Steroid production and excretion by the pregnant mouse, particularly in relation to pregnancies with fetuses deficient in Delta7-sterol reductase (Dhcr7), the enzyme associated with Smith-Lemli-Opitz syndrome.
This study has shown that the mouse has a great increase in steroid production during pregnancy in similar fashion to the human. Many steroids were provisionally identified in maternal urine of the wild-type mouse. The major progesterone metabolites appear to be hydroxylated pregnanolones, particularly with hydroxyl groups in the 16alpha position. Rather than estriol being the major end-product of feto-placental steroid synthesis as in the human, the pregnant mouse produces and excretes large amounts of androgen metabolites, ranging in polarity from androstanetriols to androstanepentols. These steroids have 15alpha- or 18-hydroxyl groups with additional hydroxylation at uncharacterized positions. From metabolite data the peak of pregnancy progesterone production appears to be between 7.5 and 14.5 gestational days, while for C(19) metabolites peak excretion is later. The starting-point of the studies was to study pregnancy steroid production by a mouse model for Smith-Lemli-Opitz syndrome, 7-dehydrosterol reductase (DHCR7) deficiency. In human pregnancies with DHCR7 deficient fetuses large amounts of 7- and 8-dehydrosteroids are excreted, products secondary to high fetal 7- and 8-dehydrocholesterol (DHC) accumulation. This agrees with existing evidence that human feto-placental steroid synthesis utilizes little maternal cholesterol as precursor. In contrast, this study has shown that pregnant mice carrying dhcr7 deficient fetuses with relatively high DHC production had essentially undetectable maternal excretions of steroids with Delta(7)- and Delta(8)-unsaturation. As mutant mouse mothers have essentially normal cholesterol production (little or no DHC build-up), this suggests maternal cholesterol is primarily utilized for pregnancy steroid synthesis in the mouse.
Matabosch
Xavier
X
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA.
Rahman
Mahbuba
M
Hughes
Beverly
B
Patel
Shailendra B
SB
Watson
Gordon
G
Shackleton
Cedric
C
D000818:Animals; D000831:Animals, Newborn; D002784:Cholesterol / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000201:enzymology*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D051379:Mice; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
D013256:Steroids; D011374:Progesterone; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D003345:Corticosterone