Postnatal chlorpyrifos exposure influences the gut microbiota and the expression of biological and neurobehavioral characteristics of the apoe genotype in an age-dependent manner
- Autores: Laia Guardia Escoté
- Directores de la Tesis: Maria Teresa Colomina Fosch (dir. tes.), Maria Cabré Bargalló (codir. tes.), Jordi Blanco Pérez (codir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Cristina Suñol Esquirol (presid.), Marta Barenys Espadaler (secret.), Ingrid Reverté Soler (voc.)
- Programa de doctorado: Programa de Doctorado en Salud, Psicología y Psiquiatría por la Universidad de Almería y la Universidad Rovira i Virgili
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Genetic determinants such as the apolipoprotein E (APOE) gene can influence the individual’s response to environmental factors. For instance the most frequent human APOE genetic variants give rise to different vulnerabilities to toxics, such as pesticides. Organophosphate pesticides – and in particular chlorpyrifos (CPF) – are extensively used worldwide. A massive use can trigger detrimental effects in non-target organisms, representing a risk to public health. In effect, general population is primarily exposed to trace levels of CPF in the food. Especial attention has been directed towards exposure during development, as higher vulnerability has been reported during this period. The main objective of this thesis was the assessment of the APOE genotype contribution on the behavioral and biochemical effects of postnatal exposure to chlorpyrifos at different times during lifespan. For that purpose, we used apoE3- and apoE4-TR mice, as well as the wild type C57BL/6. The animals were exposed to either 0 or 1 mg/kg/day of CPF from postnatal day 10 to 15. Gut microbiota composition and short-chain fatty acids (SCFAs) levels in the brain were studied in males at early ages whereas recognition memory was assessed in both male and female young adults. Furthermore, we explored the contribution of the cholinergic and GABAergic system by means of a pharmacological strategy. Spatial learning and memory were evaluated in middle-aged mice of both sexes, together with the gene expression of elements involved in the cholinergic system. Differences between APOE genotypes were observed throughout the study, modulating the response to the toxic effects of CPF. First, apoE4 presented differences in the core microbial communities, including Akkermansia muciniphila. CPF exposure induced dysbiosis at early ages, being apoE4 the most affected. Besides, apoE3-TR and CPF-treated mice were the ones presenting higher levels of certain SCFAs in the brain. In terms of recognition memory, apoE3-TR mice failed to recognize the novel object whereas CPF exposure impaired discrimination. The pharmacological challenge revealed differences between groups depending on postnatal exposure, sex and genotype. ApoE4 presented worse spatial memory compared to C57BL/6 but this was modulated by CPF exposure in a sex-dependent manner. Besides, apoE4 presented altered expression of cholinergic elements in the brain, which can also be influenced by postnatal CPF exposure. Overall, the current results show that postnatal exposure to CPF produce long-lasting effects in adults. The different characteristics conferred by the APOE genotype grant different levels of vulnerability to CPF-elicited effects in a sex-dependent manner, thereby giving further insight on gene-environment interactions at different points during lifetime.
