168,712
Views
0
CrossRef citations to date
0
Altmetric
Review Article

Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays

, , &

References

  • Abou-Donia, M. B., E. M. El-Masry, A. A. Abdel-Rahman, R. E. McLendon, and S. S. Schiffman. 2008. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health Part A 71 (21):1415–29. doi:10.1080/15287390802328630.
  • Abu-Qare, A., E. Elmasry, and M. Abou-Donia. 2003. A role for P-glycoprotein in environmental toxicology. J. Toxicol. Environ. Health Part B 6 (3):279–88. doi:10.1080/10937400306466.
  • Aclairo. 2019. Leadscope® analysis of sucralose-6-acetate and sucralose. Vienna, VA, USA: Aclairo® pharmaceutical development group.
  • Agresti, A. 2002. Categorical Data Analysis. 2nd ed. Hoboken, NJ, US: John Wiley & Sons, Inc. https://onlinelibrary.wiley.com/doi/book/10.1002/0471249688?utm_sq=gxwftwi3be.
  • Alatab, S., S. G. Sepanlou, K. Ikuta, H. Vahedi, C. Bisignano, S. Safiri, A. Sadeghi, M. R. Nixon, A. Abdoli, H. Abolhassani, et al. 2020. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet Gastroenterol. Hepatol. 5 (1):17–30. doi:10.1016/S2468-1253(19)30333-4.
  • Al Bander, Z., M. D. Nitert, A. Mousa, and N. Naderpoor. 2020. The gut microbiota and inflammation: An overview. Int. J. Environ. Res. Public Health 17 (20):7618. doi:10.3390/ijerph17207618.
  • Allbritton, N., Y. Wang, C. Sims, S. Magness, and S. Bultman. 2021. Methods to generate gastrointestinal epithelial tissue constructs. United States Patent US 11,193,110 B2, issued December 7, 2021. https://patentimages.storage.googleapis.com/69/fc/f6/07af3119a3ed6b/US11193110.pdf
  • Al-Qudsi, F., and A. Al-Dosssary. 2020. Commercial artificial sweeteners affect spermatogenesis in mice. Int. J. Life Sci. Pharma Res. 10:L6–15. doi:10.22376/ijpbs/lpr.2020.10.4.L6-15.
  • Altis Biosystems. 2020. Investigation of the effects of sucralose and sucralose-6-acetate on human colonic epithelial monolayers. Study director Bailey Zwarycz PhD. Altis Biosystems, 6 Davis Drive, Durham, NC 27709, USA.
  • Altis Biosystems. 2021. Further investigating the effects of sucralose and sucralose-6-acetate on human colonic epithelial monolayers. Study director Bailey Zwarycz, PhD. Altis Biosystems, 6 Davis Drive, Durham, NC 27709, USA.
  • Anderson, R. C., A. L. Cookson, W. C. McNabb, Z. Park, M. J. McCann, W. J. Kelly, and N. C. Roy. 2010. Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiol. 10:316. doi:10.1186/1471-2180-10-316.
  • Armitage, P. 1955. Tests for linear trends in proportions and frequencies. Biometrics 11 (3):375–86. doi:10.2307/3001775.
  • Ashburner, M., C. A. Ball, J. A. Blake, D. Botstein, H. Butler, J. M. Cherry, A. P. Davis, K. Dolinski, S. S. Dwight, J. T. Eppig, et al. 2000. Gene ontology: Tool for the unification of biology. Nat. Genetics 25 (1):25–29. doi:10.1038/75556.
  • Azad, M. B., A. Archibald, M. M. Tomczyk, A. Head, K. G. Cheung, R. J. de Souza, A. B. Becker, P. J. Mandhane, S. E. Turvey, T. J. Moraes, et al. 2020. Nonnutritive sweetener consumption during pregnancy, adiposity, and adipocyte differentiation in offspring: Evidence from humans, mice, and cells. Int. J. Obes. 44 (10):2137–48. doi:10.1038/s41366-020-0575-x.
  • Babraham Bioinformatics. 2019. Trim galore Version 0.6.1. https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/.
  • Baird, I. M., N. W. Shephard, R. J. Merritt, and G. Hildick-Smith. 2000. Repeated dose study of sucralose tolerance in human subjects. Food Chem. Toxicol. 38:S123–29. doi:10.1016/s0278-6915(00)00035-1.
  • Bansal, T., R. C. Alaniz, T. K. Wood, and A. Jayaraman. 2010. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. National Acad. Sci. USA 107 (1):228–33. doi:10.1073/pnas.0906112107.
  • Bauman, J. W., J. Liu, Y. P. Liu, and C. D. Klaassen. 1991. Increase in metallothionein produced by chemicals that induce oxidative stress. Toxicol. Appl. Pharmacol. 110 (2):347–54. doi:10.1016/S0041-008X(05)80017-1.
  • Bernacki, D. T., S. M. Bryce, J. C. Bemis, D. Kirkland, and S. D. Dertinger. 2016. γH2AX and p53 responses in TK6 cells discriminate promutagens and nongenotoxicants in the presence of rat liver S9. Environ. Mol. Mutagen. 57 (7):546–58. doi:10.1002/em.22028.
  • Bian, X., L. Chi, B. Gao, P. Tu, H. Ru, and K. Lu. 2017. Gut microbiome response to sucralose and its potential role in inducing liver inflammation in mice. Front. Physiol. 8:487. doi:10.3389/fphys.2017.00487.
  • BioDuro-Sundia. 2021a. CYP inhibition determination, Trial 1. Shanghai, China: Study director: Jaing Pu.
  • BioDuro-Sundia. 2021b. Microsomal stability assay of sucralose-6-acetate and sucralose. Shanghai, China: BioDuro-Sundia. Study director: Jaing Pu. https://bioduro-sundia.com/adme-microsomal-stability-assay/.
  • BioDuro-Sundia. 2022. CYP inhibition determination, Trial 2, repetition of sucralose-6-acetate. Shanghai, China: Study director: Jaing Pu.
  • BioReliance. 2020a. CAN MultiFLOW High-throughput 96-well assay using human TK6 cells to screen for Clastogens, Aneugens: Sucralose-6-Acetate. Study AG05LV.365.BTL. Study director: Shambhu Roy, PhD, DABT, ERT, 9630 Medical Center Drive, Rockville, MD.
  • BioReliance. 2020b. In Vitro Mammalian Cell Micronucleus Screening Assay in TK6 Cells. 2 Arm Treatment (Treatments of 4 hours +S9 and 27 hours -S9). Study AG05LV.366ICH.BTL. Study directors: Pavan Gollapudi, PhD and Shambhu Roy, PhD, Rockville, MD.
  • BioReliance. 2020c. Bacterial Reverse Mutation Assay: Sucralose and Sucralose-6-acetate. Study AG05LU-LV.501028.BTL. Study director: Shannon Bruce, MFS, 9630 Medical Center Drive, Rockville, MD.
  • BioReliance. 2021. CAN MultiFLOW High-throughput 96-well assay using human TK6 cells to screen for Clastogens, Aneugens: Sucralose. Study, AG05LU.365.BTL. Study director: Pavan Gollapudi, PhD, 9630 Medical Center Drive, Rockville, MD.
