Abstract
Sulphate contributes to numerous processes in mammalian physiology, particularly during development. Sulphotransferases mediate the sulphate conjugation (sulphonation) of numerous compounds, including steroids, glycosaminoglycans, proteins, neurotransmitters and xenobiotics, transforming their biological activities. Importantly, the ratio of sulphonated to unconjugated molecules plays a significant physiological role in many of the molecular events that regulate mammalian growth and development. In humans, the fetus is unable to generate its own sulphate and therefore relies on sulphate being supplied from maternal circulation via the placenta. To meet the gestational needs of the growing fetus, maternal blood sulphate concentrations double from mid-gestation. Maternal hyposulphataemia has been linked to fetal sulphate deficiency and late gestational fetal loss in mice. Disorders of sulphonation have also been linked to a number of developmental disorders in humans, including skeletal dysplasias and premature adrenarche. While recognised as an important nutrient in mammalian physiology, sulphate is largely unappreciated in clinical settings. In part, this may be due to technical challenges in measuring sulphate with standard pathology equipment and hence the limited findings of perturbed sulphate homoeostasis affecting human health. This review article is aimed at highlighting the importance of sulphate in mammalian development, with basic science research being translated through animal models and linkage to human disorders.
Introduction
In adults and children, approximately one third of sulphate requirements are obtained from the diet (Appel et al. 2004), although sulphate intake can vary greatly (1.5–16 mmol/day) and is dependent on the source of drinking water (undetectable to >500 mg/l) and types of food consumed (Allen et al. 1989, Florin et al. 1991, 1993). Dietary sulphate is absorbed via the intestinal epithelium into the circulation, where it is maintained at ∼0.3 mM, making sulphate the fourth most abundant anion in human plasma (Murer et al. 1992, Cole & Evrovski 1997). Circulating sulphate levels are maintained by the kidneys, which filter sulphate in the glomerulus and then reabsorb sulphate back into circulation (Ullrich & Murer 1982). The amount of sulphate that is reabsorbed is regulated by sulphate transporter proteins expressed on the plasma membrane of renal epithelial cells.
Sulphate reabsorption occurs in the proximal tubule of the kidney and is mediated by two sulphate transporter proteins, SLC13A1 (aka NaS1, sodium sulphate transporter 1) and SLC26A1 (aka SAT1, sulphate anion transporter 1) (Lee et al. 2005). SLC13A1 is expressed on the apical membrane of epithelial cells in the proximal tubule where it mediates the first step of sulphate reabsorption (Lotscher et al. 1996), and SLC26A1 mediates the second step across the basolateral membrane (Karniski et al. 1998) (Fig. 1A). Mice lacking the Slc13a1 or Slc26a1 genes have sulphate wasting into the urine (hypersulphaturia), which leads to reduced blood sulphate levels (hyposulphataemia) (Dawson et al. 2003, 2010). In addition, genetic defects in the SLC13A1 gene of dogs and sheep also lead to hyposulphataemia (Neff et al. 2012, Zhao et al. 2012). Humans with loss-of-function mutations (R12X and N174S) in the SLC13A1 gene exhibit renal sulphate wasting and hyposulphataemia (Bowling et al. 2012). This loss of sulphate from circulation reduces sulphate availability to cells throughout the body and leads to a reduced intracellular sulphate conjugation (sulphonation) capacity, as shown in the Slc13a1- and Slc26a1-null mice (Dawson et al. 2003, 2010, Lee et al. 2006).
Sufficient intracellular sulphate levels need to be maintained for sulphonation reactions to function effectively. (A) In the kidneys, filtered sulphate is reabsorbed through epithelial cells in the proximal tubule via SLC13A1 on the apical membrane and then by SLC26A1 on the basolateral membrane. (B) Intracellular sulphate is obtained from extracellular sources via sulphate transporters and is derived from the metabolism of methionine and cysteine. Sulphate and ATP are converted to the universal sulphonate donor, PAPS. Both (1) sulphonation and (2) de-sulphonation reactions are active within intracellular metabolism. Sulphonated molecules are transported across the plasma membrane of cells via ATP binding cassette (ABC) proteins, sodium-dependent organic anion transporter (SOAT) and organic anion transporter polypeptides (OATPs), where they provide a circulating reservoir for cellular uptake and intracellular de-sulphonation. R-O-SO3 represents sulphonated substrates, including steroids, neurotransmitters and proteins.
