Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

Abstract

Abstract. Sulfate is important for growth and development, and is supplied from mother to fetus throughout pregnancy. We used NaS1 sulfate transporter null (Nas1 -/-) mice to investigate the role of NaS1 in maintaining sulfate homeostasis during pregnancy and to determine the physiological consequences of maternal hyposulfataemia on fetal, placental and postnatal growth. We show that maternal serum (≤0.5 mM), fetal serum (<0.1 mM) and amniotic fluid (≤0.5 mM) sulfate levels were significantly lower in pregnant Nas1 -/-mice when compared with maternal serum (≈2.0 mM), fetal serum (≈1.5 mM) and amniotic fluid (≈1.7 mM) sulfate levels in pregnant Nas1 +/+ mice. After 12 days of pregnancy, fetal reabsorptions led to markedly reduced (by ≥50%) fetal numbers in Nas1 -/-mice. Placental labyrinth and spongiotrophoblast layers were increased (by ≈140%) in pregnant Nas1 -/-mice when compared to pregnant Nas1 +/+ mice. Birth weights of progeny from female Nas1 -/-mice were increased (by ≈7%) when compared to progeny of Nas1 +/+ mice. These findings show that NaS1 is essential to maintain high maternal and fetal sulfate levels, which is important for maintaining pregnancy, placental development and normal birth weight. Key words: Placenta, Pregnancy, Sulfate (J. Reprod. Dev. 57: [444][445][446][447][448][449] 2011) ulfate (SO4 2-) is vital for many processes in fetal growth and development, including neurogenesis and steroid metabolism [1][2][3]. The ratio of sulfonated (inactive) to unconjugated (active) steroids has important implications for many of the steroid-responsive events that regulate placental and fetal growth [4]. For example, placental estradiol-3-sulfate is taken up by the fetal brain, where it is desulfonated by steroid sulfatase to estradiol, which acts as a potent stimulator of fetal adrenocorticotropin secretion and the hypothalamus-pituitary-adrenal axis [5]. In addition, sulfonation of structural components, such as heparan sulfate proteoglycans (HSPGs), is essential for the maintenance of normal structure and function of placental and fetal tissues [6]. Together, these findings demonstrate an important role for sulfate in maintaining steroid and glycosaminoglycan homeostasis in the developing fetus. SO4 2-is obtained from the diet and from the intracellular metabolism of methionine and cysteine [6]. Circulating SO4 2-levels are maintained by the NaS1 sulfate transporter which is expressed in the kidney where it mediates sulfate reabsorption [7]. During pregnancy, maternal blood sulfate levels increase by approximately 2-fold which provides an essential supply to the placenta and developing fetus [8][9][10][11]. This increase in circulating sulfate level is correlated with increased maternal renal sulfate reabsorption [9,12]. Since the fetus has a relatively low capacity to form sulfate from methionine and cysteine [13,14], most of its sulfate must come from the maternal circulating sulfate pool. These findings are relevant to the decreased fecundity of NaS1 knockout (Nas1 -/-) mice which exhibit bot...

The Biological Roles of Steroid Sulfonation

“…This is consistent with fetal hyposulfatemia and negligible amniotic fluid sulfate levels in fetuses from pregnant hyposulfataemic NaS1 null mice [83]. Of great interest is the reduced fecundity of female NaS1 null mice [12], as a result of fetal death in late gestation (from embryonic day 12.5) [83] which is a similar gestational age when fetal death occurs in the Sult1e1 null mice [80]. These studies highlight the importance of maintaining a sufficient supply of sulfate to placental and fetal cells in mammalian gestation.…”

“…Since the placenta and fetus have a relatively low capacity to generate sulfate from methionine and cysteine [18,19], most of the sulfate in these tissues must come from the maternal circulation ( Figure 4). This is consistent with fetal hyposulfatemia and negligible amniotic fluid sulfate levels in fetuses from pregnant hyposulfataemic NaS1 null mice [83]. Of great interest is the reduced fecundity of female NaS1 null mice [12], as a result of fetal death in late gestation (from embryonic day 12.5) [83] which is a similar gestational age when fetal death occurs in the Sult1e1 null mice [80].…”

“…During human and rodent pregnancy, maternal circulating sulfate levels increase approximately 2-fold, with levels peaking in the second and third trimesters [82][83][84][85]. This increase is associated with elevated kidney NaS1 and Sat1 gene expression [83,86] and renal sulfate reabsorption [87] in the pregnant mother (Figure 4).…”

“…During human and rodent pregnancy, maternal circulating sulfate levels increase approximately 2-fold, with levels peaking in the second and third trimesters [82][83][84][85]. This increase is associated with elevated kidney NaS1 and Sat1 gene expression [83,86] and renal sulfate reabsorption [87] in the pregnant mother (Figure 4). The increased circulating sulfate level in pregnant humans (from ≈ 0.26 to 0.59 mM) [82,88,89] and mice (from ≈ 1.0 to 2.3 mM) [83] enhances sulfate availability to the placenta and fetus, and is remarkable since most circulating ions usually decrease slightly due to haemodilution [90].…”

“…This increase is associated with elevated kidney NaS1 and Sat1 gene expression [83,86] and renal sulfate reabsorption [87] in the pregnant mother (Figure 4). The increased circulating sulfate level in pregnant humans (from ≈ 0.26 to 0.59 mM) [82,88,89] and mice (from ≈ 1.0 to 2.3 mM) [83] enhances sulfate availability to the placenta and fetus, and is remarkable since most circulating ions usually decrease slightly due to haemodilution [90]. Since the placenta and fetus have a relatively low capacity to generate sulfate from methionine and cysteine [18,19], most of the sulfate in these tissues must come from the maternal circulation ( Figure 4).…”