PLoS GeneticsPub Date : 2024-11-04DOI: 10.1371/journal.pgen.1011222
Ugo Coppola, Bitan Saha, Jennifer Kenney, Joshua S Waxman
{"title":"A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish.","authors":"Ugo Coppola, Bitan Saha, Jennifer Kenney, Joshua S Waxman","doi":"10.1371/journal.pgen.1011222","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011222","url":null,"abstract":"<p><p>Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) differentiation. However, little is known about the mechanisms directing Nr2f expression in ACs. Here, we identified a conserved enhancer 3' to the nr2f1a locus, which we call 3'reg1-nr2f1a (3'reg1), that can promote Nr2f1a expression in ACs. Sequence analysis of the enhancer identified putative Lef/Tcf and Foxf TF binding sites. Mutation of the Lef/Tcf sites within the 3'reg1 reporter, knockdown of Tcf7l1a, and manipulation of canonical Wnt signaling support that Tcf7l1a is derepressed via Wnt signaling to activate the transgenic enhancer and promote AC differentiation. Similarly, mutation of the Foxf binding sites in the 3'reg1 reporter, coupled with gain- and loss-of-function analysis supported that Foxf1 promotes expression of the enhancer and AC differentiation. Functionally, we find that Wnt signaling acts downstream of Foxf1 to promote expression of the 3'reg1 reporter within ACs and, importantly, both Foxf1 and Wnt signaling require Nr2f1a to promote a surplus of differentiated ACs. CRISPR-mediated deletion of the endogenous 3'reg1 abrogates the ability of Foxf1 and Wnt signaling to produce surplus ACs in zebrafish embryos. Together, our data support that downstream members of a conserved regulatory network involving Wnt signaling and Foxf1 function on a nr2f1a enhancer to promote AC differentiation in the zebrafish heart.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-11-04DOI: 10.1371/journal.pgen.1011463
Tahereh Gholipourshahraki, Zhonghao Bai, Merina Shrestha, Astrid Hjelholt, Sile Hu, Mads Kjolby, Palle Duun Rohde, Peter Sørensen
{"title":"Evaluation of Bayesian Linear Regression models for gene set prioritization in complex diseases.","authors":"Tahereh Gholipourshahraki, Zhonghao Bai, Merina Shrestha, Astrid Hjelholt, Sile Hu, Mads Kjolby, Palle Duun Rohde, Peter Sørensen","doi":"10.1371/journal.pgen.1011463","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011463","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) provide valuable insights into the genetic architecture of complex traits, yet interpreting their results remains challenging due to the polygenic nature of most traits. Gene set analysis offers a solution by aggregating genetic variants into biologically relevant pathways, enhancing the detection of coordinated effects across multiple genes. In this study, we present and evaluate a gene set prioritization approach utilizing Bayesian Linear Regression (BLR) models to uncover shared genetic components among different phenotypes and facilitate biological interpretation. Through extensive simulations and analyses of real traits, we demonstrate the efficacy of the BLR model in prioritizing pathways for complex traits. Simulation studies reveal insights into the model's performance under various scenarios, highlighting the impact of factors such as the number of causal genes, proportions of causal variants, heritability, and disease prevalence. Comparative analyses with MAGMA (Multi-marker Analysis of GenoMic Annotation) demonstrate BLR's superior performance, especially in highly overlapped gene sets. Application of both single-trait and multi-trait BLR models to real data, specifically GWAS summary data for type 2 diabetes (T2D) and related phenotypes, identifies significant associations with T2D-related pathways. Furthermore, comparison between single- and multi-trait BLR analyses highlights the superior performance of the multi-trait approach in identifying associated pathways, showcasing increased statistical power when analyzing multiple traits jointly. Additionally, enrichment analysis with integrated data from various public resources supports our results, confirming significant enrichment of diabetes-related genes within the top T2D pathways resulting from the multi-trait analysis. The BLR model's ability to handle diverse genomic features, perform regularization, conduct variable selection, and integrate information from multiple traits, genders, and ancestries demonstrates its utility in understanding the genetic architecture of complex traits. Our study provides insights into the potential of the BLR model to prioritize gene sets, offering a flexible framework applicable to various datasets. This model presents opportunities for advancing personalized medicine by exploring the genetic underpinnings of multifactorial traits.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-29eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011464
