Steroidogenic enzyme expression in the human fetal liver and potential role in the endocrinology of pregnancy

Abstract

The human feto-maternal unit produces large amounts of steroid hormones, particularly estrogens, during the second and third trimesters. The fetal adrenal gland and the placenta are considered the principal tissues driving steroid production but the fetal liver is likely to play an essential role in this process. This study was designed to measure transcript expression of proteins involved in steroid synthesis, metabolism, conjugation and signalling in the human fetal liver and to examine sex differences and effects of maternal smoking. Liver samples were taken from 55 normal fetuses from women undergoing second trimester elective termination. Levels of 23 mRNA transcripts encoding steroid synthesis/metabolic/conjugation enzymes and steroid receptors were measured by real-time PCR. The expression of representative proteins was confirmed by western blotting and immunohistochemistry. The human fetal livers expressed high levels of CYP19A1, SULT2A1, SULT1E1, HSD17B2, SRD5A3 and CYP3A7. Lower levels of SULT1A1, STS, UGT2B17, GPER, AKR1C3, UGT2B15, AR, CYP11A1, CYP21A2, HSD17B3, HSD17B1 and SRD5A1 were also detectable. The expression of ESR, ESR2, CYP17A1 and HSD3B transcripts was undetectable in most fetal livers, although HSD3B was shown to be present by western blotting. Sex differences were limited to SRD5A3 (lower in females) and UGT2B17 (higher in females). Maternal smoking increased the expression of CYP19A1, SULT2A1, UGT2B17, HSD17B2 and AKR1C3 and reduced the expression of SRD5A3 in the male fetal liver. This study shows that the human fetal liver is likely to have an extensive effect on circulating steroid levels in the human fetus and mother. The most important of these effects will be alterations to the species, conjugation and availability of estrogens in the fetus. Maternal smoking is likely to reduce circulating androgen bioactivity in male fetuses.

From the Editor's Desk, Editorial Highlights, Letter to the Editor

“…In our study (O'Shaughnessy et al, 2013), which was not mentioned in the Divakaran et al (2014) publication, we observed no significant difference in hepatic UGT2B15 transcript between male and female fetuses at 11-21 weeks of gestation. This is despite the expression of androgen receptor (AR) transcript and protein in the human fetal liver and the plentiful circulating testosterone in the male human fetus at this time (O'Shaughnessy et al, 2007;.…”

“…Taken together, we now know from three well-powered studies that UGBTB15 expression is liver-predominant and climbs steadily from 5 weeks of gestation onwards (Divakaran et al, 2014;Ekstrom et al, 2013;O'Shaughnessy et al, 2013), indicative of an important role in fetal and then adult hepatic function. Furthermore, because of its role in fetal programming, a better understanding of the development of the human liver more generally, and its response to adverse exposure through maternal recreational drugs (including cigarettes and alcohol), is critical.…”

Estrogen receptor signaling during vertebrate development

“…During the second trimester, the human fetal liver expresses high levels of several steroidogenic enzymes, including aromatase (O’Shaughnessy et al, 2013). At the same time, the expression of steroidogenic enzymes and steroid receptors in the fetal ovary increases (Fowler et al, 2011) (Figure 2).…”

Genetic variation, expression and ontogeny of sulfotransferase SULT2A1 in humans

“…O'Shaughnessy et al 23 found higher hepatic SULT2A1 mRNA concentrations in male fetuses of smoking mothers with abortion in the second trimester. Our results did not show any significant difference in fetal SULT2A1 mRNA expression between smoking and non-smoking mothers.…”