Bisphenol F and AF Impair Cerebral Vascular Reactivity via Adrenergic and Nitric Oxide Pathways

Bisphenol F (BPF) and Bisphenol AF (BPAF) have been used as substitutes for Bisphenol A (BPA), a compound with estrogenic and androgenic properties. This endocrine disruptor compound was already associated with modifying the middle cerebral artery vascular homeostasis by interfering with the nitric oxide pathway. Although BPA has been banned in several countries, recent data suggest that some of its substitutes, such as BPF and BPAF, may pose a risk to human health. However, the available data on their neurovascular effects remain limited. Therefore, the present study evaluated the effects of BPF and BPAF on smooth muscle cells of the middle cerebral artery (SMC-MCA) of Wistar rats. Pure SMC cultures were performed from MCA explants, and MTT assays were performed to assess viability, proliferation, and cytotoxicity. The concentrations tested ranged from 0.0002 to 1000 µM. Planar Cell Surface Area (PCSA) assays were also performed to assess contractile responses to noradrenaline and relaxation responses to sodium nitroprusside at concentrations of 0.002, 0.02, 0.2, 2, and 20 µM. The results showed dose-dependent effects, and both compounds stimulated cell proliferation at low concentrations (0.02 µM) and induced cytotoxicity at high concentrations (200 and 1000 µM), revealing a non-monotonic profile characteristic of endocrine disruptors. Similar to BPA, these compounds modified the vasoactive activity of SMC-MCA, possibly by modulating α1-adrenergic receptors, the NO/sGC pathway, and Ca²⁺ channels, suggesting a potential neurovascular-disrupting effect. BPF altered only the vasorelaxant response at concentrations of 0.002 and 0.02 µM, while BPAF affected both the contractile response (0.002 µM) and the vasorelaxant response (2 µM). It was also noted that, at 0.002 µM, BPAF inhibited SNP-induced relaxation, causing a contractile response. Overall, these findings underscore the need for further studies to fully understand the mechanisms by which BPF and BPAF affect vascular function and the risk of developing neurovascular diseases.