Joon Young Park, Minchang Jang, Sang-Mok Lee, Jihoon Woo, Eun-Jin Lee, Donghyuk Kim
{"title":"Unveiling the novel regulatory roles of RpoD-family sigma factors in Salmonella Typhimurium heat shock response through systems biology approaches.","authors":"Joon Young Park, Minchang Jang, Sang-Mok Lee, Jihoon Woo, Eun-Jin Lee, Donghyuk Kim","doi":"10.1371/journal.pgen.1011464","DOIUrl":"10.1371/journal.pgen.1011464","url":null,"abstract":"<p><p>Three RpoD-family sigma factors, RpoD, RpoS, and RpoH, play critical roles in transcriptional regulation in Salmonella enterica serovar Typhimurium under heat shock conditions. However, the genome-wide regulatory mechanisms of these sigma factors in response to heat stress have remained elusive. In this study, we comprehensively identified 2,319, 2,226, and 213 genome-wide binding sites for RpoD, RpoS, and RpoH, respectively, under sublethal heat shock conditions (42°C). Machine learning-based transcriptome analysis was employed to infer the relative activity of iModulons, providing valuable insights into the transcriptional impact of heat shock. Integrative data analysis enabled the reconstruction of the transcriptional regulatory network of sigma factors, revealing how they modulate gene expression to adapt to heat stress, including responses to anaerobic and oxidative stresses. Notably, we observed a significant expansion of the RpoS sigmulon from 97 to 301 genes in response to heat shock, underscoring the crucial role of RpoS in regulating various metabolic processes. Moreover, we uncovered a competition mechanism between RpoD and RpoS within RpoS sigmulons, where RpoS significantly increases its binding within promoter regions shared with RpoD under heat shock conditions. These findings illuminate how three RpoD-family sigma factors coordinate multiple cellular processes to orchestrate the overall response of S. Typhimurium to heat stress.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011460
Amira-Talaat Moussa, Marco R Cosenza, Timothy Wohlfromm, Katharina Brobeil, Anthony Hill, Annarita Patrizi, Karin Müller-Decker, Tim Holland-Letz, Anna Jauch, Bianca Kraft, Alwin Krämer
{"title":"STIL overexpression shortens lifespan and reduces tumor formation in mice.","authors":"Amira-Talaat Moussa, Marco R Cosenza, Timothy Wohlfromm, Katharina Brobeil, Anthony Hill, Annarita Patrizi, Karin Müller-Decker, Tim Holland-Letz, Anna Jauch, Bianca Kraft, Alwin Krämer","doi":"10.1371/journal.pgen.1011460","DOIUrl":"10.1371/journal.pgen.1011460","url":null,"abstract":"<p><p>Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant interference with p53 function. These results suggest that supernumerary centrosomes impair proliferation in vitro as well as in vivo, resulting in reduced lifespan and delayed spontaneous as well as carcinogen-induced tumor formation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011458
Hans M Dalton, Naomi J Young, Alexys R Berman, Heather D Evans, Sydney J Peterson, Kaylee A Patterson, Clement Y Chow
{"title":"A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.","authors":"Hans M Dalton, Naomi J Young, Alexys R Berman, Heather D Evans, Sydney J Peterson, Kaylee A Patterson, Clement Y Chow","doi":"10.1371/journal.pgen.1011458","DOIUrl":"10.1371/journal.pgen.1011458","url":null,"abstract":"<p><p>DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-28eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011448
Bayan Kharrat, Erika Gábor, Nikolett Virág, Rita Sinka, Ferenc Jankovics, Ildikó Kristó, Péter Vilmos, Gábor Csordás, Viktor Honti
{"title":"Dual role for Headcase in hemocyte progenitor fate determination in Drosophila melanogaster.","authors":"Bayan Kharrat, Erika Gábor, Nikolett Virág, Rita Sinka, Ferenc Jankovics, Ildikó Kristó, Péter Vilmos, Gábor Csordás, Viktor Honti","doi":"10.1371/journal.pgen.1011448","DOIUrl":"10.1371/journal.pgen.1011448","url":null,"abstract":"<p><p>The hematopoietic organ of the Drosophila larva, the lymph gland, is a simplified representation of mammalian hematopoietic compartments, with the presence of hemocyte progenitors in the medullary zone (MZ), differentiated hemocytes in the cortical zone (CZ), and a hematopoietic niche called the posterior signaling centre (PSC) that orchestrates progenitor differentiation. Our previous work has demonstrated that the imaginal cell factor Headcase (Hdc, Heca) is required in the hematopoietic niche to control the differentiation of hemocyte progenitors. However, the downstream mechanisms of Hdc-mediated hematopoietic control remained unknown. Here we show that Hdc exerts this