Combined exposure of lead and high-fat diet enhanced cognitive decline via interacting with CREB-BDNF signaling in male rats

The health risks to populations induced by lead (Pb) and high-fat diets (HFD) have become a global public health problem. Pb and HFD often co-exist and are co-occurring risk factors for cognitive impairment. This study investigates effect of combined Pb and HFD on cognitive function, and explores the underlying mechanisms in terms of regulatory components of synaptic plasticity and insulin signaling pathway. We showed that the co-exposure of Pb and HFD further increased blood Pb levels, caused body weight loss and dyslipidemia. The results from Morris water maze (MWM) test and Nissl staining disclosed that Pb and HFD each contributed to cognitive deficits and neuronal damage and combined exposure enhanced this toxic injury. Pb and HFD decreased the levels of synapsin-1, GAP-43 and PSD-95 protein related to synaptic properties and SIRT1, NMDARs, phosphorylated CREB and BDNF related to synaptic plasticity regulatory, and these decreases was greater when combined exposure. Additionally, we revealed that Pb and HFD promoted IRS-1 phosphorylation and subsequently reduced downstream PI3K-Akt kinases phosphorylation in hippocampus and cortex of rats, and this process was aggravated when co-exposure. Collectively, our data suggested that combined exposure of Pb and HFD enhanced cognitive deficits, pointing to additive effects in rats than the individual stress effects related to multiple signaling pathways with CREB-BDNF signaling as the hub. This study emphasizes the need to evaluate the effects of mixed exposures on brain function in realistic environment and to better inform prevention of neurological disorders via modulating central pathway, such as CREB/BDNF signaling.