Citation: REPRODUCTION 146, 3; 10.1530/REP-13-0056
Intracellular sulphonation relies on a sufficient supply of sulphate, which is derived from the uptake of sulphate across the plasma membrane via sulphate transporters. The cell also generates sulphate from the intermediary metabolism of thiol compounds, as well as de-conjugation reactions that are mediated by sulphatases (Fig. 1B). While intracellular oxidation of cysteine provides the majority of sulphate requirements for most cell types, some tissues such as the developing liver and skeleton rely more on extracellular sources of sulphate via sulphate transporters (Ito et al. 1982, Humphries et al. 1988). In addition, the placenta and fetus rely on sulphate supplied from the maternal circulation because these tissues have negligible levels of cystathionase and cysteine oxidase, that are important for generating sulphate from the sulphur-containing amino acids (Gaull et al. 1972, Loriette & Chatagner 1978, Dawson 2011). Sulphonation reactions in all organisms require the conversion of sulphate to the universal sulphonate (SO3−) donor, 3′-phosphoadenosine 5′-phosphosulphate (PAPS) (Klassen & Boles 1997). PAPS is generated by the cytosolic enzyme, PAPS synthetase, that sulphurylates ATP to form APS followed by phosphorylation to form PAPS (Venkatachalam 2003; Fig. 1B). The sulphonate group from PAPS is then transferred to the target substrate via sulphotransferase enzymes, which can be grouped into two classes: i) cytosolic sulphotransferases that sulphonate neurotransmitters, bile acids, xenobiotics, and steroids and ii) Golgi-located sulphotransferases that have proteoglycan and lipid substrates (Gamage et al. 2006) and rely on PAPS transporters (PAPST1 and PAPST2) to mediate the translocation of PAPS from the cytosol into the Golgi (Sasaki et al. 2009). The landmark report of sulphate activation to PAPS (Lipmann 1958) and the subsequent identification of sulphotransferases (Lipmann 1958, Gamage et al. 2006), as well as the characterisation of mouse models with perturbed sulphate homoeostasis (Bullock et al. 1998, Faiyaz ul Haque et al. 1998, Ringvall et al. 2000, Dawson et al. 2003, 2010, Thiele et al. 2004, Forlino et al. 2005, Tong et al. 2005, de Agostini 2006, Habuchi et al. 2007, Holst et al. 2007, Lum et al. 2007, Settembre et al. 2007), have led to our current understanding of sulphonation and the physiological importance of this process in modulating the biological activity of steroids (Dawson 2012), thyroid hormone (Richard et al. 2001, Wu et al. 2005), glycosaminoglycans and xenobiotics (Lee et al. 2006, Dawson et al. 2010). While the clinical importance of sulphate is currently underappreciated, interest in sulphate and its roles in mammalian reproduction and development has expanded over the past decade.
Sulphate in fertility and maintenance of pregnancy
Several studies have proposed an essential role of sulphate in fertilisation and maintenance of pregnancy. Sulphonation of zona pellucida (ZP) glycoproteins during oocyte maturation contributes to the ZP acquiring the capacity to accept sperm (Lay et al. 2011). In addition, sperm from male mice lacking tyrosylprotein sulphotransferase-2 (Tpst2) have reduced ability to adhere to the egg plasma membrane, leading to male infertility (Borghei et al. 2006). To date, more than 40 tyrosine-sulphonated proteins have been identified in humans and rodents (Stone et al. 2009), including the sperm-expressed MFGE8 protein that lacks tyrosine sulphonation in infertile Tpst2-deficient male mice (Hoffhines et al. 2009). Tyrosine sulphonation of both the luteinizing hormone (LH) receptor and follicle-stimulating hormone (FSH) receptor is required for optimal function of these proteins in reproductive biology (Costagliola et al. 2002, Mi et al. 2002). Furthermore, sulphonated pregnenolone, but not unconjugated pregnenolone, enhances phospholipase A2 activity, which plays an essential role in eicosanoid production and maintenance of uterine function during gestation (Saitoh et al. 1984, Brant et al. 2006). Together, these findings show that sulphate plays numerous important physiological roles in mammalian reproductive biology.
