Postnatal chlorpyrifos exposure influences the gut microbiota and the expression of biological and neurobehavioral characteristics of the APOE genotype in an age-dependent manner

Identificador:  TDX:3011

Handle: https://hdl.handle.net/20.500.11797/TDX3011

Autores:  Guardia Escoté, Laia

Resumen:
Genetic determinants such as the polymorphism of the apolipoprotein E (APOE) gene can influence the response to environmental factors. The most frequent human APOE genetic variants confer different vulnerabilities to toxics, in particular to the worldwide used pesticide chlorpyrifos (CPF). A massive use of pesticides can trigger detrimental effects in general population, who present higher vulnerability during development. In the present study we assessed the APOE genotype contribution on behavioral and biochemical effects after postnatal exposure to CPF at different times during lifespan. ApoE3-, apoE4-TR and C57BL/6 mice were exposed to 0 or 1 mg/kg/day of CPF from postnatal day 10 to 15. Gut microbiota composition and cerebral short-chain fatty acids (SCFAs) levels were studied at early ages whereas recognition memory was assessed in young adults. Spatial learning and memory and gene expression of cholinergic elements were evaluated in middle-aged mice. Differences between APOE genotypes were observed throughout the study, modulating the response to CPF. First, apoE4-TR presented differences in the core microbial communities and was the most affected by CPF-induced dysbiosis. Besides, apoE3-TR and CPF-treated mice presented higher levels of SCFAs. Adult apoE3-TR mice failed to recognize the novel object whereas CPF impaired recognition memory. The pharmacological challenge revealed differences in cholinergic and GABAergic systems between groups. ApoE4 presented worse spatial memory compared to C57BL/6, which was modulated by CPF exposure in a sex-dependent manner, and altered expression of cholinergic elements in the brain, being also 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.