harboring Trm. Our findings, thus, reveal a circuit linking local and regional immunity whereby antigen recognition by Trm improves effector T cell recruitment to the site of infection though enhancing the efficiency of antigen presentation in the draining lymph node.
Authors
Caroline M. Finn, Kunal Dhume, Eugene Baffoe, Lauren A. Kimball, Tara M. Strutt, K. Kai McKinstry
×Abstract
Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single-mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double-mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage-tracing and organoid-modeling studies demonstrated that HPS AT2 cells were primed to persist in a Keratin-8–positive reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.
Authors
Joanna Y. Wang, Sylvia N. Michki, Sneha Sitaraman, Brandon J. Banaschewski, Reshma Jamal, Jason J. Gokey, Susan M. Lin, Jeremy B. Katzen, Maria C. Basil, Edward Cantu, Jonathan A. Kropski, Jarod A. Zepp, David B. Frank, Lisa R. Young
×Abstract
Regeneration of orofacial bone defects caused by inflammation-related diseases or trauma remains an unmet challenge. Parathyroid hormone 1 receptor (PTH1R) signaling is a key mediator of bone remodeling whereas the regulatory mechanisms of PTH1R signaling in oral bone under homeostatic or inflammatory conditions have not been demonstrated by direct genetic evidence. Here, we observed that deletion of PTH1R in Gli1+ progenitors led to increased osteogenesis and osteoclastogenesis. Single-cell and bulk RNA-Seq analysis revealed that PTH1R suppressed the osteogenic potential of Gli1+ progenitors during inflammation. Moreover, we identified upregulated IGF1 expression upon PTH1R deletion. Dual deletion of IGF1 and PTH1R ameliorated the bone-remodeling phenotypes in PTH1R-deficient mice. Furthermore, in vivo evidence revealed an inverse relationship between PTH1R and Hedgehog signaling, which was responsible for the upregulated IGF1 production. Our work underscored the negative feedback between PTH1R and IGF1 in craniofacial bone turnover and revealed mechanisms modulating orofacial bone remodeling.
Authors
Yi Fan, Ping Lyu, Jiahe Wang, Yali Wei, Zucen Li, Shiwen Zhang, Takehito Ouchi, Junjun Jing, Quan Yuan, Clifford J. Rosen, Chenchen Zhou
×Abstract
Temporomandibular joint (TMJ) osteoarthritis with pain is a highly prevalent disorder affecting patients’ quality of life. A comprehensive understanding of cell type diversity and its dynamics in painful TMJ osteoarthritis (TMJOA) is lacking. Here, we utilized an inflammatory TMJOA mouse model via intra-articular injection of CFA. TMJOA mice exhibited cartilage remodeling, bone loss, synovitis, increased osteoarthritis (OA) score, and orofacial pain, recapitulating hallmark symptoms in patients. Single-cell transcriptomic profiling of the TMJ was performed in conjunction with mouse genetic labeling, tissue clearing, light sheet and confocal 3D imaging, multiplex RNAscope, and immunodetection. We visualized, reconstructed, and analyzed the distribution and density of nociceptive innervation of TMJ at single-axon levels. We systematically mapped the heterogeneity and anatomical position of blood endothelial cells, synovial fibroblasts, and immune cells, including Cx3cr1-positive barrier macrophages. Importantly, TMJOA mice exhibited enhanced neurovascular coupling, sublining fibroblast hyperplasia, inflammatory immune cell expansion, disrupted signaling-dependent cell-cell interaction, and a breakdown of the sandwich-like organization consisting of synovial barrier macrophages and fibroblasts. By utilizing a mouse model with combined TMJ pain history and OA, we reveal the cellular diversity, anatomical structure, and cell dynamics of the TMJ at single-cell resolution, which facilitate our understanding and potential targeting of TMJOA.
Authors
Supawadee Jariyasakulroj, Yang Shu, Ziying Lin, Jingyi Chen, Qing Chang, Pao-Fen Ko, Jian-Fu Chen
×Abstract
With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria–lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.
Authors
Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Hideaki Kawai, Isao Matsui, Tadashi Yamamuro, Ryuya Edahiro, Seiji Takashima, Akira Takasawa, Yukinori Okada, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka
×Abstract
BACKGROUND Prenatal alcohol exposure (PAE) around conception in preclinical models results in placental insufficiency, likely contributing to offspring abnormalities. Altered placental DNA methylation (DNAm) and gene expression suggest epigenetic mechanisms, perhaps involving impacts on methyl donor levels. PAE around conception in women is common but placental effects are rarely examined. This cohort study investigated associations between PAE around conception and intake/plasma measures of the methyl donors folate and choline, feto-placental blood flow, and placental growth measures, gene expression, and DNAm.METHODS Pregnant participants delivered at Mater Mothers’ Hospital, Brisbane, Queensland, Australia (n = 411). Dietary intake of choline and folate were calculated and plasma concentrations measured using mass spectrometry (MS) and clinical immunoanalyzer, respectively. Cerebroplacental ratio (CPR) was calculated using Doppler measurements. Placentas were weighed/measured at delivery and samples used to quantify methyl donors (MS), global DNAm (ELISA), and gene expression (quantitative PCR). Data were compared between control/abstinent and PAE groups, by fetal sex.RESULTS A CPR <5th-centile, indicating fetal brain sparing because of placental insufficiency, was found in 2% of controls and 18% of the PAE group, mostly male fetuses (63%). Compared with controls, male PAE placentas had reduced mean thickness and placental growth factor mRNA and DNAm, whereas female PAE placentas had increased S-adenosylmethionine and a trend toward increased DNAm.CONCLUSION PAE around conception is associated with reduced CPR and altered placental growth measures, particularly in males, with potential implications for future health.FUNDING National Health and Medical Research Council (APP1191217) and Mary McConnel Career Boost Program for Women in Paediatric Research (WIS132020).
Authors
Sarah E. Steane, Christopher Edwards, Erika Cavanagh, Chelsea Vanderpeet, Jade M. Kubler, Lisa K. Akison, James S.M. Cuffe, Linda A. Gallo, Karen M. Moritz, Vicki L. Clifton
