Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

Abstract

Lead (Pb) exposure has been implicated in the impairment of synaptic plasticity in the developing hippocampus, but the mechanism remains unclear. Here, we investigated whether developmental lead exposure affects the dendritic spine formation through Wnt signaling pathway in vivo and in vitro. Sprague–Dawley rats were exposed to lead throughout the lactation period and Golgi-Cox staining method was used to examine the spine density of pyramidal neurons in the hippocampal CA1 area of rats. We found that lead exposure significantly decreased the spine density in both 14 and 21 days-old pups, accompanied by a significant age-dependent decline of the Wnt7a expression and stability of its downstream protein (β-catenin). Furthermore, in cultured hippocampal neurons, lead (0.1 and 1 µM lead acetate) significantly decreased the spine density in a dose-dependent manner. Exogenous Wnt7a application attenuated the decrease of spine density and increased the stability of the downstream molecules in Wnt signaling pathway. Together, our results suggest that lead has a negative impact on spine outgrowth in the developing hippocampus through altering the canonical Wnt pathway.

Effects of titanium dioxide nanoparticles on lead bioconcentration and toxicity on thyroid endocrine system and neuronal development in zebrafish larvae

“…However, the amount of nano-TiO 2 being released into the ecosystem is increasing (Robichaud et al, 2009), and the bioaccumulation and potential impact of NPs deserve attention. Previous reports revealed that Pb causes changes to N-methyl-d-aspartate receptor (NMDAR) complexes, AChE, ACh and spine density of brain development in rat hippocampus and the significant histopathological changes in fish tissue (Guilarte and McGlothan, 2003;Reddy et al, 2007;Ahmed et al, 2014;Hu et al, 2014). A low dose Pb can similarly decrease the expression of NMDAR to inhibit the synapse development (Nihei et al, 2000).…”

“…In addition, the altered TH levels may cause several developmental defects, particularly to the central nervous system (CNS). There were also some results had demonstrated lead could cause an damage to the CNS (Guilarte and McGlothan, 2003;Reddy et al, 2007;Ahmed et al, 2014;Hu et al, 2014). The mechanisms behind the known effects of Pb on the CNS have not been fully explained, but several studies have reported that Pb exposure may alter the hypothalamic-pituitary-thyroid axis and thus, affect the CNS (Meeker et al, 2009;Singh et al, 2000Singh et al, 2000.…”

Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period

“…Pb-induced decrease in NR2A-containing NMDA receptor expression and phosphorylation of GluR1 could be important for spine formation and morphological change. In a recent study, Pb exposure during lactation period decreased dendritic spine density by inhibiting the Wnt 7a pathway [35]. However, Wnt 5a pathway (but not Wnt 7a pathway) has numerous cross-talks with NMDA receptor signaling [36].…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…In cultured rat hippocampal neurons, low levels of Pb2+ (0.1 and 1 µM) cause reduction of dendritic spine density in a dose-dependent manner (Hu et al, 2014). In a similar in vitro model, exposure to 1 μM Pb2+ for 5 days during the period of synaptogenesis (DIV7-DIV12), significantly reduces proBDNF protein and extracellular levels of mBDNF .…”

“…Exposure of rats to Pb2+ that initiated at embryonic phase and terminated at PND 21 have revealed that at PND 14 (Pb2+ concentration in the hippocampus 0.249±0.06 µg/g) and PND 21 (Pb2+ concentration in the hippocampus 0.471±0.11 µg/g) the number of dendritic spine on hippocampal CA1 area decreases by 32.83% and 24.11%, respectively (Hu et al, 2014). The length-density of the doublecortin-positive apical dendrites in the outer portion of the dentate gyrus molecular layer has been found significantly decreased up to 36% in chronically exposed rats to environmentally relevant levels of Pb2+ (Pb2+ blood levels 25.8 ± 1.28 μg/dL) (Verina et al, 2007).…”