Titolo della tesi: Unraveling the role of Phosphodiesterase 5 in the regulation of metabolic alterations induced by long-term exposure to Bisphenol-A
Bisphenol A (BPA) is an endocrine-disrupting chemical that alters adipogenesis, increasing the risk of metabolic disorders (1). These conditions are characterized by a profound disruption in energy balance, with more calories ingested than consumed (2). Cyclic guanosine monophosphate (cGMP) is involved in the regulation of energy homeostasis and cellular metabolism, and its intracellular levels are finely controlled by phosphodiesterases (PDEs). Phosphodiesterase 5 (PDE5) is the most well-known and studied PDE responsible for cGMP degradation (3). Preclinical and clinical studies have shown that pharmacological inhibition of PDE5 improves insulin resistance and glucose metabolism (4), representing a promising therapeutic strategy for the treatment of metabolic disorders. However, the underlying molecular mechanisms remain unclear. The aim of this study is to investigate the role of PDE5 in regulating metabolic alterations induced by BPA exposure using a Pde5 knockout mouse model. Two-month-old Pde5a−/−-and C57BL6/J wild-type (WT) male mice were exposed to 4 ug/kg/day BPA in drinking water for ten weeks. Histomorphometric analysis revealed a significant increase in body weight and visceral adipose tissue mass in Pde5a−/− mice compared to WT mice following BPA treatment. Liver histological examination showed vacuolization in the WT group after BPA exposure. Surprisingly, Pde5a ablation protected the liver from BPA-induced steatosis and damage. This was further confirmed by analyzing the expression levels of Acsl3, a master regulator of lipogenesis whose levels were increased in the livers of BPA exposed WT mice but not in BPA exposed Pde5a−/− mice. To further investigate the molecular mechanism by which Pde5a ablation protects mice from BPA induced liver damage, we analyzed the inflammatory response following BPA exposure. Inflammatory status was assessed using Luminex technology, which showed that BPA induces an increase in serum levels of pro-inflammatory cytokine IL-12 and a concomitant decrease in serum levels of anti-inflammatory cytokine IL-4. This effect was not observed in Pde5 deficient mice exposed to BPA. Finally, considering BPA’s potential steroid hormone balance (5), we evaluated steroid hormones levels in mice exposed to BPA using Liquid chromatography–mass spectrometry (LC–MS). This analysis revealed that BPA exposure reduces serum levels of progesterone, 11-deoxycorticosterone and corticosterone in WT mice, but not in Pde5a−/− mice. Together, these data suggest a protective role of PDE5-cGMP-PKG signaling pathway in mitigating immuno-metabolic alterations induced by long term exposure to BPA. This protection is likely mediated by a reduction of inflammation. These findings provide new insight into the role of PDE5 and cGMP-PKG signaling in metabolic regulation and the physiological impact of EDC exposure, particularly in the context of obesity and related disorders.
References:
(1) Akash M. et al., Environmental toxicology and pharmacology, 2020
(2) Kawai T. et al., Am J Physiol Cell Physiol, 2021
(3) Campolo F. et al., J Cell Physiol, 2018
(4) Campolo F. et al., Curr Opin Pharmacol, 2021
(5) Matuszczak E. et al., International Journal of Endocrinology, 2019