Aluru Parithathvi

Lead (Pb) is a well-established potent neurotoxicant. Biochemically, overexposure to Pb is associated with alterations in synaptic signaling and neurotransmission, causing disruptions in neuronal activity and hence resulting in the manifestation of developmental-related disorders. Furthermore, lead-induced neurotoxicity triggers ferroptosis and pyroptosis through mechanical pathways, including oxidative stress, mitochondrial dysfunction, and neuroinflammatory signaling. Recently, the inhibition of ferroptosis and pyroptosis has been explored as a potential treatment strategy against neurodegenerative diseases. However, a comprehensive synthesis of the molecular mechanisms linking these regulated cell death pathways to Pb-induced neurotoxicity is lacking. This narrative review synthesizes the current evidence on how Pb may influence key regulators of ferroptosis and pyroptosis, including the dysregulation of iron homeostasis, inhibition of the antioxidant system, excess reactive oxygen species generation (ROS), lipid peroxidation, and NLRP3/caspase-1-mediated cleavage and gasdermin D-dependent release of proinflammatory cytokines. In addition, this review integrates the current understanding of the potential crosstalk between ferroptosis and pyroptosis, identifies critical knowledge gaps and discusses emerging therapeutic interventions targeting these regulated cell death pathways. Although the literature provides experimental links between exposure to Pb and non-apoptotic -regulated cell death, including ferroptosis and pyroptosis, across in vivo and in vitro models, studies underlying its molecular mechanisms are lacking. Hence, in-depth investigations and evaluations are necessary to provide a framework for exploring the convergence of these pathways in lead neurotoxicity, as well as for the development of therapeutic strategies against Pb-induced ferroptosis and pyroptosis in neurodegeneration.

Aluminium, an omnipresent environmental pollutant, has been recognized for its neurotoxic effects, particularly its ability to promote neuronal death. More research evidence links aluminium exposure to death through molecular mechanisms. This review delves into the mechanisms underlying aluminium-induced neurotoxicity, including programmed cell death pathways such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Aluminium exposure leads to disruption of oxidative homeostasis and induction of endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage, which in turn trigger different cell death pathways. Substantial changes in key signalling pathways, such as the IL-1β/JNK, PI3K/Akt/mTOR, Nrf2/Ho-1, System Xc-/GPX4, and NLRP3 inflammasome activation pathways, were observed. Overall, these intertwined pathways highlight aluminium as a potent modulator of neuronal survival pathways, driving neurodegeneration through multifactorial mechanisms. A thorough understanding of these changes provides a fundamental explanation of the role of aluminium toxicity in the etiology of neurodegenerative diseases and provides a foundation for treatment. Graphical abstract

Lead is a toxic heavy metal with significant health risks, as maternal lead exposure during pregnancy disrupts fetal neural development through placental transfer, leading to persistent neurological, developmental, and long‐term health consequences in the progeny. Lead exposure typically affects the central nervous system, which is especially harmful during fetal development and early infancy. This review emphasizes the impact of early developmental exposure leading to disruption of neurotransmitter mechanisms. Mechanistically, lead disrupts neurodevelopment through various pathways, including alterations in myelin proteins, synaptic function, and neuroinflammatory responses, by interfering with the regulatory action of calcium, as lead mimics and replaces calcium. Alterations caused by lead, particularly in the dopaminergic, cholinergic, glutamatergic, and GABAergic pathways, increase the risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and cognitive disabilities in children. Lead is known to induce cellular, molecular, and epigenetic changes that impair neuronal connectivity, synaptic plasticity, and network functionality, ultimately leading to the disruption of neurodevelopmental pathways. The cumulative evidence highlights various aspects of lead neurotoxicity and emphasizes its role in the etiology of neurodevelopmental impairments. Understanding these pathways is critical for early intervention strategies to mitigate the long‐term cognitive and behavioral consequences of lead exposure during sensitive developmental periods.

Lead is a toxic heavy metal that poses significant health risks, which include neurodevelopmental disorders such as autism spectrum disorder (ASD). This review examines the effects of lead neurotoxicity on synaptic pathways which are relatively unexplored and their potential role in the development of ASD. Lead exposure occurs through various environmental sources, including contaminated water, soil, paint, and industrial appliances. Once absorbed, lead accumulates in soft tissues and bones, causes prolonged neurological damage, especially in children. ASD is characterised by impaired communication, repetitive behaviours, and cognitive challenges, with increasing evidence linking environmental factors like heavy metal exposure to its onset. Synaptic signalling disruption is a key aspect of ASD and lead interferes with the synaptic pathways by inhibiting calcium influx, leading to cognitive impairments and memory issues. This review is an overview of the previously reported findings that explains the role of lead in reducing N-methyl-D-aspartate receptors (NMDAR) function, disrupting the brain-derived neurotrophic factor (BDNF) pathway, and impairing Wnt, GABAergic and dopaminergic signalling pathways. These alterations result in cognitive decline, impaired synaptic plasticity and increased ASD symptoms. Understanding these mechanisms is crucial for developing strategies to mitigate the adverse effects of lead exposure on neurodevelopment.

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by amyloid plaques and neurofibrillary tangles. The increasing prevalence of AD highlights the importance of comprehending the role of major factors in disease progression. heavy metals such as lead, along with age, are key drivers of neurodegeneration. Lead, a hazardous heavy metal is adequately available in the environment and its malleable and ductile properties, increased the lead consumption. As lead can pass through placenta and blood brain barrier it is very important to study the transgenerational neurodegenerative effects of lead. Allicin, naturally obtained from Allium sativum , is a strong neuroprotective agent, is involved in reducing tau hyperphosphorylation and also a natural chelator due to its sulfhydryl groups. Method: In this study, Female Sprague‐Dawley rats were exposed to lead nitrate of 2mg/Kg body weight from preconception to weaning period of F1 progeny and allicin treatment of 40μg/Kg body weight. The F1 progeny were studied after 6 months of observation for behavioural histopathological and molecular changes. Result: The 6 months old F1 progeny showed significant behavioural changes attributing to anxiety and motor dysfunction between lead exposed and allicin treated groups. Similarly, histopathological studies like Nissl and H&E staining, immunohistochemistry using tau, tubulin and NeuN markers showed significant differences between lead exposed and allicin treated groups. mRNA studies of prominent AD‐specific genes like APP, BACE1, APOE and PSEN1 showed significant differences between F1 progeny of lead exposed and allicin treated groups. Conclusion: The results indicate the transgenerational effect of lead in inducing AD‐like pathophysiology even at 6‐month‐old F1 progeny. Allicin treated groups showed a significant decrease in the effects indicating its chelating and neuroprotective effect. This study emphasises the transgenerational neurotoxic effect of lead, leading to early onset of major neurodegenerative disorders and its therapeutic interventions.

Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.