Sulphate supply to the fetus in human and animal gestation
During human and rodent pregnancy, maternal circulating sulphate levels increase approximately twofold, with levels peaking in the second and third trimesters (Tallgren 1980, Morris & Levy 1983, Cole et al. 1984, Dawson et al. 2011). This increase is due to elevated maternal kidney SLC13A1 and SLC26A1 gene expression (Lee et al. 1999, Dawson et al. 2011), which leads to enhanced renal sulphate reabsorption (Cole et al. 1985a) in the pregnant mother (Fig. 2). The increased circulating sulphate level in pregnant humans (from ≈0.26 to 0.59 mM; Cole et al. 1984, 1985b, 1992) and mice (from ≈1.0 to 2.3 mM; Dawson et al. 2011) provides a reservoir of sulphate for the placenta and fetus and is remarkable as most circulating ions usually decrease slightly due to haemodilution (Lind 1980). As the placenta and fetus have a relatively low capacity to generate sulphate from methionine and cysteine (Gaull et al. 1972, Loriette & Chatagner 1978), most of the sulphate in these tissues must come from the maternal circulation (Fig. 2). This is consistent with fetal hyposulphataemia and negligible amniotic fluid sulphate levels in fetuses from pregnant hyposulphataemic Slc13a1-null mice (Dawson et al. 2011). The reduced fecundity of pregnant female Slc13a1-null mice (Dawson et al. 2003) is due to fetal death in mid- and late gestation (from embryonic day 12.5; Dawson et al. 2011), highlighting the importance for maintaining high maternal blood sulphate levels during pregnancy.
Sulphate is supplied from maternal circulation to placental and fetal tissues, where sulphonation reactions are important for normal growth and development. (A) Increased maternal kidney SLC13A1 and SLC26A1 expression from early gestation (in mice from E4.5) enhances renal sulphate reabsorption, leading to (B) a doubling in circulating sulphate concentrations. (C) SLC13A4 expression in syncytiotrophoblasts mediates sulphate transport (ST) for generation of the universal sulphate donor PAPS. (D) Sulphate is supplied to the fetal blood and (E) taken up by fetal cells. *Intracellular generation of sulphate in fetal and placental cells is negligible.
Citation: REPRODUCTION 146, 3; 10.1530/REP-13-0056
Sulphate is supplied from maternal blood to fetal circulation, via placental sulphate transporters. Recently, the relative abundance and cellular expression of all known sulphate transporters in human and mouse placentae were described (Dawson et al. 2012, Simmons et al. 2013). Those studies identified SLC13A4 (aka NaS2) to be the most abundant placental sulphate transporter, which was localised to the syncytiotrophoblasts, where it is proposed to play an essential role in mediating sulphate supply to the placenta and fetus. The proposed roles of both placental SLC13A4 and maternal renal SLC13A1 in meeting the gestational needs of the developing fetus (Fig. 2) warrant future studies of these transporters in pregnant women with perturbed sulphate homoeostasis.
Pathophysiology of perturbed sulphate homoeostasis in human and animal development
Numerous genes involved in maintaining the required biological ratio of sulphonated to unconjugated molecules have been described in humans and animal models (Table 1). Intracellular sulphate and its sulphonate donor PAPS need to be maintained at sufficiently high levels for the sulphonation of xenobiotics, pharmacological drugs, proteoglycans and steroids (Mulder & Jakoby 1990; Fig. 3). Furthermore, the intracellular removal of sulphate from compounds is mediated by a family of 17 sulphatase enzymes (Hanson et al. 2004, Sardiello et al. 2005), and several of these have been linked to syndromes in humans (Table 1).
Pathogenetics of perturbed sulphate homoeostasis.
