Developmental Action of Estrogen Receptor-α Feminizes the Growth Hormone-Stat5b Pathway and Expression ofCyp2a4andCyp2d9Genes in Mouse Liver

Abstract

We have studied the roles of estrogen receptor-␣ (ER␣) and the Stat5b form of STAT (signal transducers and activators of transcription) in sex-specific expression of Cyp2a4 (steroid 15␣-hydroxylase) and Cyp2d9 (steroid 16␣-hydroxylase) genes using ER␣-deficient mice. ER␣ deficiency resulted in the repression of the female-specific Cyp2a4 and expression of the male-specific Cyp2d9 genes, respectively in females. In ER␣-deficient males, the Cyp2d9 gene continued to be expressed. Nuclear localization of Stat5b occurs in both sexes of ER␣-deficient mice, although it is normally observed in only wildtype males. Nuclear localization of Stat5b correlates with the repression of Cyp2a4 and expression of Cyp2d9, respectively. Because Stat5b was not detectable in liver nuclear extracts prepared from hypophysectomized ER␣-deficient females, the regulation by ER␣ appeared to be mediated through a pituitary hormone (i.e., growth hormone). Thus, ER␣ appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ER␣-GHStat5b pathway and Cyp expression. Defaulting to this ER␣-dependent mechanism results in localization of Stat5b to nuclei, which masculinizes the expression of Cyp genes in male mice.Hepatic metabolism of steroids and xenochemicals is sexually dimorphic in rodents and other animals . Sex-specific metabolism is catalyzed by cytochrome P-450s (CYPs) that are expressed either in male or female animals. Certain metabolism by sex-specific CYPs may lead to sex-dependent susceptibility for chemical toxicity and carcinogenicity (Waxman and Chang, 1995a and references therein). Various molecular and/or cellular mechanisms that may regulate transcription of sex-specific CYP genes have been proposed: DNA methylation (Yokomori et al., 1995), hepatocyte nuclear factor 6 (Lahuna et al., 1997) and the Stat5b form of STAT (signal transducers and activators of transcription) (Subramanian et al., 1995;Udy et al., 1997;Teglund et al., 1998). However, defining the regulatory mechanism of sex-specific CYP expression remains to be a major interest in continuous investigations.Hormonally, growth hormone (GH) is known to play a central role in regulating sex-specific CYP genes. Gustafsson and Stenberg (1976) first suggested the existence of a pituitary factor that feminizes steroid metabolism by rat liver microsomes and called it "a feminization factor". Later, this pituitary factor was found to be GH (Kramer and Colby, 1976). In rats, pulsatile GH secretion (in males) is required for activation of the male-specific CYP2C11 gene, whereas continuous GH secretion (in females) is essential for activating the female-specific CYP2C12 gene (Mode et al., 1981). CYP2A4 and CYP2D9 are the well-characterized sex-specific mouse steroid hydroxylases; the former is the female-specific steroid 15␣-hydroxylase, whereas the latter is the male-specific steroid 16␣-hydroxylase Negishi, 1984a,b, 1988). Using GH-deficient Little mice, we previously showed that GH activates and...

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

“…Sexually dimorphic P450s include CYP2C11, 2A2, 3A2, and 4A2, which are considered male-specific or malepredominant in the rat, while Cyp2d9 and 4a12 are well-characterized male-predominant P450s in the mouse. In contrast, CYP2C12 is female-predominant in the rat, while Cyp2a4, 2b9, 2b10, 2b13, 3a41, and 3a44 are female-predominant P450s in the mouse (Sueyoshi et al, 1999;Anakk et al, 2004;Wiwi et al, 2004).…”

Somatostatin is required for masculinization of growth hormone–regulated hepatic gene expression but not of somatic growth

“…Transcriptional regulation of these same genes differs in female liver in which there is a constitutive activation of femalespecific genes (Cyp2a4) and repression of male-specific genes (Cyp2d9) that is independent of pituitary GH (37). An important factor contributing to the female pattern is normal expression of estrogen receptor-α, presumably because of its importance in establishing the sexually dimorphic patterns of GH secretion (34).…”

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

“…This pathway for STAT5b activation is uniquely responsive to the male (pulsatile) plasma GH pattern; it results in a high level of active STAT5b in adult male, but not female, rat liver, coincident with each plasma GH pulse [15][16][17]. GH induces a similar sex-dependent activation of STAT5b in mouse liver [18]. The importance of this pathway is evident from the characterization of STAT5b-deficient male mice [19,20], which exhibit impaired body growth from approx.…”