Multi-miRNAs-Mediated Hepatic Lepr Axis Suppression: A Pparg-Dicer1 Pathway-Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome

Bisphenol 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.