Apoptotic and necrotic basal forebrain cholinergic neuronal loss and dendritic spines alteration after acute and long-term chlorpyrifos exposureLegal implications of the use of toxicogenomic profile as a biomarker of harmful effects induced under subclinical doses
- Paula Moyano 1
- Javier del Pino 1
- María José Anadón 1
- José Manuel García 1
- María Jesús Díaz 1
- Gloria Gómez 1
- Jimena García 2
- María Teresa Frejo 1
- Miguel Andrés Capó 1
- 1 Universidad Complutense de Madrid. Facultad de Veterinaria Departamento de Toxicología y Farmacología
- 2 Universidad Alfonso X. Departamento de Farmacología, Ciencias de la Salud
ISSN: 2255-0569
Año de publicación: 2016
Volumen: 31
Número: 1
Páginas: 24-34
Tipo: Artículo
Otras publicaciones en: Medicina balear
Resumen
Introduction: Chlorpyrifos (CPF) is an organophosphate insecticide reported to induce both after acute and repeated exposure learning and memory dysfunctions, although the mechanism is not completely known. CPF produces basal forebrain cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. This effect was reported to be mediated through apoptotic process, although neuronal necrosis was also described after CPF exposure. Otherwise, neuronal dendritic spines were reported to be also involved on learning and memory process regulation and their alteration could also contribute to this effect. In this regard, CPF has been reported to induce an alteration in the dendritic spines density in the prefrontal cortex and hippocampus after acute and repeated exposure to subclinical doses respectively, thus their alteration in basal forebrain cholinergic neurons could also mediate cognitive disorders. Objectives and methods: Accordingly, we hypothesized that CPF induces basal forebrain cholinergic dendritic spine alteration at low concentrations and at higher concentrations produces necrotic and apoptotic cell death. We evaluated in septal SN56 basal forebrain cholinergic neurons, the CPF effect after 24 h and 14 days exposure on dendritic spines, the necrosis induction and the apoptotic and necrotic gene expression pathways. Results: This study shows that CPF induces after acute and long-term exposure an alteration of dendritic spines at lower concentrations than which induces cell death. Evaluation of cell death pathways and genes related to dendritic spine plasticity revealed that some of them are altered at lower concentrations than which produces the effects observed and below the No Observed Adverse Effect (NOAEL). Conclusions: The present finding suggest that the use of gene expression profile could be a more sensitive and accurate way to determine the NOAEL.