Sulfate is important for numerous cellular and metabolic processes in fetal development, including the biotransformation of steroids and thyroid hormones, as well as the detoxification of certain drugs and xenobiotics¹. In human and rodent gestation, maternal serum sulfate levels increase by approximately 2-fold, which enhances sulfate availability to the growing fetus. Increased reabsorption of sulfate in the maternal kidneys, via increased expression of the SLC13A1 sulfate transporter, is critical for maintaining high circulating sulfate levels throughout pregnancy, particularly from mid-gestation when fetal sulfate requirements are high. Pregnant Slc13a1 null mice exhibit hyposulfataemia, mid-gestational fetal loss and their surviving offspring have increased growth into adulthood². In addition to the importance of maintaining high maternal blood sulfate levels in pregnancy, is the essential requirement for supplying sulfate from mother to fetus via placental sulfate transporters.
We identified SLC13A4 to be the most abundant placental sulfate transporter mRNA in mice and humans³. Placental SLC13A4 mRNA was localised specifically to syncytiotrophoblasts, where it most likely plays an important role in mediating sulfate transport across the feto-maternal blood barrier. Slc13a4 null mice, from heterozygous Slc13a4 matings, have major developmental defects and die in late gestation. We observed significantly reduced litter sizes (median = 5 pups) from heterozygous Slc13a4 matings (compared to 8 pups from heterozygous x wildtype matings), which cannot be solely attributed to loss of Slc13a4 null fetuses. This suggests reduced survival of some Slc13a4 heterozygous and wildtype littermates during pregnancy or at birth. In addition, the significant decrease in post-natal survival of offspring from Slc13a4 heterozygous mothers is suggestive of perturbed maternal care.
Together, our studies in mice have further revealed the unappreciated roles of sulfate in fetal growth and survival, which have prompted us to investigate the role of sulfate transporters in pregnant women with altered sulfate homeostasis.