In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge

Abstract

Phthalates impact adipocyte morphology in vitro, but the sex-specific adipogenic signature immediately after perinatal di(2-ethylhexyl) phthalate (DEHP) exposure and adulthood physiology following a high-fat (HF) dietary challenge are unknown. In the current study, pregnant and lactating dams received DEHP (300 mg/kg body weight) or oil. At weaning (postnatal day (PND) 21), adipose tissue was sampled for real-time PCR. The remaining offspring consumed a control or HF diet. DEHP decreased % fat in males at birth from 13.9%±0.2 to 11.8%±0.6 (mean±SEM), representing a 15.1% decrease in fat by DEHP, and these males caught up in adiposity to controls by PND21. Adult DEHP-exposed males had a 27.5% increase in fat (12.5%±0.9% in controls vs. 15.9%±1.5% in the DEHP group); adipocyte perimeter was increased as well, with fewer small/medium-sized adipocytes, and decreased cell number compared to oil controls. HF diet intake in DEHP-exposed males further increased male energy intake and body weight and led to glucose intolerance. In PND21 males, DEHP increased the expression of adipogenic markers (Pparg1, Cebpa, Adipoq, Ppard, Fabp4, Fasn, Igf1), decreased Lep, and decreased markers of mesenchymal stem cell commitment to the adipogenic lineage (Bmp2, Bmp4, Stat1, Stat5a) compared to oil controls. These data suggest that DEHP may decrease the adipocyte pool at birth, which initially increases adaptive adipocyte maturation and lipid accumulation, but leads to adipose tissue dysfunction in adulthood, decreasing the capacity to adapt to a HF diet, and leading to systemic glucose intolerance.

Maternal phthalate exposure during early pregnancy and at delivery in relation to gestational age and size at birth: A preliminary analysis

“…For example, early rodent studies found that DEHP exposure was associated with decreased fetal and birth weight (31, 32]), while similar recent studies are consistent with our findings of no association (33, 34). Animal studies of in utero DBP exposure have also observed inconsistent effects on birth weight, with several studies reporting no effect (35-38), while others reported either decreased (39-41) or increased (42) birth weight.…”

Adipose Tissue as a Site of Toxin Accumulation

“…Administration of PCB-77 to mice resulted in greater body weight and adipocyte hypertrophy (34). Similarly, in utero exposure of mice to BPA (433) or the phthalates DHEP and MEHP increased adult fat mass, lipid accumulation and body weight (142) (373). However, in general, reports of direct effects of POPs to increase lipid accumulation are limited.…”

Metabolism disrupting chemicals and metabolic disorders

“…Prenatal exposure to a nebulized PAH mixture 5 days a week for three weeks led to increased weight, fat mass and higher gene expression of PPARγ, fatty acid synthase and adiponectin in mice[375]. Developmental exposure in rats to PAHs in diesel exhaust have been shown to lead to increased obesity, insulin resistance and inflammation; these effects were observed only in adults fed a high fat diet, indicating a second hit was needed, and only in males, indicating a sexually dimorphic effect [376, 377].…”