Academic journal article Environmental Health Perspectives

DNA Methylation in Oocytes and Liver of Female Mice and Their Offspring: Effects of High-Fat-Diet-Induced Obesity

Academic journal article Environmental Health Perspectives

DNA Methylation in Oocytes and Liver of Female Mice and Their Offspring: Effects of High-Fat-Diet-Induced Obesity

Article excerpt

Introduction

The World Health Organization has reported that obesity, defined as abnormal or excessive fat accumulation that may impair health, has nearly doubled since 1980, and nearly 300 million women were obese in 2008 (World Health Organization 2013). Several years ago obesity and overweight was a problem in developed countries, but it has now become a problem in the entire world. Obese humans are prone to type 2 diabetes, hypertension, cardiovascular disease, and other disorders or diseases (Howie et al. 2009), and these conditions can be transmitted to the future generations (Fullston et al. 2012; Howie et al. 2009).

Obesity is a well-established cause of subfertility in humans and animals. In mice fed a high-fat diet (HFD) for 16 weeks, ovulation rate, embryo development, placental function, ovarian function, and mitochondrial function were affected in oocytes (Cardozo et al. 2011; Igosheva et al. 2010; Jungheim et al. 2010; Minge et al. 2008). Dunn and Bale (2009) reported that offspring of obese female mice showed a significant increase in body length. In humans, similar results were reported for oocytes from mothers with a higher body mass index (BMI) (Wattanakumtornkul et al. 2003), and children of women with high BMI tended to accumulate more fat by 9 years of age than did children of women with lower BMI (Gale et al. 2007). These reports show that obesity causes female subfertility and also that these adverse effects can be inherited by the offspring.

Obesity can be caused by genetic mutations (Graff et al. 2013), but the environment and life style are also key reasons for obesity. Currently, overweight and obesity are attributed mainly to lifestyle factors such as excessive consumption of high-carbohydrate food, low physical activities, and other factors (McAllister et al. 2009). Several studies have provided evidence that macro- or micronutrients induce epigenetic changes in offspring (Heijmans et al. 2008; Tobi et al. 2009; Waterland and Jirtle 2003; Waterland et al. 2006). Therefore, epigenetic alterations may be an important link between the environment and genes by which obese parents transmit deleterious conditions to their children.

Genomic imprinting is a parental origin-specific gene-marking phenomenon that is crucial for normal mammalian development. Differentially methylated regions (DMRs) of imprinted genes are methylated on either the paternal or maternal allele (Reik et al. 2001; Sasaki and Matsui 2008). The DNA methylation status is established during gametogenesis and early embryo development (Lucifero et al. 2002). However, methylation patterns of genomic imprinting genes tend to be altered by a deleterious environment or manipulation (Anckaert et al. 2010; Khosla et al. 2001). The detailed mechanisms underlying these changes are still unknown.

On the basis of previous reports (Fullston et al. 2012; Howie et al. 2009), we hypothesized that maternal obesity may impair DNA methylation of imprinted genes in oocytes and that it can be transmitted to the offspring. To test our hypothesis, we used mice with HFD-induced obesity, a widely used animal model (Igosheva et al. 2010; Jungheim et al. 2010; Minge et al. 2008). We investigated the methylation patterns in DMRs of paternally imprinted gene H19, maternally imprinted genes Peg3 (paternally expressed 3), Snrpn (small nuclear ribonucleoprotein N), Igf2r (insulin-like growth factor 2 receptor), and Pegl in oocytes of control and obese animals and their offspring. Because other studies have shown that the expression of leptin (Lep) and Ppar-[alpha] (peroxisome proliferator-activated receptor a) is regulated by DNA methylation in their promoters and that the two genes are correlated to metabolism (Burdge et al. 2009; Cordero et al. 2011a, 2011b), we also investigated DNA methylation of these two genes. We also investigated DNA methylation patterns of intracisternal A particle (IAP) in oocytes.

Materials and Methods

Mice provided by the Beijing Vital River Experimental Animals Centre (Beijing, People's Republic of China) were housed under conditions of 12 hr light and 12 hr dark in a temperature- (23 [+ or -] 1[degrees]C) and humidity- (60 [+ or -] 5%) controlled room. …

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