Elucidating altrenogest-induced lipid accumulation via estrogen receptor alpha modulation: Insights from computational and cell-based approaches

Abstract

The veterinary progestin altrenogest is widely used, yet its potential as an endocrine disruptor impacting metabolic health is poorly understood. This study provides the first evidence that altrenogest promotes adipogenesis (lipid accumulation) in vitro by activating estrogen receptor alpha (ERα). We combined computational modeling, which predicted altrenogest binds to ERα, with a validated ERα transcriptional activation assay (hERα-HeLa-9903), which confirmed altrenogest is an ERα agonist. In 3 T3-L1 adipocytes, altrenogest exposure significantly increased lipid accumulation and upregulated key adipogenic and lipogenic transcription factors, such as Pparg and Srebf1. Specifically, altrenogest treatment significantly increased lipid accumulation by approximately 198 % at the highest effective concentration (log M = -5). This adipogenic effect was demonstrated to be ERα-dependent, as co-treatment with the selective ERα antagonist methylpiperidino pyrazole (MPP) significantly attenuated these effects. These findings present a robust mechanistic link between altrenogest, ERα activation, and pro-adipogenic signaling. This study emphasizes the necessity for stricter regulatory oversight of environmental residues from veterinary progestins, as they may contribute to metabolic disorders such as obesity.

Keywords: Agonist; Altrenogest; Binding affinity; Estrogen receptor alpha; Lipid accumulation.