  • Bornemann, V., S. C. Werness, L. Buslinger, and S. S. Schiffman. 2018. Intestinal metabolism and bioaccumulation of sucralose in adipose tissue in the rat. J. Toxicol. Environ. Health Part A 81 (18):913–23. doi:10.1080/15287394.2018.1502560.
  • Brüwer, M., K. W. Schmid, K. A. Metz, C. F. Krieglstein, N. Senninger, and G. Schürmann. 2001. Increased expression of metallothionein in inflammatory bowel disease. Inflamm. Res. 50 (6):289–93. doi:10.1007/PL00000246.
  • Bryce, S. M., J. C. Bemis, J. A. Mereness, R. A. Spellman, J. Moss, D. Dickinson, M. J. Schuler, and S. D. Dertinger. 2014. Interpreting in vitro micronucleus positive results: Simple biomarker matrix discriminates clastogens, aneugens, and misleading positive agents. Environ. Mol. Mutagen. 55 (7):542–55. doi:10.1002/em.21868.
  • Bryce, S. M., D. T. Bernacki, J. C. Bemis, and S. D. Dertinger. 2016. Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach. Environ. Mol. Mutagen. 57 (3):171–89. doi:10.1002/em.21996.
  • Bryce, S. M., D. T. Bernacki, J. C. Bemis, R. A. Spellman, M. E. Engel, M. Schuler, E. Lorge, P. T. Heikkinen, U. Hemmann, V. Thybaud, et al. 2017. Interlaboratory evaluation of a multiplexed high information content in vitro genotoxicity assay. Environ. Mol. Mutagen. 58 (3):146–61. doi:10.1002/em.22083.
  • Bryce, S. M., D. T. Bernacki, S. L. Smith-Roe, K. L. Witt, J. C. Bemis, and S. D. Dertinger. 2018. Investigating the generalizability of the MultiFlow® DNA damage assay and several companion machine learning models with a set of 103 diverse test chemicals. Toxicol. Sci. 162 (1):146–66. doi:10.1093/toxsci/kfx235.
  • Callaghan, R., E. Crowley, I. D. Potter, S. Kerr, and I. D. Kerr. 2008. P‐glycoprotein: So many ways to turn it on. J. Clin. Pharmacol. 48 (3):365–78. doi:10.1177/0091270007311568.
  • Canada Gazette. 1991. Food and drug regulations, amendment [Sucralose] (SOR/91-527). Canada Gazette II 125 (20):3125–30.
  • Catani, S. J., J. E. Wiley, N. M. Vernon, C. M. Merkel, and E. Micinski. 2006. Process for improving sucralose purity and yield. United States Patent 6,998,480 B2, February 14, 2006. https://patentimages.storage.googleapis.com/52/51/f8/fa99e898ec5443/US6998480.pdf.
  • Chen, S., Y. Zhou, Y. Chen, and J. Gu. 2018. Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34 (17):i884–90. doi:10.1093/bioinformatics/bty560.
  • Claus, S. P., S. L. Ellero, B. Berger, L. Krause, A. Bruttin, J. Molina, A. Paris, E. J. Want, I. de Waziers, O. Cloarec, et al. 2011. Colonization-induced host-gut microbial metabolic interaction. mBio 2 (2):10.1128/mBio.00271-10. e00271-10.
  • Close, P., M. Gillard, A. Ladang, Z. Jiang, J. Papuga, N. Hawkes, L. Nguyen, J. -P. Chapelle, F. Bouillenne, J. Svejstrup, et al. 2012. DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of Elongator. J. Biol. Chem. 287 (39):32535–45. doi:10.1074/jbc.m112.402727.
  • Clouthier, D. E., M. R. Avarbock, S. D. Maika, R. E. Hammer, and R. L. Brinster. 1996. Rat spermatogenesis in mouse testis. Nature 381 (6581):418–21. doi:10.1038/381418a0.
  • Cochran, W. G. 1954. Some methods for strengthening the common χ2 tests. Biometrics 10 (4):417–51. doi:10.2307/3001616.
  • Collins, S. L., and A. D. Patterson. 2020. The gut microbiome: An orchestrator of xenobiotic metabolism. Acta Pharm. Sin. B 10 (1):19–32. doi:10.1016/j.apsb.2019.12.001.
  • CTFile Formats. 2005. https://web.archive.org/web/20070630061308/http://www.mdl.com/downloads/public/ctfile/ctfile.pdf.
  • Cui, X., Y. Cui, T. Du, X. Jiang, C. Song, S. Zhang, C. Ma, Y. Liu, Q. Ni, Y. Gao, et al. 2022. SHMT2 drives the progression of colorectal cancer by regulating UHRF1 expression. Can. J. Gastroenterol. Hepatol. 2022:3758697. doi:10.1155/2022/3758697.
  • Cummings, S. R., T. Duong, E. Kenyon, J. A. Cauley, M. Whitehead, and K. A. Krueger. 2002. Serum estradiol level and risk of breast cancer during treatment with raloxifene. J. Am. Med. Assoc. 287 (2):216–20. doi:10.1001/jama.287.2.216.
  • Cyprotex. 2022. Microsomal stability assay of sucralose-6-acetate and sucralose with and without NADPH. Cyprotex, 313 Pleasant St., Watertown, MA 02472, USA.
  • Dai, X., Z. Guo, D. Chen, L. Li, X. Song, T. Liu, G. Jin, Y. Li, Y. Liu, A. Ajiguli, et al. 2020. Maternal sucralose intake alters gut microbiota of offspring and exacerbates hepatic steatosis in adulthood. Gut Microbes. 11 (4):1043–63. doi:10.1080/19490976.2020.1738187.
  • Dai, X., C. Wang, Z. Guo, Y. Li, T. Liu, G. Jin, S. Wang, B. Wang, K. Jiang, and H. Cao. 2021. Maternal sucralose exposure induces Paneth cell defects and exacerbates gut dysbiosis of progeny mice. Food Funct. 12 (24):12634–46. doi:10.1039/d1fo02921e.
  • Dai, H., L. Wang, L. Li, Z. Huang, and L. Ye. 2021. Metallothionein 1: A new spotlight on inflammatory diseases. Front. Immunol. 12:739918. doi:10.3389/fimmu.2021.739918.
  • Dalenberg, J. R., B. P. Patel, R. Denis, M. G. Veldhuizen, Y. Nakamura, P. C. Vinke, S. Luquet, and D. M. Small. 2020. Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar in humans. Cell Metab. 31 (3):493–502. doi:10.1016/j.cmet.2020.01.014.
  • Davies, B., and T. Morris. 1993. Physiological parameters in laboratory animals and humans. Pharm. Res. 10 (7):1093–95. doi:10.1023/a:1018943613122.
  • Dearfield, K. L., B. B. Gollapudi, J. C. Bemis, R. D. Benz, G. R. Douglas, R. K. Elespuru, G. E. Johnson, D. J. Kirkland, M. J. LeBaron, A. P. Li, et al. 2017. Next generation testing strategy for assessment of genomic damage: A conceptual framework and considerations. Environ. Mol. Mutagen. 58 (5):264–83. doi:10.1002/em.22045.
