Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes
Lead (Pb) is a pervasive neurotoxicant with well-documented detrimental effects on the central nervous system, particularly in vulnerable populations such as children. Despite historical recognition of its toxicity, Pb exposure remains a significant public health concern due to its environmental per...
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MDPI AG
2025-06-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/13/7/519 |
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| author | Wagner A. Tamagno Jennifer L. Freeman |
| author_facet | Wagner A. Tamagno Jennifer L. Freeman |
| author_sort | Wagner A. Tamagno |
| collection | DOAJ |
| description | Lead (Pb) is a pervasive neurotoxicant with well-documented detrimental effects on the central nervous system, particularly in vulnerable populations such as children. Despite historical recognition of its toxicity, Pb exposure remains a significant public health concern due to its environmental persistence, historical industrial use, and ongoing applications in modern technologies. This review focuses on the mechanisms by which Pb disrupts glutamatergic signaling, a critical pathway for learning, memory, and synaptic plasticity. Pb’s interference with glutamate receptors (ionotropic NMDA and AMPA, as well as metabotropic receptors), transporters (EAATs, VGLUTs, and SNATs), and metabolic pathways (glutamate–glutamine cycle, TCA cycle, and glutathione synthesis) are detailed. By mimicking divalent cations like Ca<sup>2+</sup> and Zn<sup>2+</sup>, Pb<sup>2+</sup> disrupts calcium homeostasis, exacerbates excitotoxicity, and induces oxidative stress, ultimately impairing neuronal communication and synaptic function. These molecular disruptions manifest cognitive deficits, behavioral abnormalities, and increased susceptibility to neurodevelopmental and neurodegenerative disorders. Understanding Pb’s impact on glutamatergic neurotransmission offers critical insights into its neurotoxic profile and highlights the importance of addressing its effects on neural function. |
| format | Article |
| id | doaj-art-e849f8d5908e47e19401632ec8fed016 |
| institution | DOAJ |
| issn | 2305-6304 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxics |
| spelling | doaj-art-e849f8d5908e47e19401632ec8fed0162025-08-20T03:08:13ZengMDPI AGToxics2305-63042025-06-0113751910.3390/toxics13070519Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and PhenotypesWagner A. Tamagno0Jennifer L. Freeman1School of Health Sciences, Purdue University, West Lafayette, IN 47907, USASchool of Health Sciences, Purdue University, West Lafayette, IN 47907, USALead (Pb) is a pervasive neurotoxicant with well-documented detrimental effects on the central nervous system, particularly in vulnerable populations such as children. Despite historical recognition of its toxicity, Pb exposure remains a significant public health concern due to its environmental persistence, historical industrial use, and ongoing applications in modern technologies. This review focuses on the mechanisms by which Pb disrupts glutamatergic signaling, a critical pathway for learning, memory, and synaptic plasticity. Pb’s interference with glutamate receptors (ionotropic NMDA and AMPA, as well as metabotropic receptors), transporters (EAATs, VGLUTs, and SNATs), and metabolic pathways (glutamate–glutamine cycle, TCA cycle, and glutathione synthesis) are detailed. By mimicking divalent cations like Ca<sup>2+</sup> and Zn<sup>2+</sup>, Pb<sup>2+</sup> disrupts calcium homeostasis, exacerbates excitotoxicity, and induces oxidative stress, ultimately impairing neuronal communication and synaptic function. These molecular disruptions manifest cognitive deficits, behavioral abnormalities, and increased susceptibility to neurodevelopmental and neurodegenerative disorders. Understanding Pb’s impact on glutamatergic neurotransmission offers critical insights into its neurotoxic profile and highlights the importance of addressing its effects on neural function.https://www.mdpi.com/2305-6304/13/7/519calcium signalingEAATexcitotoxicityglutamateneurotoxicityNMDA |
| spellingShingle | Wagner A. Tamagno Jennifer L. Freeman Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes Toxics calcium signaling EAAT excitotoxicity glutamate neurotoxicity NMDA |
| title | Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes |
| title_full | Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes |
| title_fullStr | Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes |
| title_full_unstemmed | Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes |
| title_short | Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes |
| title_sort | glutamate mediated neural alterations in lead exposure mechanisms pathways and phenotypes |
| topic | calcium signaling EAAT excitotoxicity glutamate neurotoxicity NMDA |
| url | https://www.mdpi.com/2305-6304/13/7/519 |
| work_keys_str_mv | AT wagneratamagno glutamatemediatedneuralalterationsinleadexposuremechanismspathwaysandphenotypes AT jenniferlfreeman glutamatemediatedneuralalterationsinleadexposuremechanismspathwaysandphenotypes |