ERα agonists(Northeastern University)

Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-disrupting effects remain insufficiently characterized. Cyclo-di-bisphenol A diglycidyl ether (cyclo-di-BADGE), tetrabromobisphenol S (TBBPS), bisphenol SIP (BPSIP), and bisphenol TMC (BPTMC) are particularly understudied. We assessed the estrogenic activity of these four BPA analogues compared to BPA. Transactivation assays in HEK-293 cells expressing estrogen receptor alpha (ERα) revealed that BPTMC was a more potent ERα agonist than BPA, with an EC₅₀ of 87 ± 20 nM versus 400 ± 100 nM for BPA, while the other tested analogues showed no significant agonistic activity. In silico analysis attributed this higher affinity to greater hydrophobicity and a bulkier bridging group between its phenolic rings. None of the compounds inhibited 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activity. However, BPTMC selectively inhibited 17β-HSD2 (IC₅₀ = 4.8 ± 0.6 µM) but not BPA. Importantly, 24 h exposure of ERα-positive MCF-7 breast cancer cells to 1 µM BPTMC upregulated the expression of the ERα target genes GREB1, TFF1, and PGR, comparable to 10 nM E2, which was abolished by 100 nM of the ERα antagonist fulvestrant. Moreover, BPTMC stimulated MCF-7 cell proliferation at nanomolar concentrations over 72 h, and cell count analyses confirmed this effect. BPA also increased cell numbers, and both effects were reversed by fulvestrant. Collectively, we identified BPTMC as a potent ERα agonist capable of eliciting transcriptional and mitogenic responses at low concentrations, raising concerns about its endocrine-disrupting and breast cancer-promoting effects.

Obesity is often caused by an imbalance between energy intake and expenditure, with the hypothalamus essential in maintaining this balance, and any impairment in its function can contribute to obesity. Estrogen receptor alpha (ERα) plays a significant role in controlling body weight by influencing energy intake. However, the specific processes through which ERα exerts its anorexigenic effects remain insufficiently understood. This study investigates the impact of targeted ERα activation on endoplasmic reticulum (ER) stress in the hypothalamus of mice suffering from obesity induced by a high‐fat diet (HFD). The animals were divided into two primary groups: ovarian‐intact (Sham) and ovariectomized (OVX) mice, both of which were fed an HFD for 12 weeks. At the end, the OVX mice were further divided into two groups: OVX‐HFD and OVX‐HFD‐PPT (ERα agonist). The findings showed that ovariectomy led to weight gain and increased energy intake in HFD mice, which were accompanied by increased levels of orexigenic neuropeptide Y (NPY) and ER‐stress and decreased levels of anorexigenic α‐melanocyte‐stimulating hormone (α‐MSH) and leptin signaling in the hypothalamus. In contrast, treatment with PPT significantly attenuated these effects, leading to reduced body weight and energy intake. Mechanistically, PPT treatment decreased the level of NPY and increased α‐MSH in the hypothalamus. Furthermore, PPT treatment reduced hypothalamic ER stress markers, such as GRP78 and ATF6, and enhanced leptin signaling by increasing the phosphorylation of JAK2 and STAT3. We conclude that ERα activation may reduce hypothalamic ER stress and improve leptin sensitivity, thereby regulating energy intake and body weight.