JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.186409
Jessica M Devenport, Thi Tran, Brooke R Harris, Dylan Fingerman, Rachel A DeWeerd, Lojain H Elkhidir, Danielle LaVigne, Katherine Fuh, Lulu Sun, Jeffrey J Bednarski, Ronny Drapkin, Mary M Mullen, Abby M Green
{"title":"APOBEC3A drives ovarian cancer metastasis by altering epithelial-mesenchymal transition.","authors":"Jessica M Devenport, Thi Tran, Brooke R Harris, Dylan Fingerman, Rachel A DeWeerd, Lojain H Elkhidir, Danielle LaVigne, Katherine Fuh, Lulu Sun, Jeffrey J Bednarski, Ronny Drapkin, Mary M Mullen, Abby M Green","doi":"10.1172/jci.insight.186409","DOIUrl":"10.1172/jci.insight.186409","url":null,"abstract":"<p><p>High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC, and this resulted in increased metastatic behavior of HGSOC cells in culture and distant metastatic spread in vivo, which was dependent on catalytic activity of A3A. A3A activity in both primary and cultured HGSOC cells yielded consistent alterations in expression of epithelial-mesenchymal transition (EMT) genes resulting in hybrid EMT and mesenchymal signatures, providing a mechanism for their increased metastatic potential. Inhibition of key EMT factors TWIST1 and IL-6 resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesis in HGSOC and implicate A3A as a driver of HGSOC metastasis via EMT, underscoring its clinical relevance as a potential prognostic biomarker. Our study lays the groundwork for the development of targeted therapies aimed at mitigating the deleterious effect of A3A-driven EMT in HGSOC.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-06DOI: 10.1172/jci.insight.185061
Richard P Ramonell, Timothy B Oriss, Jessica C McCreary-Partyka, Sagar L Kale, Nicole R Brandon, Mark A Ross, Marc C Gauthier, Molin Yue, Taylor J Nee, Sudipta Das, Wei Chen, Alok V Joglekar, Prabir Ray, Claudette M St Croix, Dhivyaa Rajasundaram, Sally E Wenzel, Anuradha Ray
{"title":"CD8+ TEMRAs in Severe Asthma Associate with Asthma Symptom Duration and Escape Proliferation Arrest.","authors":"Richard P Ramonell, Timothy B Oriss, Jessica C McCreary-Partyka, Sagar L Kale, Nicole R Brandon, Mark A Ross, Marc C Gauthier, Molin Yue, Taylor J Nee, Sudipta Das, Wei Chen, Alok V Joglekar, Prabir Ray, Claudette M St Croix, Dhivyaa Rajasundaram, Sally E Wenzel, Anuradha Ray","doi":"10.1172/jci.insight.185061","DOIUrl":"https://doi.org/10.1172/jci.insight.185061","url":null,"abstract":"<p><p>Aberrant immune response is a hallmark of asthma, with 5-10% of patients suffering from severe disease exhibiting poor response to standard treatment. A better understanding of the immune responses contributing to disease heterogeneity is critical for improving asthma management. T cells are major players in the orchestration of asthma, in both mild and severe disease, but it is unclear whether specific T cell subsets influence asthma symptom duration. Here we show a significant association of airway CD8+ effector memory T cells re-expressing CD45RA (TEMRAs), but not CD8+ CD45RO+ or tissue resident memory (TRM) T cells, with asthma duration in patients with severe asthma (SA) but not mild to moderate asthma (MMA). Higher frequencies of IFN-γ+ CD8+ TEMRAs compared to IFN-γ+ CD45RO+ T cells were detected in SA airways, and the TEMRAs from SA but not MMA patients proliferated ex vivo, although both expressed cellular senescence-associated biomarkers. Prompted by the transcriptomic profile of SA CD8+ TEMRAs and proliferative response to IL-15, airway IL15 expression measured higher in SA compared to MMA patients. IL15 expression in asthmatic airways negatively correlated with lung function. Our findings add a new dimension to understanding asthma heterogeneity identifying IL-15 as a potential target for treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-06DOI: 10.1172/jci.insight.182694
Erin D Giles, Katherine L Cook, Ramsey M Jenschke, Karen A Corleto, Danilo Landrock, Tara N Mahmood, Katherine E Sanchez, Alina Levin, Stephen D Hursting, Bruce F Kimler, Barry S Komm, Carol J Fabian
