Sulphate in pregnancy

Abstract

Sulphate is an obligate nutrient for healthy growth and development. Sulphate conjugation (sulphonation) of proteoglycans maintains the structure and function of tissues. Sulphonation also regulates the bioactivity of steroids, thyroid hormone, bile acids, catecholamines and cholecystokinin, and detoxifies certain xenobiotics and pharmacological drugs. In adults and children, sulphate is obtained from the diet and from the intracellular metabolism of sulphur-containing amino acids. Dietary sulphate intake can vary greatly and is dependent on the type of food consumed and source of drinking water. Once ingested, sulphate is absorbed into circulation where its level is maintained at approximately 300 μmol/L, making sulphate the fourth most abundant anion in plasma. In pregnant women, circulating sulphate concentrations increase by twofold with levels peaking in late gestation. This increased sulphataemia, which is mediated by up-regulation of sulphate reabsorption in the maternal kidneys, provides a reservoir of sulphate to meet the gestational needs of the developing foetus. The foetus has negligible capacity to generate sulphate and thereby, is completely reliant on sulphate supply from the maternal circulation. Maternal hyposulphataemia leads to foetal sulphate deficiency and late gestational foetal death in mice. In humans, reduced sulphonation capacity has been linked to skeletal dysplasias, ranging from the mildest form, multiple epiphyseal dysplasia, to achondrogenesis Type IB, which results in severe skeletal underdevelopment and death in utero or shortly after birth. Despite being essential for numerous cellular and metabolic functions, the nutrient sulphate is largely unappreciated in clinical settings. This article will review the physiological roles and regulation of sulphate during pregnancy, with a particular focus on animal models of disturbed sulphate homeostasis and links to human pathophysiology.

Figure 1

Biological roles of sulphate and pathways of sulphate homeostasis. (A) Sulphonation contributes to numerous cellular and metabolic functions in human physiology; (B) Pathways of intracellular sulphate generation and sulphonation. Methionine is converted to cysteine via the transsulphuration pathway involving cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). Cysteine is converted to sulphate via two pathways: A minor pathway involving CBS, CTH, sulphide quinone reductase-like (SQRDL), thiosulphate sulphurtransferase (TST) and sulphite oxidase (SUOX); and a major pathway involving cysteine dioxygenase (CDO), glutamic-oxaloacetic transaminase 1 (GOT1) and SUOX. ST, Sulphate transporters; PAPSS2, PAPS synthetase; SULT, sulphotransferases; R represents those substrates shown in (A); (C) Flux of intracellular sulphate and sulphonated molecules. In adults and children, sulphate is obtained from: (i) extracellular sources via sulphate transporters; (ii) catabolism of methionine and cysteine; (iii) hydrolysis of proteoglycans in the lysosome; and (iv) sulphatase-mediated removal of sulphate from substrates in the cytosol.

Figure 2

Fluxes of sulphate between tissues. (A) Contribution of the small intestine, kidneys and cells to sulphate homeostasis (B) Maternal, foetal and postnatal contributions to chondroitin sulphation. Disruption of pathways that maintain a sufficient supply of sulphate for chondrocytes (steps 1–3) or intracellular sulphonation of chondroitin (steps 4–5) lead to chondrodysplasias.