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.

Laia Guardia-Escote,Fiona Peris-Sampedro,Judit Biosca-Brull,Rikst Nynke Verkaik-Schakel,Pia Basaure,Fernando Sánchez-Santed,José L Domingo,Maria Teresa Colomina,Maria Cabré,Torsten Plösch,Jordi Blanco,Cristian Pérez-Fernández

doi:10.3390/ijerph18010184

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.

Highlights

This article is an open access articleObesity has undeniably increased its worldwide prevalence in recent decades
Epigenetic of APOE4 several genes in the hypothalamic area, which is involved in Thereafter, we introduced a high-fat diet to focus on how these factors influenced metafeeding control and energy balance
The methylation status was analyzed for each CpG position within the target region of the genes studied: Pomc, Npy, Lepr, and Igf2

Summary

Introduction

This article is an open access article. Obesity has undeniably increased its worldwide prevalence in recent decades. It is a major risk factor for other common diseases such as type 2 diabetes, metabolic syndrome, and some types of cancer [1]. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, early life factors such as diet, stress, or exposure to toxicants can increase vulnerability to chronic diseases later in life [2,3].

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