Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α
Emerging evidence links bisphenol A (BPA) to insulin resistance, but the underlying mechanisms remain unclear. In this study, lactating mother mice and their male offspring post-weaning were exposed to bisphenol A (BPA) via drinking water at human-relevant (2.5 μg/L) and high human-relevant (25 μg/L...
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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/S0147651325011364 |
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| author | Zhang-Hong Ke Yue-Hong Li Ai-Li Yu Xue-Fen Cai Yan-Ying Lin Shun-He Lin Chu-Chu Zheng Chen-Xi Yu Bei-Hong Zheng Yan Sun |
| author_facet | Zhang-Hong Ke Yue-Hong Li Ai-Li Yu Xue-Fen Cai Yan-Ying Lin Shun-He Lin Chu-Chu Zheng Chen-Xi Yu Bei-Hong Zheng Yan Sun |
| author_sort | Zhang-Hong Ke |
| collection | DOAJ |
| description | Emerging evidence links bisphenol A (BPA) to insulin resistance, but the underlying mechanisms remain unclear. In this study, lactating mother mice and their male offspring post-weaning were exposed to bisphenol A (BPA) via drinking water at human-relevant (2.5 μg/L) and high human-relevant (25 μg/L) concentrations, corresponding to daily intakes of 0.5 and 5 μg/kg body weight, respectively. At 8 weeks of age, male offspring exposed to BPA exhibited evident insulin resistance. RNA sequencing of skeletal muscle identified the insulin signaling pathway as the most significantly disrupted, with Irs1 showing the highest degree of differential expression among key genes involved in glucose metabolism. RT-qPCR and Western blot validation in skeletal muscle, using an expanded sample set, confirmed that Irs1 was uniquely and significantly dysregulated among genes essential for glucose metabolism after exposure to both BPA doses. Furthermore, BPA within and around human-relevant concentrations reduced Irs1 expression and impaired insulin signaling in skeletal muscle in a dose-dependent manner, both in vivo and in C2C12 myotubes. Mechanistic analyses using CUT&Tag, ChIP-qPCR, and luciferase reporter assays demonstrated that BPA disrupts estrogen receptor-α (ERα) binding to the estrogen response element in Irs1 promoter, thereby suppressing Irs1 transcription and antagonizing estrogen’s regulatory effects. This study demonstrates that chronic and early-life exposure of BPA at human-relevant concentrations induces insulin resistance in young adults. BPA around human-relevant concentrations induces insulin resistance by dose-dependently suppressing Irs1 expression in skeletal muscle via interference with ERα binding, highlighting a molecular mechanism of metabolic toxicity and the need for broader exposure control. |
| format | Article |
| id | doaj-art-99d8bd4248ab46018a93baf37bf4f2c0 |
| 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-99d8bd4248ab46018a93baf37bf4f2c02025-08-20T03:57:56ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130311879110.1016/j.ecoenv.2025.118791Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-αZhang-Hong Ke0Yue-Hong Li1Ai-Li Yu2Xue-Fen Cai3Yan-Ying Lin4Shun-He Lin5Chu-Chu Zheng6Chen-Xi Yu7Bei-Hong Zheng8Yan Sun9Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Fujian Clinical Research Center for Maternal-Fetal Medicine, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Fujian Medical University, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, ChinaFujian Medical University, Fuzhou 350001, ChinaFujian Medical University, Fuzhou 350001, ChinaFujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; Fujian Key Laboratory of Prenatal Diagnosis and Birth Defect, China; Corresponding authors at: Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China.Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China; National Key Obstetric Clinical Specialty Construction Institution of China, China; Corresponding authors at: Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China.Emerging evidence links bisphenol A (BPA) to insulin resistance, but the underlying mechanisms remain unclear. In this study, lactating mother mice and their male offspring post-weaning were exposed to bisphenol A (BPA) via drinking water at human-relevant (2.5 μg/L) and high human-relevant (25 μg/L) concentrations, corresponding to daily intakes of 0.5 and 5 μg/kg body weight, respectively. At 8 weeks of age, male offspring exposed to BPA exhibited evident insulin resistance. RNA sequencing of skeletal muscle identified the insulin signaling pathway as the most significantly disrupted, with Irs1 showing the highest degree of differential expression among key genes involved in glucose metabolism. RT-qPCR and Western blot validation in skeletal muscle, using an expanded sample set, confirmed that Irs1 was uniquely and significantly dysregulated among genes essential for glucose metabolism after exposure to both BPA doses. Furthermore, BPA within and around human-relevant concentrations reduced Irs1 expression and impaired insulin signaling in skeletal muscle in a dose-dependent manner, both in vivo and in C2C12 myotubes. Mechanistic analyses using CUT&Tag, ChIP-qPCR, and luciferase reporter assays demonstrated that BPA disrupts estrogen receptor-α (ERα) binding to the estrogen response element in Irs1 promoter, thereby suppressing Irs1 transcription and antagonizing estrogen’s regulatory effects. This study demonstrates that chronic and early-life exposure of BPA at human-relevant concentrations induces insulin resistance in young adults. BPA around human-relevant concentrations induces insulin resistance by dose-dependently suppressing Irs1 expression in skeletal muscle via interference with ERα binding, highlighting a molecular mechanism of metabolic toxicity and the need for broader exposure control.http://www.sciencedirect.com/science/article/pii/S0147651325011364Bisphenol ASkeletal muscleInsulin resistanceInsulin receptor substrate 1Estrogen receptor-α |
| spellingShingle | Zhang-Hong Ke Yue-Hong Li Ai-Li Yu Xue-Fen Cai Yan-Ying Lin Shun-He Lin Chu-Chu Zheng Chen-Xi Yu Bei-Hong Zheng Yan Sun Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α Ecotoxicology and Environmental Safety Bisphenol A Skeletal muscle Insulin resistance Insulin receptor substrate 1 Estrogen receptor-α |
| title | Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α |
| title_full | Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α |
| title_fullStr | Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α |
| title_full_unstemmed | Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α |
| title_short | Human-relevant doses of bisphenol a induce insulin resistance by downregulating Irs1 expression in skeletal muscle through estrogen receptor-α |
| title_sort | human relevant doses of bisphenol a induce insulin resistance by downregulating irs1 expression in skeletal muscle through estrogen receptor α |
| topic | Bisphenol A Skeletal muscle Insulin resistance Insulin receptor substrate 1 Estrogen receptor-α |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325011364 |
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