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Title: Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate

Abstract

Perinatal exposure of rats and mice to the typically reported 4 mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2 mg/g bd wt on alternate days for the first 9 days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11more » ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. - Highlights: • A “low” neonatal dose of MSG causes an immediate but transient growth hormone depletion. • Adult circulating growth hormone contains mini pulses in an otherwise male profile. • CYP2C11 is permanently overexpressed > 250%; CYP2C6, 2C7 and albumin remain normal. • The bulk of the overexpressed CYP2C11 mRNA consists of an intron-retained form. • SOCS2 and miRNAs are subnormal, ubiquitination is elevated but JAK2/STAT5b is normal.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22465725
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 284; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALBUMINS; CHROMATIN; DOSES; FOOD ADDITIVES; INHIBITION; LIVER CELLS; MALES; MESSENGER-RNA; METABOLIC DISEASES; MICE; PLANT GROWTH; PROMOTERS; PULSES; RATS; RECEPTORS; SECRETION; STH; TRANSCRIPTION; TRANSDUCERS

Citation Formats

Banerjee, Sarmistha, Das, Rajat Kumar, Giffear, Kelly A., and Shapiro, Bernard H., E-mail: shapirob@vet.upenn.edu. Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.02.009.
Banerjee, Sarmistha, Das, Rajat Kumar, Giffear, Kelly A., & Shapiro, Bernard H., E-mail: shapirob@vet.upenn.edu. Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate. United States. doi:10.1016/J.TAAP.2015.02.009.
Banerjee, Sarmistha, Das, Rajat Kumar, Giffear, Kelly A., and Shapiro, Bernard H., E-mail: shapirob@vet.upenn.edu. Wed . "Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate". United States. doi:10.1016/J.TAAP.2015.02.009.
@article{osti_22465725,
title = {Permanent uncoupling of male-specific CYP2C11 transcription/translation by perinatal glutamate},
author = {Banerjee, Sarmistha and Das, Rajat Kumar and Giffear, Kelly A. and Shapiro, Bernard H., E-mail: shapirob@vet.upenn.edu},
abstractNote = {Perinatal exposure of rats and mice to the typically reported 4 mg/g bd wt dose of monosodium glutamate (MSG) results in a complete block in GH secretion as well as obesity, growth retardation and a profound suppression of several cytochrome P450s, including CYP2C11, the predominant male-specific isoform — all irreversible effects. In contrast, we have found that a lower dose of the food additive, 2 mg/g bd wt on alternate days for the first 9 days of life results in a transient neonatal depletion of plasma GH, a subsequent permanent overexpression of CYP2C11 as well as subnormal (mini) GH pulse amplitudes in an otherwise normal adult masculine episodic GH profile. The overexpressed CYP2C11 was characterized by a 250% increase in mRNA, but only a 40 to 50% increase in CYP2C11 protein and its catalytic activity. Using freshly isolated hepatocytes as well as primary cultures exposed to the masculine-like episodic GH profile, we observed normal induction, activation, nuclear translocation and binding to the CYP2C11 promoter of the GH-dependent signal transducers required for CYP2C11 transcription. The disproportionately lower expression levels of CYP2C11 protein were associated with dramatically high expression levels of an aberrant, presumably nontranslated CYP2C11 mRNA, a 200% increase in CYP2C11 ubiquitination and a 70–80% decline in miRNAs associated, at normal levels, with a suppression of CYP2C expression. Whereas the GH-responsiveness of CYP2C7 and CYP2C6 as well as albumin was normal in the MSG-derived hepatocytes, the abnormal expression of CYP2C11 was permanent and irreversible. - Highlights: • A “low” neonatal dose of MSG causes an immediate but transient growth hormone depletion. • Adult circulating growth hormone contains mini pulses in an otherwise male profile. • CYP2C11 is permanently overexpressed > 250%; CYP2C6, 2C7 and albumin remain normal. • The bulk of the overexpressed CYP2C11 mRNA consists of an intron-retained form. • SOCS2 and miRNAs are subnormal, ubiquitination is elevated but JAK2/STAT5b is normal.},
doi = {10.1016/J.TAAP.2015.02.009},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 284,
place = {United States},
year = {Wed Apr 01 00:00:00 EDT 2015},
month = {Wed Apr 01 00:00:00 EDT 2015}
}