| Gene | Species and phenotype/syndrome | References |
|---|---|---|
| Sulphate transporters | ||
| SLC13A1 | Human: renal sulphate wasting, hyposulphataemia | Bowling et al. (2012) |
| Slc13a1 | Mice: renal sulphate wasting, hyposulphataemia, fetal loss, growth retardation, behavioural abnormalities, altered steroid/lipid profiles impaired gastrointestinal function, drug-induced hepatotoxicity | Dawson et al. (2003, 2004, 2005, 2006, 2008, 2009, 2011) and Lee et al. (2006, 2007) |
| SLC13a1 | Dog: hyposulphataemia, osteochondrodysplasia, growth retardation | Neff et al. (2012) |
| SLC13a1 | Sheep: hyposulphataemia, osteochondrodysplasia, growth retardation | Zhao et al. (2012) |
| Slc26a1 | Mice: renal sulphate wasting, hyposulphataemia, urolithiasis | Dawson et al. (2010) |
| SLC26A2 | Human: chondrodysplasias (MED, DTD, AO2, ACG1B) | Dawson et al. (2005) |
| Slc26a2 | Mice: chondrodysplasias | Forlino et al. (2005) |
| PAPS synthetase and transporter | ||
| PAPSS2 | Human: spondyloepimetaphyseal dysplasia, premature pubarche | Faiyaz ul Haque et al. (1998) and Noordam et al. (2009) |
| Papss2 | Mice: brachymorphism | Faiyaz ul Haque et al. (1998) |
| papst1 | Zebrafish: cartilage defects | Clément et al. (2008) |
| Sulphotransferases | ||
| Sult1e1 | Mice: spontaneous fetal loss | Tong et al. (2005) |
| Tst1 | Mice: fetal loss and reduced body weight | Ouyang et al. (2002) |
| Tpst2 | Mice: dwarfism and thyroid hypoplasia | Sasaki et al. (2007) |
| CHST3 | Human: spondyloepimetaphyseal dysplasia | Thiele et al. (2004) |
| Hs3t1 | Mice: reduced fecundity, delayed placental development | de Agostini (2006) |
| Hs2st (Hs2st1) | Mice: eye and skeletal defects, kidney agenesis, neonatal death | Bullock et al. (1998) |
| Hs6st (Hs6st1) | Mice: reduced fecundity, perturbed placental development | Habuchi et al. (2007) |
| Ndst1 | Mice: mammary gland development, reduced fecundity, neonatal death | Crawford et al. (2010) and Ringvall et al. (2000) |
| Sulphatases | ||
| ARSA | Human: metachromatic leucodystrophy | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| ARSB | Human: Maroteaux–Lamy syndrome | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| ARSC | Human: X-linked ichthyosis | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| ARSE | Human: chondrodysplasia punctata 1 | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| GALNS | Human: Morquio A syndrome | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| GNS | Human: Sanfilippo D syndrome | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| IDS | Human: Hunter syndrome | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| SGSH | Human: Sanfilippo A syndrome | Diez-Roux & Ballabio (2005) and Sardiello et al. (2005) |
| SULF1 | Human: Mesomelia-synostoses syndrome | Isidor et al. (2010) |
| Sulf1 | Mouse: reduced growth, skeletal defects, perinatal death | Holst et al. (2007) |
| Sulf2 | Mouse: reduced growth, skeletal defects, perinatal death | Holst et al. (2007) and Lum et al. (2007) |
| SUMF1 | Human: Multiple sulphatase deficiencies | Cosma et al. (2003) |
| Sumf1 | Mice: growth retardation, skeletal and neurological abnormalities, mortality | Settembre et al. (2007) |
Fetal and placental tissues rely on sulphate supply from maternal stores for numerous physiological roles. (A) Kidney sulphate transporters maintain high maternal circulating sulphate levels during pregnancy, which supply a reservoir of sulphate to the fetus via placental sulphate transport. R, includes steroids, proteoglycans, xenobiotics and pharmacological drugs. (B) Sulphate conjugation in fetal and placental tissues plays an important role in bio-transforming numerous endogenous and exogenous molecules.
Citation: REPRODUCTION 146, 3; 10.1530/REP-13-0056
Sulphonation of xenobiotics and pharmacological drugs
In human and animal gestation, the fetus has negligible capacity to detoxify xenobiotics and certain drugs via the glucuronidation pathway (Hines & McCarver 2002, McCarver & Hines 2002). However, the fetal liver expresses abundant levels of sulphotransferases, which are important for the sulphonation and clearance of numerous compounds that are potentially detrimental to fetal development (Stanley et al. 2005, Alnouti & Klaassen 2006). Both the Slc13a1 and Slc26a1 mouse models of hyposulphataemia have a reduced capacity to sulphonate acetaminophen, which leads to enhanced acetaminophen-induced hepatotoxicity (Lee et al. 2006, Dawson et al. 2010). This may be relevant to earlier studies that proposed a potential link between human birth defects and a variable acetaminophen sulphonation capacity of the fetal liver (Adjei et al. 2008). Nonetheless, sulphonation is an important process for the detoxification of xenobiotics and certain drugs in fetal tissues (reviewed in Gamage et al. (2006)).