{"title":"Metabolic and transcriptional effects of bazedoxifene/conjugated estrogens in a model of obesity-associated breast cancer risk.","authors":"Erin D Giles, Katherine L Cook, Ramsey M Jenschke, Karen A Corleto, Danilo Landrock, Tara N Mahmood, Katherine E Sanchez, Alina Levin, Stephen D Hursting, Bruce F Kimler, Barry S Komm, Carol J Fabian","doi":"10.1172/jci.insight.182694","DOIUrl":"https://doi.org/10.1172/jci.insight.182694","url":null,"abstract":"<p><p>Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Investigation of a mouse model of Prader-Willi syndrome with combined disruption of Necdin and Magel2.","authors":"Pierre-Yves Barelle, Alicia Sicardi, Fabienne Schaller, Julie Buron, Denis Becquet, Felix Omnes, Françoise Watrin, Marie-Sophie Alifrangis, Catarina Santos, Clément Menuet, Anne-Marie François-Bellan, Emilie Caron, Jessica Klucznik, Vincent Prevot, Sebastien G Bouret, Françoise Muscatelli","doi":"10.1172/jci.insight.185159","DOIUrl":"https://doi.org/10.1172/jci.insight.185159","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene have been generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 \"PWS\" genes and generated a mouse model (named \"Del Ndn-Magel2\" mice) with a deletion including both genes. A subset of Del Ndn-Magel2 mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Del Ndn-Magel2 mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance, and altered puberty. Adult mutant mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function similar to PWS patients. At neuroanatomical levels, Del Ndn-Magel2 mice had an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Del Ndn-Magel2 mouse is a pertinent and genetically relevant model of PWS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-06DOI: 10.1172/jci.insight.187487
Dan Hao, Qian Wang, Misa Ito, Jianyao Xue, Ling Guo, Bin Huang, Chieko Mineo, Philip W Shaul, Xiang-An Li
{"title":"The ACTH test fails to diagnose adrenal insufficiency and augments cytokine production in sepsis.","authors":"Dan Hao, Qian Wang, Misa Ito, Jianyao Xue, Ling Guo, Bin Huang, Chieko Mineo, Philip W Shaul, Xiang-An Li","doi":"10.1172/jci.insight.187487","DOIUrl":"https://doi.org/10.1172/jci.insight.187487","url":null,"abstract":"<p><p>The ACTH test diagnoses relative adrenal insufficiency (RAI) or critical illness-related corticosteroid insufficiency (CIRCI). Initially, guidelines recommended corticosteroid/glucocorticoid (GC) therapy for septic patients with RAI, but later trials did not show a survival benefit, leading to updated guidelines that abandon targeting RAI or CIRCI. Recent studies with an RAI mouse model showed a clear survival benefit from GC therapy in mice with RAI, suggesting that inconclusive GC clinical trials might be due to issues with the ACTH test rather than targeting RAI. To investigate, we performed the ACTH test in septic mice. Interestingly, the ACTH test identified most mice as having adrenal insufficiency in early and middle stages of sepsis, even those with a normal adrenal stress response. Surprisingly, the ACTH test increased inflammatory cytokine to lethal levels, moderately increasing mortality in septic mice. This study revealed significant flaws in the ACTH test for diagnosing RAI/CIRCI. It not only fails to correctly identify these conditions, leading to misguided use of GC, but also induces a lethal inflammatory response in sepsis. These findings suggest that inconclusive GC therapy trials may be due to the problematic nature of the ACTH test rather than ineffectiveness of targeting RAI/CIRCI.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-06DOI: 10.1172/jci.insight.181885
Han Xiaojuan, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun
{"title":"MSC transplantation ameliorates depression in lupus by suppressing Th1 cell-shaped synaptic stripping.","authors":"Han Xiaojuan, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun","doi":"10.1172/jci.insight.181885","DOIUrl":"https://doi.org/10.1172/jci.insight.181885","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetic lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell-derived IFNγ to inhibit neuronal JAK-STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFNγ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFNγ-CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-06DOI: 10.1172/jci.insight.183080