function by negatively regulating the insulin/mTOR signaling in the niche. When Hdc is depleted in the PSC, the overactivation of this pathway triggers reactive oxygen species (ROS) accumulation and, in turn, the differentiation of effector lamellocytes non-cell-autonomously. Although overactivation of insulin/mTOR signaling normally leads to an increase in the size of the hematopoietic niche, this effect is concealed by cell death caused by hdc loss-of-function. Moreover, we describe here that hdc silencing in progenitors causes cell-autonomous ROS elevation and JNK pathway activation, resulting in decreased MZ size and differentiation of lamellocytes. Similarly to the PSC niche, knocking down hdc in the MZ also leads to caspase activation. Notably, depleting Hdc in the progenitors triggers proliferation, an opposing effect to what is observed in the niche. These findings further our understanding of how progenitor maintenance in the larval lymph gland is controlled autonomously and non-cell-autonomously, and point towards new mechanisms potentially regulating HSC maintenance across vertebrates.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-25eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011452
Petros Skiadas, Sofía Riera Vidal, Joris Dommisse, Melanie N Mendel, Joyce Elberse, Guido Van den Ackerveken, Ronnie de Jonge, Michael F Seidl
{"title":"Pangenome graph analysis reveals extensive effector copy-number variation in spinach downy mildew.","authors":"Petros Skiadas, Sofía Riera Vidal, Joris Dommisse, Melanie N Mendel, Joyce Elberse, Guido Van den Ackerveken, Ronnie de Jonge, Michael F Seidl","doi":"10.1371/journal.pgen.1011452","DOIUrl":"10.1371/journal.pgen.1011452","url":null,"abstract":"<p><p>Plant pathogens adapt at speeds that challenge contemporary disease management strategies like the deployment of disease resistance genes. The strong evolutionary pressure to adapt, shapes pathogens' genomes, and comparative genomics has been instrumental in characterizing this process. With the aim to capture genomic variation at high resolution and study the processes contributing to adaptation, we here leverage an innovative, multi-genome method to construct and annotate the first pangenome graph of an oomycete plant pathogen. We expand on this approach by analysing the graph and creating synteny based single-copy orthogroups for all genes. We generated telomere-to-telomere genome assemblies of six genetically diverse isolates of the oomycete pathogen Peronospora effusa, the economically most important disease in cultivated spinach worldwide. The pangenome graph demonstrates that P. effusa genomes are highly conserved, both in chromosomal structure and gene content, and revealed the continued activity of transposable elements which are directly responsible for 80% of the observed variation between the isolates. While most genes are generally conserved, virulence related genes are highly variable between the isolates. Most of the variation is found in large gene clusters resulting from extensive copy-number expansion. Pangenome graph-based discovery can thus be effectively used to capture genomic variation at exceptional resolution, thereby providing a framework to study the biology and evolution of plant pathogens.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-25eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011454
H Auguste Dutcher, James Hose, Hollis Howe, Julie Rojas, Audrey P Gasch
{"title":"The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast.","authors":"H Auguste Dutcher, James Hose, Hollis Howe, Julie Rojas, Audrey P Gasch","doi":"10.1371/journal.pgen.1011454","DOIUrl":"10.1371/journal.pgen.1011454","url":null,"abstract":"<p><p>Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with different chromosome duplications, in wild-type cells (SSD1+) and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1 (ssd1Δ). We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking SSD1 or in SSD1+ aneuploid cells with different chromosome duplications. Several of the most deleterious genes are linked to translation. In contrast, duplication of other genes benefits multiple ssd1Δ aneuploids over controls, and this group is enriched for translational effectors. Furthermore, both wild-type and especially ssd1Δ aneuploids with different chromosome amplifications show increased sensitivity to translational inhibitor nourseothricin. We used comparative modeling of aneuploid growth defects, based on the cumulative fitness costs measured for single-gene duplication. Our results present a model in which the deleterious effects of aneuploidy emerge from an interaction between the cumulative burden of many amplified genes on a chromosome and a subset of duplicated genes that become toxic in that context. These findings provide a perspective on the dual impact of individual genes and overall genomic burden, offering new avenues for understanding aneuploidy and its cellular consequences.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-24eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011459