  • Delomenie, C., S. Fouix, S. Longuemaux, N. Brahimi, C. Bizet, B. Picard, E. Denamur, and J. -M. Dupret. 2001. Identification and functional characterization of arylamine N-acetyltransferases in eubacteria: Evidence for highly selective acetylation of 5-aminosalicylic acid. J. Bacteriol. 183 (11):3417–27. doi:10.1128/JB.183.11.3417-3427.2001.
  • De Oliveira, D. N., M. de Menezes, and R. R. Catharino. 2015. Thermal degradation of sucralose: A combination of analytical methods to determine stability and chlorinated byproducts. Sci. Rep. 5 (1):9598. doi:10.1038/srep09598.
  • Dooley, T. P., E. V. Curto, S. P. Reddy, R. L. Davis, G. W. Lambert, T. W. Wilborn, and C. O. Elson. 2004. Regulation of gene expression in inflammatory bowel disease and correlation with IBD drugs: Screening by DNA microarrays. Inflamm. Bowel Dis. 10 (1):1–14. doi:10.1097/00054725-200401000-00001.
  • DrugBank. 2022. https://go.drugbank.com
  • DuBois, G. E., D. E. Walters, S. S. Schiffman, Z. S. Warwick, B. J. Booth, S. D. Pecore, K. Gibes, B. T. Carr, and L. M. Brands. 1991. Concentration-response relationships of sweeteners: A systematic study. In Sweeteners. Discovery, Molecular Design, and Chemoreception. ACS Symposium Series 450, ed. D. E. Walters, F. T. Orthoefer, and G. E. DuBois, pp. 261–76. Washington, D.C: American Chemical Society.
  • Dull, B. J., K. Salata, and P. Goldman. 1987. Role of the intestinal flora in the acetylation of sulfasalazine metabolites. Biochem. Pharmacol. 36 (21):3772–74. doi:10.1016/0006-2952(87)90034-7.
  • Eisenreich, A., R. Gürtler, and B. Schäfer. 2020. Heating of food containing sucralose might result in the generation of potentially toxic chlorinated compounds. Food Chem. 321:126700. doi:10.1016/j.foodchem.2020.126700.
  • Elbrecht, D. H., C. J. Long, and J. J. Hickman. 2016. Transepithelial/Endothelial Electrical Resistance (TEER) theory and applications for microfluidic body-on-a-chip devices. J. Rare Dis. Res. Treat. 1 (3):46–52. doi:10.29245/2572-9411/2016/3.1026.
  • European Food Safety Authority (EFSA). 2016. Review of the threshold of Toxicological Concern (TTC) approach and development of new TTC decision tree. EFSA Supporting Publ. 13 (3):1–50. doi:10.2903/sp.efsa.2016.EN-1006.
  • European Union (EU). 2004. Directive 2003/115/EC of the European Parliament and of the Council of 22 December 2003 amending Directive 94/35/EC on sweeteners for use in foodstuffs. Off. J. Eur. Union 47 (L24):65–71. https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:024:0065:0071:EN:PDF.
  • Ewaschuk, J. B., H. Diaz, L. Meddings, B. Diederichs, A. Dmytrash, J. Backer, M. Looijer-van Langen, and K. L. Madsen. 2008. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am. J. Physiol-Gastr. L. 295 (5):G1025–34. doi:10.1152/ajpgi.90227.2008.
  • Farid, A., M. Hesham, M. El-Dewak, and A. Amin. 2020. The hidden hazardous effects of stevia and sucralose consumption in male and female albino mice in comparison to sucrose. Saudi Pharm. J. 28 (10):1290–300. doi:10.1016/j.jsps.2020.08.019.
  • Feng, Q., W. Yang, Z. Gao, X. Ruan, and Y. Zhang. 2019. Up-regulation of P-gp via NF-κB activation confers protection against oxidative damage in the retinal pigment epithelium cells. Exp. Eye Res. 181:367–73. doi:10.1016/j.exer.2018.11.024.
  • Fisher, R. A. 1954. Statistical methods for research workers. Edinburg: Oliver and Boyd. ISBN 0-05-002170-2.
  • Frazee, A. C., G. Pertea, A. E. Jaffe, B. Langmead, S. L. Salzberg, and J. T. Leek. 2015. Ballgown bridges the gap between transcriptome assembly and expression analysis. Nat. Biotechnol. 33 (3):243–46. doi:10.1038/nbt.3172.
  • GeneCards. 2023. https://www.genecards.org/
  • The Gene Ontology Consortium. 2019. The gene ontology resource: 20 years and still GOing strong. Nucleic Acids Res. 47 (D1):D330–38. doi:10.1093/nar/gky1055.
  • Giulioni, C., V. Maurizi, D. Castellani, S. Scarcella, E. Skrami, G. Balercia, and A. B. Galosi. 2022. The environmental and occupational influence of pesticides on male fertility: A systematic review of human studies. Andrology 10 (7):1250–71. doi:10.1111/andr.13228.
  • Goldsmith, L. A. 2000. Acute and subchronic toxicity of sucralose. Food Chem. Toxicol. 38:S53–69. doi:10.1016/s0278-6915(00)00028-4.
  • Gooderham, N. J., S. M. Cohen, G. Eisenbrand, S. Fukushima, F. P. Guengerich, S. S. Hecht, I. M. C. M. Rietjens, T. J. Rosol, M. Bastaki, M. J. Linman, et al. 2020. The safety evaluation of food flavoring substances: The role of genotoxicity studies. Crit. Rev. Toxicol. 50 (1):1–27. doi:10.1080/10408444.2020.1712589.
  • Grice, H. C., and L. A. Goldsmith. 2000. Sucralose—an overview of the toxicity data. Food Chem. Toxicol. 38:S1–6. doi:10.1016/s0278-6915(00)00023-5.
  • Griffiths, S. K., and J. P. Campbell. 2015. Placental structure, function and drug transfer. Continuing Edu. Anaesth. Crit. Care Pain 15 (2):84–89. doi:10.1093/bjaceaccp/mku013.
  • Guo, M., X. Liu, Y. Tan, F. Kang, X. Zhu, X. Fan, C. Wang, R. Wang, Y. Liu, X. Qin, et al. 2021. Sucralose enhances the susceptibility to dextran sulfate sodium (DSS) induced colitis in mice with changes in gut microbiota. Food Funct. 12 (19):9380–90. doi:10.1039/d1fo01351c.
  • Hao, X. 2011. Process for the preparation of sucralose. United States Patent US7,932,380 B2. Apr. 26, 2011. https://patentimages.storage.googleapis.com/7c/7e/01/cafc2dd77e7bbf/US7932380.pdf.
  • Hevener, K. E. 2018. Computational toxicology methods in chemical library design and high-throughput screening hit validation. Meth. Mol. Biol. 1800:275–85. doi:10.1007/978-1-4939-7899-1_13.
  • Hirako, N., and S. Takahashi. 2021. Upregulation of metallothionein-1G accelerates G1/S transition in the growth phase of acute promyelocytic leukemia NB4 cells. Ann. Clin. Lab. Sci. 51:38–43. PMID:33653779.
  • Hough, L., and S. P. Phadnis. 1976. Enhancement in the sweetness of sucrose. Nature 263 (5580):800. doi:10.1038/263800a0.
  • Houston, J. B. 1994. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47 (9):1469–79. doi:10.1016/0006-2952(94)90520-7.
