Feminization imprinted by developmental growth hormone

Abstract

Previously, we identified early developmental exposure to growth hormone (GH) as the requisite organizer responsible for programming the masculinization of the hepatic cytochromes P450 (CYP)-dependent drug metabolizing enzymes (Das et al., 2014, 2017). In spite of the generally held dogma that mammalian feminization requires no hormonal imprinting, numerous reports that the sex-dependent regulation and expression of hepatic CYPs in females are permanent and irreversible would suggest otherwise. Consequently, we selectively blocked GH secretion in a cohort of newborn female rats, some of whom received concurrent GH replacement or GH releasing factor. As adults, the feminine circulating GH profile was restored in the treated animals. Two categories of CYPs were measured. The principal and basically female specific CYP2C12 and CYP2C7; both completely and solely dependent on the adult feminine continuous GH profile for expression, and the female predominant CYP2C6 and CYP2E1 whose expression is maximum in the absence of plasma GH, suppressed by the feminine GH profile but more so by the masculine episodic GH profile. Our findings indicate that early developmental exposure to GH imprints the inchoate CYP2C12 and CYP2C7 in the differentiating liver to be solely dependent on the feminine GH profile for expression in the adult female. In contrast, adult expression of CYP2C6 and CYP2E1 in the female rat appears to require no GH imprinting.

Early expression of requisite developmental growth hormone imprinted cytochromes P450 and dependent transcription factors

“…Moreover, episodic GH acts as an inducer, but instead, acts as a repressor in regulating CYP3A2 and CYP2C6 expression. Similarly, delimited effects of GH imprinting on CYP isoforms expressed in female rats have been reported ( 60 ).…”

Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

“…Of note, however, this response is largely not a direct result of a loss of sex differential cohesin and/or CTCF binding at distal male-biased enhancers, as only 5 of 32 distally regulated male-biased genes have male-biased CTCF/cohesin binding at their distal male-biased enhancers. Alternatively, the sex-biased enhancer–promoter and enhancer–enhancer loops that we describe here might be determined by intrinsic sex differences [ 88 ], or might be established by early postnatal hormone exposures that program liver gene expression [ 97 ]. Studies to detect dynamic changes in DNA looping and quantify changes in chromatin interaction strength, e.g., during the course of a male plasma growth hormone pulse [ 74 ], will likely require improvements to the 4C-seq protocol, including the use of unique molecular identifiers for more accurate quantification of interactions [ 69 ] and the elimination of any PCR artifacts associated with over-amplification, which are difficult to address using conventional 4C-seq methods [ 45 ] and may have decreased the magnitude of the apparent sex differences in chromatin interactions seen in our work.…”

Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver

“…Of note, however, this response is largely not a direct result of a loss of sex differential cohesin and/or CTCF binding at distal male-biased enhancers, as only 5 of 32 distally-regulated male biased genes have male-biased CTCF/cohesin binding at their distal male-biased enhancers. Alternatively, the sex-biased enhancer-promoter and enhancer-enhancer loops that we describe here might be determined by intrinsic sex differences [89], or might be established by early postnatal hormone exposures that program liver gene expression [98]. Studies to detect dynamic changes in DNA looping and quantify changes in chromatin interaction strength, e.g., during the course of a male plasma growth hormone pulse [75], will likely require improvements to the 4C-seq protocol, including the use of unique molecular identi ers for more accurate quanti cation of interactions [70] and the elimination of any PCR artifacts associated with over-ampli cation, which are di cult to address using conventional 4C-seq methods [45] and may have decreased the magnitude of the apparent sex differences in chromatin interactions seen in our work.…”