Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging
Arsenic, a widespread environmental toxicant, is increasingly implicated in female reproductive dysfunction. Long-term exposure to low concentrations of arsenic leads to diminished ovarian reserve. However, the mechanisms by which arsenic exposure accelerates ovarian aging remain unclear. Here, we d...
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325009509 |
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| author | Tuo Zhang Jin Niu Lu Yang Yuanyuan Yu Meina He Changfa Wu Zengmei Cheng Mei Pan Zerui Hong Jian Sun Yuan Gao Tengxiang Chen Zhengrong Wang Wei Pan |
| author_facet | Tuo Zhang Jin Niu Lu Yang Yuanyuan Yu Meina He Changfa Wu Zengmei Cheng Mei Pan Zerui Hong Jian Sun Yuan Gao Tengxiang Chen Zhengrong Wang Wei Pan |
| author_sort | Tuo Zhang |
| collection | DOAJ |
| description | Arsenic, a widespread environmental toxicant, is increasingly implicated in female reproductive dysfunction. Long-term exposure to low concentrations of arsenic leads to diminished ovarian reserve. However, the mechanisms by which arsenic exposure accelerates ovarian aging remain unclear. Here, we demonstrate that arsenic exposure induces widespread disruption of pre-mRNA splicing programs in granulosa cells, and these aberrantly spliced genes are predominantly responsible for maintaining genomic stability. Arsenic exposure induces proteasomal degradation of the RNA helicase DDX5 through the UBE3A-mediated ubiquitin-proteasome pathway. Loss of DDX5 impairs the alternative splicing of FANCA, a core gene in the Fanconi anemia pathway, resulting in the production of a truncated isoform. This aberration leads to the excessive accumulation of R-loops and γH2AX-marked DNA damage in ovarian granulosa cells. Consequently, arsenic-exposed mice exhibit hallmark features of premature ovarian aging. Our findings establish the DDX5-FANCA axis as a novel paradigm in which environmental toxins dysregulate RNA splicing, driving reproductive aging through R-loops-mediated genomic instability. These insights highlight splice-switching therapies as a promising strategy to counteract pollutant-induced fertility decline. |
| format | Article |
| id | doaj-art-85acaf992d2346c2b7edeaf4ac310936 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-85acaf992d2346c2b7edeaf4ac3109362025-08-20T03:36:10ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130211860510.1016/j.ecoenv.2025.118605Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian agingTuo Zhang0Jin Niu1Lu Yang2Yuanyuan Yu3Meina He4Changfa Wu5Zengmei Cheng6Mei Pan7Zerui Hong8Jian Sun9Yuan Gao10Tengxiang Chen11Zhengrong Wang12Wei Pan13Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Center for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, China; Correspondence to: Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Guiyang, Guizhou, China.Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, ChinaReproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, ChinaReproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, ChinaTransformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, ChinaTransformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, ChinaReproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, ChinaTransformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, ChinaTransformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, ChinaCenter for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, ChinaCenter for Reproductive Medicine, Shandong University, Jinan, Shandong 250012, ChinaTransformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Correspondence to: Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Guiyang, Guizhou, China.Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; Correspondence to: Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Guiyang, Guizhou, China.Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550025, China; Correspondence to: Prenatal Diagnosis Center in Guizhou Province, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Guiyang, Guizhou, China.Arsenic, a widespread environmental toxicant, is increasingly implicated in female reproductive dysfunction. Long-term exposure to low concentrations of arsenic leads to diminished ovarian reserve. However, the mechanisms by which arsenic exposure accelerates ovarian aging remain unclear. Here, we demonstrate that arsenic exposure induces widespread disruption of pre-mRNA splicing programs in granulosa cells, and these aberrantly spliced genes are predominantly responsible for maintaining genomic stability. Arsenic exposure induces proteasomal degradation of the RNA helicase DDX5 through the UBE3A-mediated ubiquitin-proteasome pathway. Loss of DDX5 impairs the alternative splicing of FANCA, a core gene in the Fanconi anemia pathway, resulting in the production of a truncated isoform. This aberration leads to the excessive accumulation of R-loops and γH2AX-marked DNA damage in ovarian granulosa cells. Consequently, arsenic-exposed mice exhibit hallmark features of premature ovarian aging. Our findings establish the DDX5-FANCA axis as a novel paradigm in which environmental toxins dysregulate RNA splicing, driving reproductive aging through R-loops-mediated genomic instability. These insights highlight splice-switching therapies as a promising strategy to counteract pollutant-induced fertility decline.http://www.sciencedirect.com/science/article/pii/S0147651325009509OvaryArsenicDDX5R-loopsGenome instabilityAlternative splicing |
| spellingShingle | Tuo Zhang Jin Niu Lu Yang Yuanyuan Yu Meina He Changfa Wu Zengmei Cheng Mei Pan Zerui Hong Jian Sun Yuan Gao Tengxiang Chen Zhengrong Wang Wei Pan Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging Ecotoxicology and Environmental Safety Ovary Arsenic DDX5 R-loops Genome instability Alternative splicing |
| title | Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging |
| title_full | Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging |
| title_fullStr | Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging |
| title_full_unstemmed | Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging |
| title_short | Environmental arsenic hijacks DDX5-mediated FANCA splicing to impair R-loops resolution and drive ovarian aging |
| title_sort | environmental arsenic hijacks ddx5 mediated fanca splicing to impair r loops resolution and drive ovarian aging |
| topic | Ovary Arsenic DDX5 R-loops Genome instability Alternative splicing |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325009509 |
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