  • Hu, N., X. Liu, Q. Mu, M. Yu, H. Wang, Y. Jiang, R. Chen, and L. Wang. 2021. The gut microbiota contributes to the modulation of intestinal CYP3A1 and P-gp in streptozotocin-induced type 1 diabetic rats. Eur. J. Pharm. Sci. 162:105833. doi:10.1016/j.ejps.2021.105833.
  • The Human Protein Atlas. 2023. https://www.proteinatlas.org/.
  • Hung, P.-H., M. Savidge, M. De, J. Kang, S. M. Healy, and L. G. Valerio Jr. 2020. In vitro and in silico genetic toxicity screening of flavor compounds and other ingredients in tobacco products with emphasis on ENDS. J. Appl. Toxicol. 40 (11):1566–87. doi:10.1002/jat.4020.
  • Japanese Ministry of Health and Welfare (JMHW). 1999. Approval of new high-intensity Sweetener: Sucralose: Revision of the enforcement regulations under the food sanitation law and of the standards and specifications for food and food additives, etc.(published in Official Gazette, No. 2678, July 30, 1999). Japanese Ministry of Health and Welfare (JMHW), Ministry of Health and Welfare Ordinance No.75 (Ministerial Ordinance to Revise Part of the Enforcement regulations under the Food Sanitation Law) and Ministry of Health and Welfare Announcement No. 167.
  • Jiang, Y., H. Huang, X. Zhu, M. Wu, M. Ye, B. Xiao, C. Yu, H. Fang, F. Liu, and S. Lv. 2019. ZSCAN10 promotes cell proliferation, upregulates OCT4 expression, and activates Wnt/β-catenin signaling in glioma. Int. J. Clin. Exp. Pathol. 12 (3):700–10.
  • Jiang, W., T. Wu, X. Shi, and J. Xu. 2021. Overexpression of EWSR1 (Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1) predicts poor survival in patients with hepatocellular carcinoma. Bioengineered 12 (1):7941–49. doi:10.1080/21655979.2021.1982844.
  • John, B. A., S. G. Wood, and D. R. Hawkins. 2000a. The pharmacokinetics and metabolism of sucralose in the mouse. Food Chem. Toxicol. 38:S107–10. doi:10.1016/s0278-6915(00)00032-6.
  • John, B. A., S. G. Wood, and D. R. Hawkins. 2000b. The pharmacokinetics and metabolism of sucralose in the rabbit. Food Chem. Toxicol. 38:S111–13. doi:10.1016/s0278-6915(00)00033-8.
  • Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1991. Trichlorogalactosucrose, in: Toxicological evaluation of certain food additives and contaminants. 37th JECFA Report, June 5–14, 1990, World Health Organization (WHO), Geneva, Switzerland , WHO Food Additives Series, No. 28, pp. 219–28. http://www.inchem.org/documents/jecfa/jecmono/v28je14.htm.
  • Ketola, K., M. Hilvo, T. Hyötyläinen, A. Vuoristo, A. -L. Ruskeepää, M. Orešič, O. Kallioniemi, and K. Iljin. 2012. Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br. J. Cancer 106 (1):99–106. doi:10.1038/bjc.2011.530.
  • Kille, J. W., W. C. Ford, P. McAnulty, J. M. Tesh, F. W. Ross, and C. R. Willoughby. 2000b. Sucralose: Lack of effects on sperm glycolysis and reproduction in the rat. Food Chem. Toxicol. 38:S19–29. doi:10.1016/s0278-6915(00)00025-9.
  • Kille, J. W., J. M. Tesh, P. A. McAnulty, F. W. Ross, C. R. Willoughby, G. P. Bailey, O. K. Wilby, and S. A. Tesh. 2000a. Sucralose: Assessment of teratogenic potential in the rat and the rabbit. Food Chem. Toxicol. 38:S43–52. doi:10.1016/s0278-6915(00)00027-2.
  • Kim, D., B. Langmead, and S. L. Salzberg. 2015. HISAT: A fast spliced aligner with low memory requirements. Nat. Methods 12 (4):357–60. doi:10.1038/nmeth.3317.
  • Kim, D., J. M. Paggi, C. Park, C. Bennett, and S. L. Salzberg. 2019. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37 (8):907–15. doi:10.1038/s41587-019-0201-4.
  • Koppel, N., V. M. Rekdal, and E. P. Balskus. 2018. Chemical transformation of xenobiotics by the human gut microbiota. Science 356 (6344):eaag2770. doi:10.1126/science.aag2770.
  • Kreuch, D., D. J. Keating, T. Wu, M. Horowitz, C. K. Rayner, and R. L. Young. 2018. Gut mechanisms linking intestinal sweet sensing to glycemic control. Front. Endocrinol. 9:741. doi:10.3389/fendo.2018.00741.
  • Kroes, R., A. G. Renwick, M. Cheeseman, J. Kleiner, I. Mangelsdorf, A. Piersma, B. Schilter, J. Schlatter, F. van Schothorst, J. G. Vos, et al. 2004. Structure-based thresholds of toxicological concern (TTC): Guidance for application to substances present at low levels in the diet. Food Chem. Toxicol. 42 (1):65–83. doi:10.1016/j.fct.2003.08.006.
  • Ku, H. -C., and C. -F. Cheng. 2020. Master regulator activating transcription factor 3 (ATF3) in metabolic homeostasis and cancer. Front. Endocrinol. 11:556. doi:10.3389/fendo.2020.00556.
  • Kundu, N., C. C. Domingues, J. Patel, M. Aljishi, N. Ahmadi, M. Fakhri, A. C. Sylvetsky, and S. Sen. 2020. Sucralose promotes accumulation of reactive oxygen species (ROS) and adipogenesis in mesenchymal stromal cells. Stem Cell Res. Therapy 11 (1):1–7. doi:10.1186/s13287-020-01753-0.
  • Kuno, T., M. Hirayama-Kurogi, S. Ito, and S. Ohtsuki. 2016. Effect of intestinal flora on protein expression of drug-metabolizing enzymes and transporters in the liver and kidney of germ-free and antibiotics-treated mice. Mol. Pharm. 13 (8):2691–701. doi:10.1021/acs.molpharmaceut.6b00259.
  • Labare, M. P., and M. Alexander. 1994. Microbial cometabolism of sucralose, a chlorinated disaccharide, in environmental samples. Appl. Microbiol. Biotechnol. 42 (1):173–78. doi:10.1007/bf00170242.
  • Leadscope®. 2019. www.leadscope.com
  • Lee, S. H. 2015. Intestinal permeability regulation by tight junction: Implication on inflammatory bowel diseases. Intestinal Res. 13 (1):11. doi:10.5217/ir.2015.13.1.11.
  • Lenoir, C., V. Rollason, J. A. Desmeules, and C. F. Samer. 2021. Influence of inflammation on cytochromes P450 activity in adults: A systematic review of the literature. Front. Pharmacol. 12:733935. doi:10.3389/fphar.2021.733935.
  • Lertrit, A., S. Srimachai, S. Saetung, S. Chanprasertyothin, L. -O. Chailurkit, C. Areevut, P. Katekao, B. Ongphiphadhanakul, and C. Sriphrapradang. 2018. Effects of sucralose on insulin and glucagon-like peptide-1 secretion in healthy subjects: A randomized, double-blind, placebo-controlled trial. Nutrition 55-56:125–30. doi:https://doi.org/10.1016/j.nut.2018.04.001.
