US EPA

3070990 

Journal Article 

Mono-2-ethylhexyl phthalate (MEHP) alters histiotrophic nutrition pathways and epigenetic processes in the developing conceptus 

Sant, KE; Dolinoy, DC; Jilek, JL; Shay, BJ; Harris, C 

2016 

1 

Journal of Nutritional Biochemistry
ISSN: 0955-2863
EISSN: 1873-4847 

ELSEVIER SCIENCE INC 

NEW YORK 

27 

211-218 

English 

26507544 

10.1016/j.jnutbio.2015.09.008 

WOS:000367409800023 

http://www.sciencedirect.com/science/article/pii/S0955286315002442
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Histiotrophic nutrition pathways (HNPs) are processes by which the organogenesis-stage conceptus obtains nutrients, amino acids, vitamins and cofactors required for protein biosynthesis and metabolic activities. Nutrients are captured from the maternal milieu as whole proteins and cargoes via receptor-mediated endocytosis in the visceral yolk sac (VYS), degraded by lysosomal proteolysis and delivered to the developing embryo (EMB). Several nutrients obtained by HNPs are required substrates for one-carbon (C1) metabolism and supply methyl groups required for epigenetic processes, including DNA and histone methylation. Increased availability of methyl donors has been associated with reduced risk for neural tube defects (NTDs). Here, we show that mono-2-ethylhexyl phthalate (MEHP) treatment (100 or 250μM) alters HNPs, C1 metabolism and epigenetic programming in the organogenesis-stage conceptus. Specifically, 3-h MEHP treatment of mouse EMBs in whole culture resulted in dose-dependent reduction of HNP activity in the conceptus. To observe nutrient consequences of decreased HNP function, C1 components and substrates and epigenetic outcomes were quantified at 24h. Treatment with 100-μM MEHP resulted in decreased dietary methyl donor concentrations, while treatment with 100- or 250-μM MEHP resulted in dose-dependent elevated C1 products and substrates. In MEHP-treated EMBs with NTDs, H3K4 methylation was significantly increased, while no effects were seen in treated VYS. DNA methylation was reduced in MEHP-treated EMB with and without NTDs. This research suggests that environmental toxicants such as MEHP decrease embryonic nutrition in a time-dependent manner and that epigenetic consequences of HNP disruption may be exacerbated in EMB with NTDs. 

Embryonic development; Neural tube defects; DNA methylation; Histone methylation; Histiotrophic nutrition; One-carbon metabolism