Sulphonation of proteoglycans
In mammals, sulphonated proteoglycans are an essential component of extracellular matrices throughout the body, particularly in connective tissues (Habuchi et al. 2004, Klüppel 2010). Proteoglycan sulphates are also a major component of the mucous barrier in the respiratory, gastrointestinal and reproductive tracts, where they are proposed to play a role in protecting the underlying epithelium (Nieuw Amerongen et al. 1998, Argüeso & Gipson 2006, Dawson et al. 2009). The sulphate content of proteoglycans influences cell signalling function and the structural integrity of tissues (Mulder & Jakoby 1990). Highly sulphonated glycoproteins, including heparan sulphate proteoglycans (HSPGs), are critical for maintaining developmental cell signalling pathways in Drosophila and Caenorhabditis elegans (Sen et al. 1998, Lin et al. 1999, Dejima et al. 2006) and contribute to tissue remodelling of the reproductive tract during gestation (Yanagishita 1994) and fetal kidney and brain development (Bullock et al. 1998, Yamaguchi 2001). The importance of HSPG sulphonation in mammalian gestation is highlighted by the phenotypes of heparan sulphotransferase knockout (Hs3t1−/−) mice, which exhibit reduced fecundity due to delayed placental development (de Agostini 2006). Sulphate is also important for modulating the physiological roles of chondroitin proteoglycan (CSPG) in numerous developing tissues, with links to modulation of the Indian Hedgehog signalling pathway (Cortes et al. 2009). Importantly, sulphonation of CSPGs in chondrocytes is essential for normal skeletal growth and development, and several chrondrodysplasias have been attributed to genetic defects that lead to decreased CSPG sulphonation capacity (Table 1).
Chondrocytes rely on an abundant supply of extracellular sulphate to meet the intracellular requirements for CSPG sulphonation. Interestingly, defects in the renal SLC13a1 gene of dogs and sheep lead to hyposulphataemia and osteochondrodysplasias (Neff et al. 2012, Zhao et al. 2012), which are most likely to result from a decreased CSPG sulphonation capacity. Sulphate is transported into chondrocytes via the SLC26A2 sulphate transporter (Rossi et al. 1997). Numerous variants in the human SLC26A2 gene have been linked to chondrodysplasias (Dawson & Markovich 2005), with the underlying metabolic defect being reduced sulphonation of proteoglycans in chondrocytes (Cornaglia et al. 2009). Mutant Slc26a2 mice also exhibit chondrodysplasias, which mimic the biochemical and morphological phenotypes found in humans (Hästbacka et al. 1994, Forlino et al. 2005, Cornaglia et al. 2009). Treatment of the mutant Slc26a2 mice with N-acetyl cysteine showed increased proteoglycan sulphonation and improved skeletal phenotypes, suggesting that thiol-containing compounds can bolster the intracellular sulphate levels needed for sulphonation of CSPGs (Pecora et al. 2006).
Loss of PAPS synthetase has also been linked to impaired CSPG sulphonation and skeletal dysplasias (Sugahara & Schwartz 1982). Mammalian genomes contain two PAPS synthetase genes, PAPSS1 and PAPSS2 (Kurima et al. 1998, Xu et al. 2000). However, only PAPSS2 has been linked to human pathophysiology, with similar skeletal phenotypes found in Papss2 mutant mice (Faiyaz ul Haque et al. 1998, Xu et al. 2000). In addition, disruption of the zebrafish PAPS transporter gene (papst1, aka pinscher) leads to cartilage defects (Clément et al. 2008). Skeletal phenotypes are also found in patients with mutations in the chondroitin 6-O-sulphotransferase gene (Thiele et al. 2004; Table 1), showing that proteoglycan sulphonation is important for maintaining healthy bone development.
Sulphonation of steroids
Early studies proposed that steroid sulphates were end products of metabolism, with the sulphate moiety merely increasing the water solubility of the steroid and enhancing its excretion into the urine (Mulder & Jakoby 1990). However, more recent studies have shown steroid sulphates to be important precursors of biologically active steroids or to have physiological roles that are distinct from non-sulphonated steroids (Strott 1996, 2002). Sulphonation is a molecular mechanism for inactivating steroids, as most steroid sulphonates do not bind their target receptor (Strott 1996). Sulphate also plays an important role in the modulation of cholesterol function. In addition to serving as a substrate for adrenal and ovarian steroidogenesis, cholesterol sulphate has been linked to several biological processes, including regulation of cholesterol synthesis, plasmin and thrombin activities, sperm capacitation and activation of protein kinase C (Reed et al. 2005).
