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Multi‐miRNAs‐Mediated Hepatic Lepr Axis Suppression: A Pparg–Dicer1 Pathway‐Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome
https://orcid.org/0000-0001-9923-9465
https://orcid.org/0009-0002-7491-9012
https://orcid.org/0009-0009-8211-2180
https://orcid.org/0000-0001-7792-0364
https://orcid.org/0009-0005-4313-5989
https://orcid.org/0009-0005-4599-4875
https://orcid.org/0009-0006-0429-8619
https://orcid.org/0000-0001-5645-6013
AbstractBisphenol A (BPA) is an “environmental obesogen” and this study aims to investigate the intergenerational impacts of BPA‐induced metabolic syndrome (MetS), specifically focusing on unraveling mechanisms. Exposure to BPA induces metabolic disorders in the paternal mice, which are then transmitted to offspring, leading to late‐onset MetS. Mechanistically, BPA upregulates Srebf1, which in turn promotes the Pparg‐dependent transcription of Dicer1 in spermatocytes, increasing the levels of multiple sperm microRNAs (miRNAs). Several of these miRNAs are highly expressed in a synchronized manner in liver of the offspring. miR149‐5p, miR150‐5p, and miR700‐5p target a specific region in the Lepr 3′UTR, termed “SMITE” (“Several MiRNAs Targeting Elements”), to negatively regulate Lepr. These inherited anti‐Lepr miRNAs, also referred to inherited anti‐Lepr miRNAs (IAL‐miRs), modulate hepatic steatosis, and insulin signaling through the Lepr regulatory Igfbp2, Egfr, and Ampk. Furthermore, IAL‐miRs inhibit Ccnd1 not only via binding to “SMITE” but also via Lepr–Igfbp2 axis, which contribute to hepatocyte senescence. These pathological processes interact in a self‐reinforcing cycle, worsening MetS in the paternal BPA‐exposed offspring. The findings reveal mechanism wherein lipid metabolism reprogramming in spermatocytes‐induced perturbations of sperm miRNAs, triggered by BPA, leads to intergenerational inheritance of paternal MetS through suppression of the hepatic Lepr axis in the offspring.
Multi‐miRNAs‐Mediated Hepatic Lepr Axis Suppression: A Pparg–Dicer1 Pathway‐Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome
https://orcid.org/0000-0001-9923-9465
https://orcid.org/0009-0002-7491-9012
https://orcid.org/0009-0009-8211-2180
https://orcid.org/0000-0001-7792-0364
https://orcid.org/0009-0005-4313-5989
https://orcid.org/0009-0005-4599-4875
https://orcid.org/0009-0006-0429-8619
https://orcid.org/0000-0001-5645-6013
AbstractBisphenol A (BPA) is an “environmental obesogen” and this study aims to investigate the intergenerational impacts of BPA‐induced metabolic syndrome (MetS), specifically focusing on unraveling mechanisms. Exposure to BPA induces metabolic disorders in the paternal mice, which are then transmitted to offspring, leading to late‐onset MetS. Mechanistically, BPA upregulates Srebf1, which in turn promotes the Pparg‐dependent transcription of Dicer1 in spermatocytes, increasing the levels of multiple sperm microRNAs (miRNAs). Several of these miRNAs are highly expressed in a synchronized manner in liver of the offspring. miR149‐5p, miR150‐5p, and miR700‐5p target a specific region in the Lepr 3′UTR, termed “SMITE” (“Several MiRNAs Targeting Elements”), to negatively regulate Lepr. These inherited anti‐Lepr miRNAs, also referred to inherited anti‐Lepr miRNAs (IAL‐miRs), modulate hepatic steatosis, and insulin signaling through the Lepr regulatory Igfbp2, Egfr, and Ampk. Furthermore, IAL‐miRs inhibit Ccnd1 not only via binding to “SMITE” but also via Lepr–Igfbp2 axis, which contribute to hepatocyte senescence. These pathological processes interact in a self‐reinforcing cycle, worsening MetS in the paternal BPA‐exposed offspring. The findings reveal mechanism wherein lipid metabolism reprogramming in spermatocytes‐induced perturbations of sperm miRNAs, triggered by BPA, leads to intergenerational inheritance of paternal MetS through suppression of the hepatic Lepr axis in the offspring.
Multi‐miRNAs‐Mediated Hepatic Lepr Axis Suppression: A Pparg–Dicer1 Pathway‐Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome
https://orcid.org/0000-0001-9923-9465
https://orcid.org/0009-0002-7491-9012
https://orcid.org/0009-0009-8211-2180
https://orcid.org/0000-0001-7792-0364
https://orcid.org/0009-0005-4313-5989
https://orcid.org/0009-0005-4599-4875
https://orcid.org/0009-0006-0429-8619
https://orcid.org/0000-0001-5645-6013
AbstractBisphenol A (BPA) is an “environmental obesogen” and this study aims to investigate the intergenerational impacts of BPA‐induced metabolic syndrome (MetS), specifically focusing on unraveling mechanisms. Exposure to BPA induces metabolic disorders in the paternal mice, which are then transmitted to offspring, leading to late‐onset MetS. Mechanistically, BPA upregulates Srebf1, which in turn promotes the Pparg‐dependent transcription of Dicer1 in spermatocytes, increasing the levels of multiple sperm microRNAs (miRNAs). Several of these miRNAs are highly expressed in a synchronized manner in liver of the offspring. miR149‐5p, miR150‐5p, and miR700‐5p target a specific region in the Lepr 3′UTR, termed “SMITE” (“Several MiRNAs Targeting Elements”), to negatively regulate Lepr. These inherited anti‐Lepr miRNAs, also referred to inherited anti‐Lepr miRNAs (IAL‐miRs), modulate hepatic steatosis, and insulin signaling through the Lepr regulatory Igfbp2, Egfr, and Ampk. Furthermore, IAL‐miRs inhibit Ccnd1 not only via binding to “SMITE” but also via Lepr–Igfbp2 axis, which contribute to hepatocyte senescence. These pathological processes interact in a self‐reinforcing cycle, worsening MetS in the paternal BPA‐exposed offspring. The findings reveal mechanism wherein lipid metabolism reprogramming in spermatocytes‐induced perturbations of sperm miRNAs, triggered by BPA, leads to intergenerational inheritance of paternal MetS through suppression of the hepatic Lepr axis in the offspring.
Multi‐miRNAs‐Mediated Hepatic Lepr Axis Suppression: A Pparg–Dicer1 Pathway‐Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome
Advanced Science
Lin, Yi (author) / Ni, Xiuye (author) / Zhu, Lin (author) / Lin, Yilong (author) / Peng, Cai (author) / Lei, Zhao (author) / Wang, Yihui (author) / Wang, Huan (author) / You, Xiang (author) / Li, Juan (author)
Advanced Science ; 12
2025-03-01
Article (Journal)
Electronic Resource
English
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