Eric Engelbrecht, Bryce F Stamp, Lewis Chew, Omar Sadi Sarkar, Phillip Harter, Sabine J Waigel, Eric C Rouchka, Julia Chariker, Andrei Smolenkov, Jason Chesney, Kelly McMasters, Corey T Watson, Kavitha Yaddanapudi
{"title":"Single-cell transcriptomics of melanoma sentinel lymph nodes identifies immune cell signatures associated with metastasis.","authors":"Eric Engelbrecht, Bryce F Stamp, Lewis Chew, Omar Sadi Sarkar, Phillip Harter, Sabine J Waigel, Eric C Rouchka, Julia Chariker, Andrei Smolenkov, Jason Chesney, Kelly McMasters, Corey T Watson, Kavitha Yaddanapudi","doi":"10.1172/jci.insight.183080","DOIUrl":"10.1172/jci.insight.183080","url":null,"abstract":"<p><p>The sentinel lymph node (SLN) is the first lymph node encountered by a metastatic cancer cell and serves as a predictor of poor prognosis, as cases with clinically occult SLN metastases are classified as stage III with elevated rates of recurrence and diminished overall survival. However, the dynamics of immune infiltrates in SLNs remain poorly characterized. Here, using an unbiased cellular indexing of transcriptomes and epitopes by sequencing technique, we profiled 97,777 cells from SLN tissues obtained from patients with stages I/II and III cutaneous melanoma. We described the transcriptional programs of a multitude of T, B, and myeloid cell subtypes in SLNs. Based on the proportions of cell types, we determined that SLN subtypes stratified along a naive → activated axis; patients with a \"high activated\" signature score appeared to be undergoing a robust melanoma antigen-driven adaptive immune response and, thus, could be responsive to immunotherapy. Additionally, we identified transcriptomic signatures of SLN-infiltrating dendritic cell subsets that compromise antitumor immune responses. Our analyses provide valuable insights into tumor-driven immune changes in the SLN tissue, offering a powerful tool for the informed design of immune therapies for patients with high-risk melanoma.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.184348
Lue Ping Zhao, George K Papadopoulos, Jay S Skyler, William W Kwok, George P Bondinas, Antonis K Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C Nelson, Daniel E Geraghty, Åke Lernmark
{"title":"Two DRB3 residues predictively associate with the progression to type 1 diabetes among DR3 carriers.","authors":"Lue Ping Zhao, George K Papadopoulos, Jay S Skyler, William W Kwok, George P Bondinas, Antonis K Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C Nelson, Daniel E Geraghty, Åke Lernmark","doi":"10.1172/jci.insight.184348","DOIUrl":"10.1172/jci.insight.184348","url":null,"abstract":"<p><p>HLA-DR genes are associated with the progression from stage 1 and stage 2 to onset of stage 3 type 1 diabetes (T1D), after accounting HLA-DQ genes with which they are in high linkage disequilibrium. Based on an integrated cohort of participants from 2 completed clinical trials, this investigation finds that, sharing a haplotype with the DRB1*03:01 (DR3) allele, DRB3*01:01:02 and *02:02:01 have respectively negative and positive associations with the progression. Furthermore, we uncovered 2 residues (β11, β26, participating in pockets 6 and 4, respectively) on the DRB3 molecule responsible for the progression among DR3 carriers; motif RY and LF respectively delay and promote the progression (hazard ratio [HR] = 0.73 and 2.38, P = 0.039 and 0.017, respectively). Two anchoring pockets 6 and 4 probably bind differential autoantigenic epitopes. We further investigated the progression association with the motifs RY and LF among carriers of DR3 and found that carriers of the motif LF have significantly faster progression than carriers of RY (HR = 1.48, P = 0.019 in unadjusted analysis; HR = 1.39, P = 0.047 in adjusted analysis), results of which provide an impetus to examine the possible role of specific DRB3-binding peptides in the progression to T1D.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.188962