When sulphonated, steroids avidly bind to serum proteins, particularly albumin as well as corticosteroid-binding globulin (aka CBG, transcortin) and sex hormone binding globulin (aka SHBG, androgen-binding protein, testosterone-binding β-globulin) (Puche & Nes 1962, Chader et al. 1972, Weiser et al. 1979, Dunn et al. 1981, Strott 1996). Binding of steroid sulphates to serum proteins decreases their urinary clearance by approximately two orders of magnitude, when compared with unconjugated steroids (Wang et al. 1967). This is relevant to circulating steroid sulphate levels being much higher when compared with those of their non-sulphonated forms, as shown for oestrogen sulphate, which has circulating levels several-fold higher than unconjugated oestrogen (Strott 1996, 2002). Circulating albumin-bound steroid sulphates are proposed to provide a pool of inactive steroids, which can be taken up by peripheral target tissues, where de-conjugation via steroid sulphatases generate active steroids.
Synthesised in both maternal and placental tissues, cholesterol sulphate is an essential precursor of steroids for maintaining fetal growth and development. Although fetal steroid biosynthesis is limited, DHEAS is produced in the fetal adrenal gland (zona reticularis) and then circulated to the placenta where it provides the major supply of DHEAS (≈90%) for production of oestrone, oestradiol (E2) and other fetal steroids (Dawson 2011). In addition, DHEAS is also converted to 16α-hydroxy DHEAS in the fetal liver, via 16α-hydroxylase, and subsequently converted to oestriol (>60 mg/day during the third trimester of human gestation) in the placenta. While decreased levels of oestriol in maternal circulation have been used as a marker for certain developmental disorders, including Down syndrome, trisomy 18, idiopathic pregnancy loss and anencephaly (Alldred et al. 2012), the role of perturbed sulphonation of DHEA and oestriol in modifying maternal oestriol levels and potentially human fetal development awaits further investigation.
Disturbances in the balance of sulphonated to unconjugated steroids can have detrimental effects on steroid-responsive events in development (Strott 1996). For example, mid-gestational fetal loss and placental thrombosis have been shown in mice lacking the Sult1e1 oestrogen sulphotransferase gene (Tong et al. 2005). Sult1e1 is highly expressed in the placenta where it is essential for generating oestrone sulphate, E2-3-sulphate and oestriol sulphate.
Perturbed sulphonation capacity, due to inactivating mutations in the PAPSS2 gene, has also been linked to altered endocrine function in humans (Noordam et al. 2009). One XX female patient with premature pubarche had an abnormal endocrine profile with androstenedione and testosterone levels at twofold above the upper limit of normal ranges, a DHEA level at the upper limit of the normal range and DHEAS level at one order of magnitude below the normal range. The clinical presentations of this patient were proposed to be a consequence of reduced DHEA sulphonation, which led to increased circulating levels of unconjugated DHEA that was converted to androgens. More recent studies have shown a trend (P=0.06) for a lower ratio of circulating DHEAS to DHEA, in children with premature adrenarche, and harbouring a polymorphism (rs182420) in the SULT2A1 gene (Utriainen et al. 2012). SULT2A1 genetic variants have also been associated with reduced DHEAS and inherited adrenal androgen excess in some women with polycystic ovary syndrome (Goodarzi et al. 2007). These findings indicate a pathogenetic role of PAPSS2 and SULT2A1 in androgen excess disorders. Together, these studies provide evidence that disruption of steroid sulphonation, including decreased sulphate and PAPS supply, as well as steroid sulphotransferase activity, leads to perturbed endocrine profiles and associated clinical manifestations (Table 1).
Summary
Sulphate is an obligate nutrient for healthy fetal growth and development. The field of sulphate research brings together families of genes that encode sulphate transporters, PAPS synthetases and transporters, sulphotransferases and sulphatases. All these contribute to maintaining the required physiological balance of sulphonated and unconjugated compounds. While the importance of sulphate in human growth and development is largely unappreciated, its significance is being realised with the generation of animal models, as well as links to human pathophysiologies, particularly chondrodysplasias. These findings warrant future studies to further delineate the roles for sulphate in fetal growth and development, as well as to determine its physiological importance in placental development and maternal adaptation to pregnancy, particularly for the role of steroid sulphonation. Future research will be important to further unravel how perturbed sulphonation affects health outcomes for both mother and child.
Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.
Funding
The preparation of this manuscript was supported by the Mater Medical Research Institute. P A Dawson is a recipient of a Mater Foundation Fellowship.
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