Genetic Polymorphisms of Human Sulfate Transporters

Dawson, Paul A.; Markovich, Daniel

doi:10.2174/157016007782793692

Cited by 13 publications

(9 citation statements)

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“…These transporters move sulfate across the apical and basolateral membranes (respectively) of the renal tubule cells, and SAT-1 also functions in other organs such as the brain. In addition, there are sulfate transporters expressed in the brain, suggesting they may play a role in the transport of sulfate into the cells of the central nervous system (CNS) [77]. …”

Section: Research Evidencementioning

confidence: 99%

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Kern

Haley

Geier

et al. 2013

IJERPH

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Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of the children experience a developmental regression characterized by a loss of previously acquired skills and abilities. Typically reported are losses of verbal, nonverbal, and social abilities. Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules.

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Section: Research Evidencementioning

confidence: 99%

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Kern

Haley

Geier

et al. 2013

IJERPH

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“…However, the developing fetus has negligible capacity to generate sulfate from methionine and cysteine [22,23] and relies on sulfate to be supplied from maternal circulation via placental sulfate transporters. To date, 10 human and rodent sulfate transporters have been identified belonging to the solute linked carrier (SLC) 13 and SLC26 gene families [24]. While NaS2 (SLC13A4), SLC26A2, SLC26A7, and SLC26A11 mRNAs have been detected in the placenta at late gestation [24][25][26][27], the temporal and spatial expression of these and other sulfate transporter mRNAs at earlier gestational ages has not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…To date, 10 human and rodent sulfate transporters have been identified belonging to the solute linked carrier (SLC) 13 and SLC26 gene families [24]. While NaS2 (SLC13A4), SLC26A2, SLC26A7, and SLC26A11 mRNAs have been detected in the placenta at late gestation [24][25][26][27], the temporal and spatial expression of these and other sulfate transporter mRNAs at earlier gestational ages has not been reported. To build a model of directional sulfate transport in the placenta, we investigated the relative abundance, temporal profile, and spatial expression of the 10 known sulfate transporter mRNAs in mouse placenta from gestational ages E6.5 to E18.5.…”

Section: Introductionmentioning

confidence: 99%

Placental, Renal, and Ileal Sulfate Transporter Gene Expression in Mouse Gestation1

Dawson

Rakoczy

Simmons

2012

Biology of Reproduction

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Sulfate is important for mammalian growth and development. During pregnancy, maternal circulating sulfate levels increase by 2-fold, enhancing sulfate availability to the fetus. We used quantitative real-time PCR to determine sulfate transporter mRNA levels during mouse gestation in three tissues: kidney and ileum, to identify transporters involved in sulfate absorption and maintaining high maternal circulating sulfate level; and placenta, to build a model of directional sulfate transport from mother to fetus. In the kidney, Slc13a1 and Slc26a1 were the most abundant sulfate transporter mRNAs, which increased by ≈2-fold at E4.5 or E6.5, whereas lower levels of Slc26a2, Slc26a6, and Slc26a7 mRNA increased by ≈3- to 6-fold from E4.5. Ileal sulfate transporter mRNA levels were not increased in gestation, but slight decreases (by ≈30-40%) were found for Slc26a3 and Slc26a6. In placentae, Slc13a4 and Slc26a2 mRNAs were most abundant, with levels increasing from E10.5 and peaking (≈8-fold) from E14.5 to E18.5, whereas Slc26a1 increased by ≈3-fold at E18.5. The spatial expression of placental mRNAs was determined by in situ hybridization showing Slc13a4 and Slc26a6 in yolk sac, Slc26a1 in spongiotrophoblasts, and Slc13a4, Slc26a2, Slc26a3, and Slc26a7 in the labyrinthine layer. Within the labyrinth, cell-specific staining revealed Slc13a4 expression in syncytiotrophoblast-II (SynT-II) and Slc26a2 in SynT-I. Together, these data show kidney Slc13a1 and Slc26a1 and placental Slc13a4 and Slc26a2 to be the most abundant sulfate transporter mRNAs in mouse gestation, which likely play important physiological roles in maintaining high maternal serum sulfate levels during pregnancy and mediating sulfate supply to the fetus.