  • Li, H., B. Handsaker, A. Wysoker, T. Fennell, J. Ruan, N. Homer, G. Marth, G. Abecasis, and R. Durbin. 2009. The sequence alignment/map format and SAMtools. Bioinformatics 25 (16):2078–79. doi:10.1093/bioinformatics/btp352.
  • Li, X., Y. Liu, Y. Wang, X. Li, X. Liu, M. Guo, Y. Tan, X. Qin, X. Wang, and M. Jiang. 2020. Sucralose promotes colitis-associated colorectal cancer risk in a murine model along with changes in microbiota. Front. Oncol. 10:710. doi:10.3389/fonc.2020.00710.
  • Liu, C. -W., L. Chi, P. Tu, J. Xue, H. Ru, and K. Lu. 2019. Quantitative proteomics reveals systematic dysregulations of liver protein metabolism in sucralose-treated mice. J. Proteomics 196:1–10. doi:10.1016/j.jprot.2019.01.011.
  • Liu, C., L. Wang, X. Liu, Y. Tan, L. Tao, Y. Xiao, P. Deng, H. Wang, Q. Deng, Y. Lin, et al. 2021. Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation. Theranostics 11 (6):2966–86. doi:10.7150/thno.48699.
  • Liu, Z., Z. Yang, S. Jiang, Q. Zou, Y. Yuan, J. Li, D. Li, L. Liang, M. Chen, and S. Chen. 2016. MCM2 and TIP30 are prognostic markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of the gallbladder. Mol. Med. Rep. 14 (5):4581–92. doi:10.3892/mmr.2016.5851.
  • Li, R., J. Zheng, M. Jiang, Y. Liu, X. Qin, and X. Wang. 2016. Increased digestive proteases and decreased β-glucuronidase in feces of rats treated with sucralose and saccharin—Another critical evidence that these dietary chemicals may be important causative factors for inflammatory bowel disease. Inflamm. Bowel Dis. 22 (8):E29–30. doi:10.1097/mib.0000000000000859.
  • Mah-Som, A. Y., M. P. Keppel, J. M. Tobin, A. Kolicheski, N. Saucier, V. Sexl, A. R. French, J. A. Wagner, T. A. Fehniger, and M. A. Cooper. 2021. Reliance on Cox10 and oxidative metabolism for antigen-specific NK cell expansion. Cell Rep. 35 (9):109209. doi:10.1016/j.celrep.2021.109209.
  • Margolskee, R. F., J. Dyer, Z. Kokrashvili, K. S. H. Salmon, E. Ilegems, K. Daly, E. L. Maillet, Y. Ninomiya, B. Mosinger, and S. P. Shirazi-Beechey. 2007. T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proc. National Acad. Sci. USA 104 (38):15075–80. doi:10.1073/pnas.0706678104.
  • Marioni, J. C., C. E. Mason, S. M. Mane, M. Stephens, and Y. Gilad. 2008. RNA-seq: An assessment of technical reproducibility and comparison with gene expression arrays. Genome Res. 18 (9):1509–17. doi:10.1101/gr.079558.108.
  • Martin, M. 2011. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMB Net J. 17 (1):10–12. doi:10.14806/ej.17.1.200.
  • MedlinePlus. 2023. CHST3 gene. https://medlineplus.gov/genetics/gene/chst3/#:~:text=The%20CHST3%20gene%20provides%20instructions,and%20maintenance%20of%20the%20skeleton
  • Méndez-García, L. A., N. Bueno-Hernández, M. A. Cid-Soto, K. L. De León, V. M. Mendoza-Martínez, A. J. Espinosa-Flores, M. Carrero-Aguirre, M. Esquivel-Velázquez, M. León-Hernández, R. Viurcos-Sanabria, et al. 2022. Ten-week sucralose consumption induces gut dysbiosis and altered glucose and insulin levels in healthy young adults. Microorganisms 10 (2):434. doi:10.3390/microorganisms10020434.
  • Migliaccio, V., L. Lionetti, R. Putti, and R. Scudiero. 2020. Exposure to dichlorodiphenyldichloroethylene (DDE) and metallothionein levels in rats fed with normocaloric or high-fat diet: A review. Int. J. Mol. Sci. 21 (5):1903. doi:10.3390/ijms21051903.
  • Mohandas, S., and B. Vairappan. 2017. Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases. World J. Hepatol. 9 (32):1210. doi:10.4254/wjh.v9.i32.1210.
  • Mufti, K. S., and R. A. Khan. 1983. Process for the preparation of 4,1’,6’-trichloro-4,1’,6’-trideoxygalactosucrose (TGS). United States Patent 4,380,476, Apr. 19, 1983. https://patentimages.storage.googleapis.com/65/97/df/34eeba00c9c026/US4380476.pdf
  • Nagai, F., E. Kato, and H. -O. Tamura. 2004. Oxidative stress induces GSTP1 and CYP3A4 expression in the human erythroleukemia cell line, K562. Biol. Pharm. Bull. 27 (4):492–95. doi:10.1248/bpb.27.492.
  • Nguyen, T. H., P. L. Vemu, G. E. Hoy, S. Boudjadi, B. Chatterjee, J. F. Shern, J. Khan, W. Sun, and F. G. Barr. 2021. Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification. J. Clin. Invest. 131 (15):e138022. doi:10.1172/JCI138022.
  • Obach, R. S., R. L. Walsky, K. Venkatakrishnan, E. A. Gaman, J. B. Houston, and L. M. Tremaine. 2006. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J. Pharmacol. Exp. Ther. 316 (1):336–48. doi:10.1124/jpet.105.093229.
  • Olivier-Van Stichelen, S., K. I. Rother, and J. A. Hanover. 2019. Maternal exposure to non-nutritive sweeteners impacts progeny’s metabolism and microbiome. Front. Microbiol. 10:1360. doi:10.3389/fmicb.2019.01360.
  • OpAns. 2021. HPLC-MS/MS quantification of sucralose and sucralose-6-acetate from transwell apical and basal reservoir supernatants as well as samples of sucralose from Sigma-Aldrich, Study directors Jose Mendoza PhD and Tony Leesnitzer. OpAns, LLC. 4134 S. Alston Ave., Durham, NC 27713, USA.
  • Organization of Economic Cooperation and Development (OECD). 2016. Test No. 487: In Vitro Mammalian cell micronucleus test, OECD guideline for the testing of chemicals, Section 4. Paris: OECD Publishing. doi:10.1787/9789264264861-en.
  • Organization of Economic Cooperation and Development (OECD). 2020. Test No. 471: Bacterial reverse mutation test. OECD guideline for the testing of chemicals, Section 4. Paris: OECD Publishing. doi:10.1787/9789264071247-en.
  • Ostrakhovitch, E. A., P. -E. Olsson, S. Jiang, and M. G. Cherian. 2006. Interaction of metallothionein with tumor suppressor p53 protein. FEBS Lett. 580 (5):1235–38. doi:10.1016/j.febslet.2006.01.036.
