Role of SIRT1 in Potentially Toxic Trace Elements (Lead, Fluoride, Aluminum and Cadmium) Associated Neurodevelopmental Toxicity

Abstract

The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.

Keywords: Memory; Mitochondrial dysfunction; Neurogenesis; Neurotoxicity; SIRT1.

Fig. 1

Possible function of SIRT1 in neurodevelopmental toxicity caused by exposure to Pb: Lead exposure in developing rats leads to accumulation of Pb ions in the hippocampus thereby downregulating SIRT1 expression. Pb ions are also linked with overproduction of ROS reducing the NAD⁺ levels and ultimately downregulates the SIRT1 expression. Moreover, SIRT1 downregulation resulted in accumulation of p53 thereby, inducing neuronal cell apoptosis leading to cognitive deficits and brain damage. Due to its deacetylating property, SIRT1 has a pivotal role in attenuating cell apoptosis by deacetylating p53 protein, which is responsible for stimulating neuronal apoptosis by increasing the transcription of Bax and cleaved caspase 3. SIRT1 downregulation has led to decreased CREB and BDNF expressions that primarily leads to reduced neurogenesis and learning and memory deficits. Note: This SIRT1 downregulated pathological pathway can be blocked by supplementation with SIRT1 activators like resveratrol and GM1

Fig. 2

Pathophysiological role of SIRT1 in developmentally fluoride exposure induced neurotoxicity: Developmentally, fluoride exposure leads to accumulation of fluoride in the rat hippocampus which in turn resulted in reduced SIRT1 activity and in SHSY5Y cells. Furthermore, due to reduced SIRT1 activity there is downregulation of PGC-1α/NRF1/TFAM signalling pathway thereby, resulting in decreased mitochondrial biogenesis which further promotes mitochondrial dysfunction and ultimately leads to developmental neurotoxicity in the offspring rats. NOTE: SIRT1 downregulated neurodevelopmental toxicity due to fluoride exposure can be reversed by administration of SIRT1 activator such as resveratrol and vice versa with SIRT1 antagonist