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

Abstract

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 250 µM) alters HNPs, C1 metabolism, and epigenetic programming in the organogenesis-stage conceptus. Specifically, 3 h MEHP treatment of mouse embryos 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 24 h. 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.

Mono-2-ethylhexyl phthalate disrupts neurulation and modifies the embryonic redox environment and gene expression

“…This concept agrees with previous studies showing that inhibition of the histiotrophic nutrition pathways (HNP), through which the vast majority of conceptal nutrients are obtained, results in convincing proteomic evidence that the activation of ribosome biogenesis and autophagy pathways are selective indicators of toxicity. We have previously demonstrated that MEHP significantly reduces HNP activity in the mouse model used in the study [74]. This indicates that MEHP-induced changes in nutrient availability and processing could be a factor in observed developmental toxicity.…”

“…Additional indirect amino acid metabolic pathways, such as GSH metabolism and TCA cycle were also affected. Because all of these pathways rely on the supply of amino acids, it is possible that MEHP treatment is inducing a form of amino acid starvation through decreased nutrient availability as previously found [74]. Amino acid starvation has been discovered to have numerous physiological and metabolic consequences, namely effects on energy metabolism including oxidative phosphorylation [75, 76].…”

“…Amino acid starvation has been discovered to have numerous physiological and metabolic consequences, namely effects on energy metabolism including oxidative phosphorylation [75, 76]. MEHP has been demonstrated to decrease protein uptake into the conceptus, reducing the amino acids available for protein synthesis and metabolism [74]. It is therefore likely that MEHP-induced amino acid starvation could have numerous downstream consequences affecting signaling and overall growth and differentiation.…”

“…Disruption of oxidative phosphorylation and amino acid metabolism, oxidation of GSH/GSSG redox potential, decreased vitamin transport processes, compounded with prior evidence of decreased nutritional clearance, suggest that MEHP treatment can produce severe nutritional deficiencies during early organogenesis [74]. Often during such deficiencies, processes governing mitochondrial function are stimulated or supported at the expense of cytosolic processes [87].…”

Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth

“…Phthalates and BPA have been shown to cause oxidative stress, hormonal disturbances, and epigenetic modifications that all could have deleterious effects on growth. 15-19 Inconsistencies in previous studies of phthalate or BPA exposure and fetal growth may be due to the fact that the majority model associations with birthweight or other measures at delivery only. 3, 20-23 Longitudinal studies with repeated ultrasound measurements taken during gestation have greater power to detect effects.…”