  • Pałkowska-Goździk, E., A. Bigos, and D. Rosołowska-Huszcz. 2018. Type of sweet flavour carrier affects thyroid axis activity in male rats. Eur. J. Nutr. 57 (2):773–82. doi:https://doi.org/10.1007/s00394-016-1367-x.
  • Pan, H., W. Xue, W. Zhao, and M. Schachner. 2020. Expression and function of chondroitin 4‐sulfate and chondroitin 6‐sulfate in human glioma. The FASEB J. 34 (2):2853–68. doi:10.1096/fj.201901621RRR.
  • Parsa, S., A. Ortega-Molina, H. -Y. Ying, M. Jiang, M. Teater, J. Wang, C. Zhao, E. Reznik, J. P. Pasion, D. Kuo, et al. 2020. The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing. Nat. Cancer 1 (6):653–64. doi:10.1038/s43018-020-0080-0.
  • Pasqualli, T., P. E. E. Chaves, L. da Veiga Pereira, É. Adílio Serpa, L. F. S. de Oliveira, and M. M. Machado. 2020. Sucralose causes non‐selective CD4 and CD8 lymphotoxicity via probable regulation of the MAPK8/APTX/EID1 genes: An in vitro/in silico study. Clin. Exp. Pharmacol. Physiol. 47:1751–57. doi:10.1111/1440-1681.13362.
  • Pepino, M. Y., C. D. Tiemann, B. W. Patterson, B. M. Wice, and S. Klein. 2013. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care 36 (9):2530–35. doi:https://doi.org/10.2337/dc12-2221.
  • Pertea, M., D. Kim, G. M. Pertea, J. T. Leek, and S. L. Salzberg. 2016. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat. Protoc. 11 (9):1650–67. doi:10.1038/nprot.2016.095.
  • Pertea, M., G. M. Pertea, C. M. Antonescu, T. -C. Chang, J. T. Mendell, and S. L. Salzberg. 2015. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33 (3):290–95. doi:10.1038/nbt.3122.
  • PubChem. 2022. https://pubchem.ncbi.nlm.nih.gov/
  • Qin, X. 2011. What caused the recent worldwide increase of inflammatory bowel disease: Should sucralose be added as a suspect? Inflamm. Bowel Dis. 17 (10):E139. doi:10.1002/ibd.21823.
  • Qu, Y., R. Li, M. Jiang, and X. Wang. 2017. Sucralose increases antimicrobial resistance and stimulates recovery of Escherichia coli mutants. Curr. Microbiol. 74 (7):885–88. doi:10.1007/s00284-017-1255-5.
  • Rahn, A., and V. A. Yaylayan. 2010. Thermal degradation of sucralose and its potential in generating chloropropanols in the presence of glycerol. Food Chem. 118 (1):56–61. doi:10.1016/j.foodchem.2009.04.133.
  • Raudvere, U. L., I. Kolberg, T. Kuzmin, P. Arak, H. P. Adler, J. Vilo, and J. Vilo. 2019. G: Profiler: A web server for functional enrichment analysis and conversions of gene lists. Nucleic Acids Res. 47 (W1):W191–98. https://biit.cs.ut.ee/gprofiler/gost.
  • Raya, S. A., A. M. Aboul-Enein, M. M. El-Nikeety, R. S. Mohamed, and W. M. Abdelwahid. 2020. In vivo comet assay of food additives’ combinations and their effects on biochemical parameters in albino rats. Biointerface Res. Appl. Chem. 11 (2):9170–83. doi:10.33263/briac112.91709183.
  • Roberts, A., A. G. Renwick, J. Sims, and D. J. Snodin. 2000. Sucralose metabolism and pharmacokinetics in man. Food Chem. Toxicol. 38:S31–41. doi:10.1016/s0278-6915(00)00026-0.
  • Rodrigo, M. A. M., A. M. J. Jimemez, Y. Haddad, K. Bodoor, P. Adam, S. Krizkova, Z. Heger, and V. Adam. 2020. Metallothionein isoforms as double agents–their roles in carcinogenesis, cancer progression and chemoresistance. Drug Resist. Update. 52:100691. doi:10.1016/j.drup.2020.100691.
  • Rodriguez-Palacios, A., A. Harding, P. Menghini, C. Himmelman, M. Retuerto, K. P. Nickerson, M. Lam, C. M. Croniger, M. H. McLean, S. K. Durum, et al. 2018. The artificial sweetener Splenda promotes gut proteobacteria, dysbiosis, and myeloperoxidase reactivity in Crohn’s disease–like ileitis. Inflamm. Bowel Dis. 24 (5):1005–20. doi:10.1093/ibd/izy060.
  • Romo-Romo, A., C. A. Aguilar-Salinas, G. X. Brito-Córdova, R. A. Gómez-Díaz, and P. Almeda-Valdes. 2018. Sucralose decreases insulin sensitivity in healthy subjects: A randomized controlled trial. Am. J. Clin. Nutr. 108 (3):485–91. doi:https://doi.org/10.1093/ajcn/nqy152.
  • Rosales-Gómez, C. A., B. E. Martínez-Carrillo, A. A. Reséndiz-Albor, N. Ramírez-Durán, R. Valdés-Ramos, T. Mondragón-Velásquez, and J. A. Escoto-Herrera. 2018. Chronic consumption of sweeteners and its effect on glycaemia, cytokines, hormones, and lymphocytes of GALT in CD1 mice. Biomed. Res. Int. 2018:1345282. doi:10.1155/2018/1345282.
  • Ruttkay-Nedecky, B., L. Nejdl, J. Gumulec, O. Zitka, M. Masarik, T. Eckschlager, M. Stiborova, V. Adam, and R. Kizek. 2013. The role of metallothionein in oxidative stress. Int. J. Mol. Sci. 14 (3):6044–66. doi:10.3390/ijms14036044.
  • Sánchez-Alcoholado, L., R. Ordóñez, A. Otero, I. Plaza-Andrade, A. Laborda-Illanes, J. A. Medina, B. Ramos-Molina, J. Gómez-Millán, and M. I. Queipo-Ortuño. 2020. Gut microbiota-mediated inflammation and gut permeability in patients with obesity and colorectal cancer. Int. J. Mol. Sci. 21 (18):6782. doi:10.3390/ijms21186782.
  • Sasaki, Y. F., S. Kawaguchi, A. Kamaya, M. Ohshita, K. Kabasawa, K. Iwama, K. Taniguchi, and S. Tsuda. 2002. The comet assay with 8 mouse organs: Results with 39 currently used food additives. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 519 (1–2):103–19. doi:10.1016/s1383-5718(02)00128-6.
  • Schiffman, S. S., and K. I. Rother. 2013. Sucralose, a synthetic organochlorine sweetener: Overview of biological issues J. Toxicol. Environ. Health Part B. 16 (7):399–451. doi:10.1080/10937404.2013.842523.
  • Schiffman, S. S., E. A. Sattely-Miller, and I. E. Bishay. 2008. Sensory properties of neotame: Comparison with other sweeteners. Sweetness and Sweeteners: Biology, Chemistry and Psychophysics. ACS Symposium Series 979, ed. D. K. Weerasinghe, and G. E. DuBois, pp. 511–29. New York, NY: Oxford University Press.
