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

Abstract

Perinatal exposure of rats and mice to the typically reported 4mg/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, 2mg/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.

Feminization imprinted by developmental growth hormone

“…In agreement with previous studies (Oliver et al 1982; Kacsoh et al 1989) as well as our own report (Banerjee et al 2015), plasma GH levels in the control group were maximum the first few postpartum days of life, thereafter declining ~55% by 5 days of age and by ~85% from 11 through 15 days of age (Fig. 1).…”

“…Plasma GH concentrations were determined by a sensitive sandwich ELISA method as described previously (Das et al 2013). Procedures for collecting unstressed postnatal plasma as well as adult serial blood sampling for GH determinations have been reported (Pampori, et al 1991b; Banerjee et al 2015).…”

“…We previously reported that adult male rats and men cannot be induced (regardless of GH treatment) to express the normal female profile of CYPs (Pampori & Shapiro 1999; Thangavel, et al 2004; Dhir, et al 2006; Thangavel & Shapiro 2008) nor can adult female rats or women be induced to fully express the masculine CYP profile (Pampori, et al 2001; Dhir et al 2006; Thangavel, et al 2006; Thangavel & Shapiro 2007). The response to each of the dozen or so sex- dependent rat CYP isoforms to GH regulation has been described (Thangavel & Shapiro 2008; Das, et al 2013; Banerjee, et al 2015). If CYP enzymes were not imprinted, then irrespective of sex, the same adult treatment should produce the same CYP expression levels in males and females.…”

Generation and Characterization of a CYP2C11-Null Rat Model by Using the CRISPR/Cas9 Method

“…CYP2C11 is the most abundant cytochrome P450 (P450) in the livers of adult male rats, where it accounts for ;50% of the total P450s (Morgan et al, 1985;Banerjee et al, 2015). CYP2C11 is exclusively expressed in the livers of adult male rats; this male-specific expression is activated by the male pattern of plasma growth hormone pulsation (Choi and Waxman, 2000).…”

Defects of the exchange of amino acids in the perinatal period

“…Споживання при вагітності високих доз глута-мату натрію щурами призводить до ожиріння, за-тримки росту і пригнічення цитохрому Р450 [43].…”