Perinatal phthalate and high-fat diet exposure induce sex-specific changes in adipocyte size and DNA methylation

Environmental factors such as diet and endocrine-disrupting chemicals have individually been shown to mediate metabolic function. However, the underlying mechanism by which the combination disrupts adipocyte morphology and fat storage remains unknown. The current study evaluated early-life programming by diet and phthalate exposure. During gestation and lactation, pregnant Long–Evans hooded rat dams were fed either a control (C) or high-fat (HF) diet and were orally administered one of three phthalate dosages (0, 200 or 1000 μg/kg/day), yielding six groups of offspring: C-0, C-200, C-1000, HF-0, HF-200 and HF-1000. On postnatal day (PND) 90, gonadal fat pads were collected and analyzed for histology, gene expression and DNA methylation. Differences in body weight were observed only in males. Hematoxylin and eosin staining revealed larger adipocyte size in HF-0 vs. C-0 females. Exposure to 200 or 1000 μg/kg/day phthalates modulated diet-induced changes in adipose morphology. Compared to C-0 females, HF-0 females also had higher expression of the adipogenesis gene Wnt receptor, frizzled 1 (Fzd1) and the triglyceride cleaving enzyme lipoprotein lipase (Lpl). These increases in gene expression were accompanied by lower DNA methylation surrounding the transcription start sites of the two genes. Diet-driven effects were observed in unexposed females but not in phthalate-treated rats. Results suggest a sex-specific association between perinatal HF diet and body weight, adipocyte size and DNA methylation. Perinatal phthalate exposure appears to produce a phenotype that more closely resembles HF-fed animals.