Nguyen Thi Khanh Nhu, Brian M Forde, Nouri L Ben Zakour, Minh-Duy Phan, Leah W Roberts, Scott A Beatson, Mark A Schembri
{"title":"Evolution of the pheV-tRNA integrated genomic island in Escherichia coli.","authors":"Nguyen Thi Khanh Nhu, Brian M Forde, Nouri L Ben Zakour, Minh-Duy Phan, Leah W Roberts, Scott A Beatson, Mark A Schembri","doi":"10.1371/journal.pgen.1011459","DOIUrl":"10.1371/journal.pgen.1011459","url":null,"abstract":"<p><p>Escherichia coli exhibit extensive genetic diversity at the genome level, particularly within their accessory genome. The tRNA integrated genomic islands (GIs), a part of the E. coli accessory genome, play an important role in pathogenicity. However, studies examining the evolution of GIs have been challenging due to their large size, considerable gene content variation and fragmented assembly in draft genomes. Here we examined the evolution of the GI integrated at pheV-tRNA (GI-pheV), with a primary focus on uropathogenic E. coli (UPEC) and the globally disseminated multidrug resistant ST131 clone. We show the gene content of GI-pheV is highly diverse and arranged in a modular configuration, with the P4 integrase encoding gene intP4 the only conserved gene. Despite this diversity, the GI-pheV gene content displayed conserved features among strains from the same pathotype. In ST131, GI-pheV corresponding to the reference strain EC958 (EC958_GI-pheV) was found in ~90% of strains. Phylogenetic analyses suggested that GI-pheV in ST131 has evolved together with the core genome, with the loss/gain of specific modules (or the entire GI) linked to strain specific events. Overall, we show GI-pheV exhibits a dynamic evolutionary pathway, in which modules and genes have evolved through multiple events including insertions, deletions and recombination.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2024-10-24eCollection Date: 2024-10-01DOI: 10.1371/journal.pgen.1011434
Ayana L Henderson, Rajendiran Karthikraj, Emma L Berdan, Shannan Ho Sui, Kurunthachalam Kannan, Monica P Colaiácovo
{"title":"Exposure to benzyl butyl phthalate (BBP) leads to increased double-strand break formation and germline dysfunction in Caenorhabditis elegans.","authors":"Ayana L Henderson, Rajendiran Karthikraj, Emma L Berdan, Shannan Ho Sui, Kurunthachalam Kannan, Monica P Colaiácovo","doi":"10.1371/journal.pgen.1011434","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011434","url":null,"abstract":"<p><p>Benzyl butyl phthalate (BBP), a plasticizer found in a wide range of consumer products including vinyl flooring, carpet backing, food packaging, personal care products, and children's toys, is an endocrine-disrupting chemical linked to impaired reproduction and development in humans. Despite evidence that BBP exposure perturbs the integrity of male and female gametes, its direct effect on early meiotic events is understudied. Here, using the nematode Caenorhabditis elegans, we show that BBP exposure elicits a non-monotonic dose response on the rate of X-chromosome nondisjunction measured using a high-throughput screening platform. From among the range of doses tested (1, 10, 100 and 500 μM BBP), we found that 10 μM BBP elicited the strongest effect on the germline, resulting in increased germ cell apoptosis and chromosome organization defects. Mass spectrometry analysis shows that C. elegans efficiently metabolizes BBP into its primary metabolites, monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP), and that the levels of BBP, MBP, and MBzP detected in the worm are within the range detected in human biological samples. Exposure to 10 μM BBP leads to germlines with enlarged mitotic nuclei, altered meiotic progression, activation of a p53/CEP-1-dependent DNA damage checkpoint, increased double-strand break levels throughout the germline, chromosome morphology defects in oocytes at diakinesis, and increased oxidative stress. RNA sequencing analysis indicates that BBP exposure results in the altered expression of genes involved in xenobiotic metabolic processes, extracellular matrix organization, oocyte morphogenesis, meiotic cell cycle, and oxidoreduction. Taken together, we propose that C. elegans exposure to BBP leads to increased oxidative stress and double-strand break formation, thereby compromising germline genomic integrity and chromosome segregation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}