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- Guardia-Escote, L., et al.
(författare)
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Sex and Exposure to Postnatal Chlorpyrifos Influence the Epigenetics of Feeding-Related Genes in a Transgenic APOE Mouse Model: Long-Term Implications on Body Weight after a High-Fat Diet
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Developmental exposure to toxicants and diet can interact with an individual's genetics and produce long-lasting metabolic adaptations. The different isoforms of the apolipoprotein E (APOE) are an important source of variability in metabolic disorders and influence the response to the pesticide chlorpyrifos (CPF). We aimed to study the epigenetic regulation on feeding control genes and the influence of postnatal CPF exposure, APOE genotype, and sex, and how these modifications impact on the metabolic response to a high-fat diet (HFD). Both male and female apoE3- and apoE4-TR mice were exposed to CPF on postnatal days 10-15. The DNA methylation pattern of proopiomelanocortin, neuropeptide Y, leptin receptor, and insulin-like growth factor 2 was studied in the hypothalamus. At adulthood, the mice were given a HFD for eight weeks. The results highlight the importance of sex in the epigenetic regulation and the implication of CPF treatment and APOE genotype. The body weight progression exhibited sex-dimorphic differences, apoE4-TR males being the most susceptible to the effects induced by CPF and HFD. Overall, these results underscore the pivotal role of sex, APOE genotype, and developmental exposure to CPF on subsequent metabolic disturbances later in life and show that sex is a key variable in epigenetic regulation.
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- Guardia-Escote, L., et al.
(författare)
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APOE genetic background and sex confer different vulnerabilities to postnatal chlorpyrifos exposure and modulate the response to cholinergic drugs
- 2019
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 376
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Tidskriftsartikel (refereegranskat)abstract
- Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups. © 2019 Elsevier B.V.
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