Cheng Ai, Huiying Li, Chunyan Wang, Yanchun Ji, Douglas C Wallace, Junbin Qian, Yimin Zhu, Min-Xin Guan
{"title":"Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.","authors":"Cheng Ai, Huiying Li, Chunyan Wang, Yanchun Ji, Douglas C Wallace, Junbin Qian, Yimin Zhu, Min-Xin Guan","doi":"10.1172/jci.insight.188962","DOIUrl":"https://doi.org/10.1172/jci.insight.188962","url":null,"abstract":"<p><p>Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood and there has been no effective treatment or cure for this disorder. Using a mice model bearing a LHON-linked ND6P25L mutation, we demonstrated that the mutation caused retinal cell-specific deficiencies, especially in retinal ganglion cells (RGC), rods and Müller cells. Single-cell RNA sequencing revealed cell-specific dysregulation of oxidative phosphorylation and visual signaling pathways in the mutant retina. Strikingly, ND6 mutation-induced dysfunctions caused abnormal vitamin A (VA) metabolism essential for visual function. VA supplementation remarkably alleviated retinal deficiencies, including reduced fundus lesion and retinal thickness, and increasing numbers of RGCs, photoreceptors and Müller cell neurites. The restoration of visual functions with VA treatment were further evidenced by correcting dysregulations of phototransduction cascade and neurotransmitter transmission and restoring electrophysiological properties. Interestingly, VA supplementation markedly rescued the abnormal mitochondrial morphologies and functions in the mutant retina. These findings provide new insight into retina-specific pathophysiology of mitochondrial retinopathy arising from vitamin A deficiency and mitochondrial dysfunction induced by mtDNA mutation and step toward for therapeutic intervention for LHON and other mitochondrial retinopathy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.188931
Eric A Rhon-Calderon, Cassidy N Hemphill, Alexandra J Savage, Laren Riesche, Richard M Schultz, Marisa S Bartolomei
{"title":"In Vitro Fertilization induces reproductive changes in male mouse offspring and hasmultigenerational effects.","authors":"Eric A Rhon-Calderon, Cassidy N Hemphill, Alexandra J Savage, Laren Riesche, Richard M Schultz, Marisa S Bartolomei","doi":"10.1172/jci.insight.188931","DOIUrl":"10.1172/jci.insight.188931","url":null,"abstract":"<p><p>In vitro fertilization (IVF) is a non-coital method of conception used to treat human infertility. Although IVF is viewed as largely safe, it is associated with adverse outcomes in the fetus, placenta, and adult offspring. Because studies focusing on the effect of IVF on the male reproductive system are limited, we used a mouse model to assess the morphological and molecular effects of IVF on male offspring. We evaluated three developmental stages: 18.5-day fetuses and 12- and 39-week-old adults. Regardless of age, we observed changes in testicular-to-body weight ratios, serum testosterone levels, testicular morphology, gene expression, and DNA methylation. Also, sperm showed changes in morphology and DNA methylation. To assess multigenerational phenotypes, we mated IVF and naturally conceived males with wild-type females. Offspring from IVF males exhibited decreased fetal-to-placental weight ratios and changes in placenta gene expression and morphology regardless of sex. At 12-weeks-of-age, offspring showed higher body weights and differences in glucose, triglycerides, insulin, total cholesterol, HDL and LDL/VLDL levels. Both sexes showed changes in gene expression in liver, testes and ovaries, and decreased global DNA methylation. Collectively, our findings demonstrate that male IVF offspring exhibit abnormal testicular and sperm morphology and molecular alterations with a multigenerational impact.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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