  • Schwartz, J. L., R. Jordan, H. H. Evans, M. Lenarczyk, and H. L. Liber. 2004. Baseline levels of chromosome instability in the human lymphoblastoid cell TK6. Mutagenesis 19 (6):477–82. doi:10.1093/mutage/geh060.
  • Scientific Committee on Food (SCF). 2000. Opinion of the scientific committee on food on sucralose (Adopted by the SCF on 7 September 2000). European Commission Health & Consumer Protection Directorate-General Directorate C – Scientific Opinions C3 – Management of scientific committees II; scientific co-operation and networks. Scientific Committee on Food [SCF/CS/ADDS/EDUL/190 Final 12/9/2000]. https://ec.europa.eu/food/system/files/2020-12/sci-com_scf_out68_en.pdf
  • Selwyn, F. P., S. L. Cheng, C. D. Klaassen, and J. Y. Cui. 2016. Regulation of hepatic drug-metabolizing enzymes in germ-free mice by conventionalization and probiotics. Drug Metab. Dispos. 44 (2):262–74. doi:10.1124/dmd.115.067504.
  • Serafimova, R., T. Coja, and G. E. Kass. 2021. Application of the threshold of toxicological concern (TTC) in food safety: Challenges and opportunities. Front. Toxicol. 3:655951. doi:10.3389/ftox.2021.655951.
  • Shchulkin, A. V., Y. V. Abalenikhina, P. D. Erokhina, I. V. Chernykh, and E. N. Yakusheva. 2021. The role of P-glycoprotein in decreasing cell membranes permeability during oxidative stress. Biochem. 86 (2):197–206. doi:10.1134/S0006297921020085.
  • Shigetomi, K., Y. Ono, K. Matsuzawa, and J. Ikenouchi. 2023. Cholesterol-rich domain formation mediated by ZO proteins is essential for tight junction formation. Proc. National Acad. Sci. USA 120 (8):e2217561120. doi:10.1073/pnas.2217561120.
  • Shil, A., and H. Chichger. 2021. Artificial sweeteners negatively regulate pathogenic characteristics of two model gut bacteria, E. coli and E. faecalis. Int. J. Mol. Sci. 22 (10):5228. doi:10.3390/ijms22105228.
  • Shil, A., O. Olusanya, Z. Ghufoor, B. Forson, J. Marks, and H. Chichger. 2020. Artificial sweeteners disrupt tight junctions and barrier function in the intestinal epithelium through activation of the sweet taste receptor, T1R3. Nutrients 12 (6):1862. doi:10.3390/nu12061862.
  • Si, M., and J. Lang. 2018. The roles of metallothioneins in carcinogenesis. J. Hematol. Oncol. 11 (1):107. doi:10.1186/s13045-018-0645-x.
  • Sims, J., A. Roberts, J. W. Daniel, and A. G. Renwick. 2000. The metabolic fate of sucralose in rats. Food Chem. Toxicol. 38:S115–21. doi:10.1016/S0278-6915(00)00034-X.
  • Soffritti, M., M. Padovani, E. Tibaldi, L. Falcioni, F. Manservisi, M. Lauriola, L. Bua, M. Manservigi, and F. Belpoggi. 2016. Sucralose administered in feed, beginning prenatally through lifespan, induces hematopoietic neoplasias in male Swiss mice. Int. J. Occup. Environ. Health 22 (1):7–17. doi:10.1080/10773525.2015.1106075.
  • Srinivasan, B., A. R. Kolli, M. B. Esch, H. E. Abaci, M. L. Shuler, and J. J. Hickman. 2015. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20 (2):107–26. doi:10.1177/2211068214561025.
  • Strolin-Benedetti, M., G. Brogin, M. Bani, F. Oesch, and J. G. Hengstler. 1999. Association of cytochrome P450 induction with oxidative stress in vivo as evidenced by 3-hydroxylation of salicylate. Xenobiotica 29 (11):1171–80. doi:10.1080/004982599238038.
  • Suez, J., Y. Cohen, R. Valdés-Mas, U. Mor, M. Dori-Bachash, S. Federici, N. Zmora, A. Leshem, M. Heinemann, R. Linevsky, et al. 2022. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell 185 (18):1–22. doi:10.1016/j.cell.2022.07.016.
  • Suez, J., T. Korem, D. Zeevi, G. Zilberman-Schapira, C. A. Thaiss, O. Maza, D. Israeli, N. Zmora, S. Gilad, A. Weinberger, et al. 2014. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514 (7521):181–86. doi:10.1038/nature13793.
  • Sun, J., L. Chen, B. Lou, Y. Bai, X. Yu, M. Zhao, and Z. Wang. 2017. Acetylation and deacetylation for sucralose preparation by a newly isolated Bacillus amyloliquefaciens WZS01. J. Biosci. Bioeng. 123 (5):576–80. doi:10.1016/j.jbiosc.2016.12.013.
  • Sun, E. W., D. De Fontgalland, P. Rabbitt, P. Hollington, L. Sposato, S. L. Due, D. A. Wattchow, C. K. Rayner, A. M. Deane, R. L. Young, et al. 2017. Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine. Diabetes 66 (8):2144–49. doi:10.2337/db17-0058.
  • Sylvetsky, A. C., A. L. Gardner, V. Bauman, J. E. Blau, H. M. Garraffo, P. J. Walter, and K. I. Rother. 2015. Nonnutritive sweeteners in breast milk. J. Toxicol. Environ. Health Part A 78 (16):1029–32. doi:10.1080/15287394.2015.1053646.
  • Sylvetsky, A. C., S. Sen, P. Merkel, F. Dore, D. B. Stern, C. J. Henry, H. Cai, P. J. Walter, K. A. Crandall, K. I. Rother, et al. 2020. Consumption of diet soda sweetened with sucralose and acesulfame‐potassium alters inflammatory transcriptome pathways in females with overweight and obesity. Mol. Nutr. Food Res. 64 (11):1901166. doi:10.1002/mnfr.201901166.
  • Tang, Z., Y. Yang, W. Chen, E. Li, and T. Liang. 2022. Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients. J. Transl. Med. 20 (1):49. doi:10.1186/s12967-022-03249-2.
  • Toda, T., N. Saito, N. Ikarashi, K. Ito, M. Yamamoto, A. Ishige, K. Watanabe, and K. Sugiyama. 2009. Intestinal flora induces the expression of CYP3a in the mouse liver. Xenobiotica 39 (4):323–34. doi:10.1080/00498250802651984.
  • Togao, M., K. Kawakami, J. Otsuka, G. Wagai, Y. Ohta‐takada, and S. Kado. 2020. Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: Midazolam. Biopharm. Drug Dispos. 41 (7):275–82. doi:10.1002/bdd.2244.
  • Tong, Z. -B., J. Braisted, P. -H. Chu, and D. Gerhold. 2020. The MT1G gene in LUHMES neurons is a sensitive biomarker of neurotoxicity. Neurotox. Res. 38 (4):967–78. doi:10.1007/s12640-020-00272-3.
