Abstract
Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression. Butyl benzyl phthalate (BBP) was found to directly inhibit mRNA translation in vitro but showed a complicated pattern of affecting mRNA translation in cells. In human kidney embryonic cell (HEK-293T), BBP increased cap-dependent mRNA translation at lower concentrations but showed inhibitory effect at higher concentrations. Cap-independent translation was not affected. On the other hand, mono (2-ethylhexyl) phthalate (MEHP) as a major metabolite of another important phthalate di (2-ethylhexyl) phthalate (DEHP) inhibited both can-dependent and -independent mRNA translation in vivo. In contrast, BBP and MEHP exhibited an overall promoting effect on mRNA translation in cancer cells. Mechanistic studies identified that the level and phosphorylation of eIF4E-BP (eIF4E binding protein) and the amount of eIF4GI in eIF4F complex were altered in accordance with the effect of BBP on translation. BBP was also identified to directly bind to eIF4E, providing a further mechanism underlying the regulation of mRNA by phthalate. At the cellular level BBP inhibited normal cell growth but slightly promoted cancer cells (HT29) growth. Overall, this study provides the first evidence that phthalates can directly regulate mRNA translation as a novel mechanism to mediate their biological toxicities.
Highlights
Phthalates are a group of diesters of 1, 2-benzenedicarboxylic acid that widely used as plasticizers and solvents in a broad range of consumer products, construction materials, food package, child products, cosmetic products and medical devices [1, 2]
Molecular mechanism studies have been more focused on the regulation of gene transcription [16, 17] and the functioning through nuclear receptors, such as peroxisome proliferators-activated receptor (PPAR), estrogen receptor [18], androgen receptor [19], and glucocorticoid receptor [20]. mRNA translation/protein synthesis as a critical regulatory step of gene expression has been much less studied
MRNA translation machinery is localized in cytoplasm and more sensitive to environmental stimuli than gene transcription [21], rationalizing this study to be significant by directly examining the effects of phthalates on mRNA translation
Summary
Phthalates are a group of diesters of 1, 2-benzenedicarboxylic acid that widely used as plasticizers and solvents in a broad range of consumer products, construction materials, food package, child products, cosmetic products and medical devices [1, 2]. Regulation of mRNA Translation by Phthalates phthalate affects a large population of humans and causes a huge health burden [3]. Toxicity of phthalates has been inferred in at least 20 diseases, including endocrine and reproductive disorders, liver, cardiovascular, and urologic diseases [5]. The other major toxicity of phthalate is liver carcinogenicity [11], which is mainly through the interaction with the peroxisome proliferators-activated receptor (PPAR) α [12]. Molecular mechanism studies have been more focused on the regulation of gene transcription [16, 17] and the functioning through nuclear receptors, such as PPARs, estrogen receptor [18], androgen receptor [19], and glucocorticoid receptor [20]. MRNA translation machinery is localized in cytoplasm and more sensitive to environmental stimuli than gene transcription [21], rationalizing this study to be significant by directly examining the effects of phthalates on mRNA translation
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