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“…(14)(15)(16)(17) This mouse model provides important insights into the physiological consequences of hyposulfatemia and the function of the NaS1 gene, which is yet to be linked with human disease. These studies are relevant to single nucleotide polymorphisms (R12X and N174S) in the human NaS1 gene, (18) which lead to 100% and 60% loss of function, respectively.(19) The aim of this study was to determine the growth of tumor cells injected subcutaneously into hyposulfatemic Nas1) ⁄ ) mice and compare them to wildtype (Nas1 + ⁄ + ) normosulfatemic mice. Our findings show increased tumor growth and vascularization, as well as reduced tumor core necrosis, collagen content, and immunoreactivity to heparan sulfate (HS), HS-, and chondroitin 4-sulfate-(C4S) epitopes in tumors from Nas1 ) ⁄ ) mice when compared to Nas1 + ⁄ + mice.…”

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confidence: 99%

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Enhanced tumor growth in the NaS1 sulfate transporter null mouse

et al. 2010

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Sulfate plays an important role in maintaining normal structure and function of tissues, and its content is decreased in certain cancers including lung carcinoma. In this study, we investigated tumor growth in a mouse model of hyposulfatemia (Nas1 ) ⁄ ) ) and compared it to wild-type (Nas1 + ⁄ + ) mice. Lung epithelial tumor cells (TC-1 cell line) were injected subcutaneously into male Nas1and Nas1 + ⁄ + mice on a mixed 129Sv and C57BL ⁄ 6 genetic background. Tumor sections were stained with anti-glycosaminoglycan antibodies to assess the distribution of proteoglycans and Gomori's trichrome to detect collagen. After 14 days, tumor weights were markedly increased (by 12-fold) in Nas1) ⁄ ) mice when compared with Nas1 + ⁄ + mice. Histological analyses of tumors revealed increased (by 2.4-fold) vessel content, as well as markedly reduced collagen and immunoreactivity against glycosaminoglycan structural epitopes in the tumors from Nas1 ) ⁄ ) mice. No significant differences were found for the growth of cultured TC-1 cells supplemented with Nas1) ⁄ ) or Nas1 + ⁄ + serum, as determined by 3 H-thymidine incorporation, implying that the cell culture conditions may not reflect the in vivo situation of enhanced tumor growth. This study has revealed increased tumor growth and an altered extracellular tumor matrix in hyposulfatemic Nas1) ⁄ ) mice. These findings highlight the importance of blood sulfate levels as a possible modulator of tumor growth, and could lead to future cancer studies in humans with altered sulfate homeostasis. (Cancer Sci 2010; 101: 369-373) S ulfate (SO 4 2) ) is an abundant anion in the human body and is essential for numerous cellular and metabolic processes.(1) SO 4 2) conjugation or sulfonation of glycosaminoglycans (GAGs) is important for maintaining the structure and function of tissues.(2) Heparan sulfate proteoglycans (HSPGs) are a group of variably sulfonated GAGs found at the cell surface and extracellular matrix, which play a major role in regulating growth factor signaling in tumors.(3) In particular, the sulfate content of HSPGs is a critical factor in modulating tumor growth and angiogenesis.(4) Desulfonation of HSPGs by sulfatases promotes the release of growth factors that enhance tumor growth, (5) and increased sulfatase activity is associated with a poor prognosis in patients with hepatocellular carcinoma, breast, and pancreatic cancers. (6)(7)(8) In addition, the removal of highly sulfonated regions of HSPGs, using heparanase I, leads to accelerated tumor growth, neovascularization, and decreased apoptosis in a mouse model of lung carcinoma.(3) Highly sulfonated HSPGs or heparins, as well as sulfonated polymers such as laminarin sulfate, act as inhibitors of heparanase activity and have beneficial outcomes in preventing tumor growth and angiogenesis in vivo.(9) These studies highlight the importance of sulfate in modulating tumor growth and angiogenesis. SO 4 2) is obtained directly from the diet and from the oxidation of sulfur containing amino acids, methionine and cysteine....

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Genetic Polymorphisms of Human Sulfate Transporters

Cited by 13 publications

References 100 publications

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Thimerosal Exposure and the Role of Sulfation Chemistry and Thiol Availability in Autism

Placental, Renal, and Ileal Sulfate Transporter Gene Expression in Mouse Gestation1

Enhanced tumor growth in the NaS1 sulfate transporter null mouse

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