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

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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.

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