  • Uchimura, K., K. Kadomatsu, H. Nishimura, H. Muramatsu, E. Nakamura, N. Kurosawa, O. Habuchi, F. M. El-Fasakhany, Y. Yoshikai, and T. Muramatsu. 2002. Functional analysis of the chondroitin 6-sulfotransferase gene in relation to lymphocyte subpopulations, brain development, and oversulfated chondroitin sulfates. J. Biol. Chem. 277 (2):1443–50. doi:10.1074/jbc.M104719200.
  • Ugai, T., N. Sasamoto, H. -Y. Lee, M. Ando, M. Song, R. M. Tamimi, I. Kawachi, P. T. Campbell, E. L. Giovannucci, E. Weiderpass, et al. 2022. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat. Rev. Clin. Oncol. 19 (10):656–73. doi:10.1038/s41571-022-00672-8.
  • Uhlén, M., L. Fagerberg, B. M. Hallström, C. Lindskog, P. Oksvold, A. Mardinoglu, Å. Sivertsson, C. Kampf, E. Sjöstedt, A. Asplund, et al. 2015. Tissue-based map of the human proteome. Science 347 (6220):1260419. doi:10.1126/science.1260419.
  • Ukena, S. N., A. Singh, U. Dringenberg, R. Engelhardt, U. Seidler, W. Hansen, A. D. Bruder, G. Franzke, A. Rogler, S. Suerbaum, et al. 2007. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLos One 2 (12):e1308. doi:10.1371/journal.pone.0001308.
  • United States Food and Drug Administration (US FDA). 1998. Food additives permitted for direct addition to food for human consumption; sucralose. 21CFR Part 172 [Docket No. 87F-0086]. Fed. Regist. 63 (64):16417–33. http://www.gpo.gov/fdsys/pkg/FR-1998-04-03/pdf/98-8750.pdf.
  • United States Food and Drug Administration (US FDA). 1999. Food additives permitted for direct addition to food for human consumption: Sucralose [21CFR Part 172; Docket No. 99F–0001]. Fed. Regist. 64 (155):43908–09. https://www.govinfo.gov/content/pkg/FR-1999-08-12/pdf/99-20888.pdf
  • United States Food and Drug Administration (US FDA). 2018. M7(R1) assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential
  • United States Food and Drug Administration (US FDA). 2020. In Vitro Drug Interaction Studies —Cytochrome P450 Enzyme- and Transporter Mediated Drug Interactions. Guidance for Industry. Center for Drug Evaluation and Research (CDER). https://www.fda.gov/media/134582/download
  • United States Food and Drug Administration (US FDA). 2021. Data accessed from the sucralose food additive petition (FAP) filed by McNeil Specialty Products Co. Exhibit E: Safety, Page 002211. Obtained from the US FDA Office of Food Additive Safety on February 8, 2021.
  • Utami, R. A., A. Hakiki, S. Asyarie, and D. S. Retnoningrum. 2018. Gliadin peptide facilitates FITC dextran transport across the non-everted gut sac of rat small intestine. Sci. Pharm. 86 (2):13. doi:10.3390/scipharm86020013.
  • Van Eyk, A. D. 2015. The effect of five artificial sweeteners on Caco-2, HT-29 and HEK-293 cells. Drug. Chem. Toxicol. 38 (3):318–27. doi:10.3109/01480545.2014.966381.
  • Van Nguyen, G., M. C. Tran, L. Van Nguyen, H. T. Quynh, and M. N. Nguyen. 2021. Up-regulation of SET nuclear proto-oncogene is associated with early recurrence and poorer prognosis of hepatocellular carcinoma. VNUHCM J. Health Sci. 2:110–21.
  • Wang, Z., M. Gerstein, and M. Snyder. 2009. RNA-Seq: A revolutionary tool for transcriptomics. Nat. Rev. Genet. 10 (1):57–63. doi:10.1038/nrg2484.
  • Wang, X., J. Guo, Y. Liu, H. Yu, and X. Qin. 2019. Sucralose increased susceptibility to colitis in rats. Inflamm. Bowel Dis. 25 (2):e3–4. doi:10.1093/ibd/izy196.
  • Wang, F., H. He, X. Yang, Y. Yu, and Z. Fan. 2011. Method of sucralose synthesis yield. United States Patent US 7,884,203 B2. Feb. 8, 2011. https://patentimages.storage.googleapis.com/6e/f0/41/27b2650c7022ac/US7884203.pdf
  • Welcker, K., A. Martin, P. Kolle, M. Siebeck, and M. Gross. 2004. Increased intestinal permeability in patients with inflammatory bowel disease. Eur. J. Med. Res. 9 (10):456–60.
  • Werness, S. 2021. Chemical analysis of 18 food-grade commercial samples of sucralose extracted with ethyl acetate to determine the presence of impurities including sucralose-6-acetate. Report to Department of Biomedical Engineering at North Carolina State University. Study director: Stephen Werness, Director of Mass Spectrometry Laboratory, Avazyme, Inc., 2202 Ellis Rd #A, Durham, NC 27703.
  • Werness, S., and S. S. Schiffman. 2020. Comparison of chromatographic results from sucralose-6-acetate (synthesized by Jiangyin PharmaAdvance, Inc., P. R. China) with chromatographic and mass spectrometry data from Bornemann et al. 2018.
  • Westbrook, A. M., B. Wei, J. Braun, and R. H. Schiestl. 2011. Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice. Int. J. Cancer 129 (8):1815–25. doi:10.1002/ijc.26146.
  • Wingender, E. 2008. The TRANSFAC project as an example of framework technology that supports the analysis of genomic regulation. Brief. Bioinformatics 9 (4):326–32. doi:10.1093/bib/bbn016.
  • Wood, S. G., B. A. John, and D. R. Hawkins. 2000. The pharmacokinetics and metabolism of sucralose in the dog. Food Chem. Toxicol. 38:S99–106. doi:10.1016/s0278-6915(00)00031-4.
  • Xu, F., Y. Guan, P. Zhang, L. Xue, X. Yang, K. Gao, and T. Chong. 2020. The impact of TNFSF14 on prognosis and immune microenvironment in clear cell renal cell carcinoma. Genes Genomics 42 (9):1055–66. doi:10.1007/s13258-020-00974-0.
  • Yin, X., J. W. Dewille, and T. Hai. 2008. A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 27 (15):2118–27. doi:10.1038/sj.onc.1210861.
  • Young, R. L., N. J. Isaacs, G. Schober, T. Wu, N. Cvijanovic, N. Pezos, M. Bound, D. J. Keating, C. K. Rayner, and M. Horowitz. 2017. Impact of artificial sweeteners on glycaemic control in healthy humans (193). OP 33 Gastro-entero-pancreatic interactions. Diabetologia 60 (Suppl 1):S91. doi:10.1007/s00125-017-4350-z.
  • Zhang, H., Y. Che, B. Xuan, X. Wu, and H. Li. 2022. Serine hydroxymethyltransferase 2 (SHMT2) potentiates the aggressive process of oral squamous cell carcinoma by binding to interleukin enhancer-binding factor 2 (ILF2). Bioengineered 13 (4):8785–97. doi:10.1080/21655979.2022.2051886.
  • Zheng, Z., Y. Xiao, L. Ma, W. Lyu, H. Peng, X. Wang, Y. Ren, and J. Li. 2022. Low dose of sucralose alter gut microbiome in mice. Front. Nutr. 9:848392. doi:10.3389/fnut.2022.848392.