近年來食品安全問題層出不窮，食品加工過程生成的食品污染物對於人體的健康不良反應逐漸被大眾關注。3-單氯二醇(3-Monochloropropane-1,2-diol, 3-MCPD)和縮水甘油(glycidol)做為一存在於精製植物油、嬰兒配方奶粉、烘焙產品中的食品污染物，在過去研究中指出攝入兩物質可能會導致腎臟功能受損及雄性生殖指標下降。隨著分子生物學技術之發展，許多研究以多體學 (Multi-omics)之形式，整合多筆體學數據探討物質誘導毒性之潛在因果關係。目前對於3-MCPD和glycidol引起毒性機制可能與粒線體功能缺失引發細胞程序性死亡有關，然而其造成腎臟和生殖毒性的確切機轉仍未知。因此，以多體學模式結合細胞實驗了解3-MCPD和glycidol對腎臟和生殖毒性之毒理機轉是為本研究重要的目標。此外，具抗發炎性質之天然多酚物質紫檀芪 (Pterostilbene, PT)也將於本研究探討其對3-MCPD和glycidol毒性之預防效果，以做為未來毒性預防策略發展之基石。
本研究使用過去探討3-MCPD和glycidol單獨或合併紫檀芪暴露C57BL/6小鼠研究之腎臟檢體進行RNA定序篩選出表達顯著差異之基因進行Gene Ontology (GO)和Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway富集分析，於基因體層次找出具顯著差異生物途徑和代謝途徑；同時也以16S rDNA定序技術分析糞便檢體探討3-MCPD暴露對於腸道微生物組成變化，並以PICRUSt軟體預測各處理組別菌群之代謝功能。代謝體學分析則採用先前研究3-MCPD毒性試驗及回復性動物模式之尿液檢體，以LC-MS無特定標的小分子代謝體分析兩模式中生成量顯著差異之代謝物以了解3-MCPD暴露於代謝功能的影響。此外，OECD內分泌干擾物測試指南也被應用檢測雌激素轉錄活性和睪固酮生成量，同時以MitoSOX Red 染色分析觀察粒線體超氧化物生成量變化，以了解3-MCPD和glycidol暴露潛在的生殖內分泌毒理機制。
本研究中藉由基因體學、轉錄體學、代謝體學及微生物體學分析等體學模式探討3-MCPD和glycidol暴露對於腎臟和生殖內分泌系統的影響。從結果發現3-MCPD和glycidol單獨或合併紫檀芪暴露在基因體層次影響與免疫發炎反應調控之途徑以調節腎臟發炎反應，同時也觀察到激素調節應激途徑改變，揭露兩物質潛在的內分泌干擾風險。此外，腸道菌相分析結果表明3-MCPD暴露改變腸道微生物組成，並預測該組成變化與多條代謝功能途徑有關。而代謝體學分析結果則顯示3-MCPD暴露造成代謝物生成量改變；回復性試驗結果則觀察到停止給藥四週後，調節粒線體蛋白轉譯作用的胺基酸N-Formylmethionine (fMet)生成顯著下調，表明3-MCPD誘導之代謝變化可能與粒線體作用相關，與先前研究相呼應。體外細胞實驗結果表明暴露不同濃度之3-MCPD和 glycidol會促進雌激素轉錄活性、睪固酮生成量下降，並對小鼠睪丸間質細胞具有毒殺效應，且glycidol在暴露初期使粒線體超氧化物生成量上升。
綜合上述結果，本研究揭露3-MCPD和glycidol單獨或合併紫檀芪暴露在不同體學層次與體外試驗結果皆顯示對腎臟和生殖內分泌系統之潛在影響，與先前研究結果相呼應，為未來相關毒理機轉之探討提供新視野。
關鍵字：3-單氯丙二醇、縮水甘油、多體學、腎臟毒性、生殖毒性、紫檀芪

3-Monochloropropane-1,2-diol (3-MCPD) and glycidol are food contaminants found in refined vegetable oils, infant formula, and bakery products, which have been proven to cause nephrotoxicity and reproductive toxicity. Nowadays, omics studies have been conducted to provide more information in risk assessments of xenobiotics. Therefore, integration of omics technologies in toxicology research is a trend that cannot be ignored. Recent researches have shown that the toxicological mechanism of 3-MCPD and glycidol are related to mitochondrial dysfunction while the exact mechanisms are still unclear. Hence, the purpose of this study is to explore the nephrotoxicity and reproductive toxicity induced by 3-MCPD and glycidol through the integration of omics approaches and in vitro study. Additionally, the preventive effects of pterostilbene (PT), an anti-inflammatory natural compound to toxicity induced by 3-MCPD and glycidol are investigated in this study. The effects of 3-MCPD and glycidol treatment alone or in combination with pterostilbene are analyzed by integrating genomics, transcriptomics, metabolomics, microbiomics techniques and in vitro approaches. The results showed that 3-MCPD and glycidol treatment alone or in combination with pterostilbene affect the gene expression in renal tissue. Additionally, 3-MCPD alters the composition of gut microbiome, causing the changes in the metabolic processes and regulates the responses to inflammatory and hormone. In the in vitro study, 3-MCPD and glycidol induced the increase of mitochondrial superoxide and induce cytotoxicity effects in mouse Leydig cell. We also discovered that 3-MCPD and glycidol are likely to promote ER transactivation and reduce the testosterone levels. These results correspond to our omics study, showing the potential risks of the exposure of 3-MCPD and glycidol. Therefore, we suggest that there should be more studies to investigate the exact molecular mechanisms of 3-MCPD and glycidol.
Keywords: 3-MCPD, glycidol, multi-omics, pterostilbene, nephrotoxicity, reproductive toxicity

劉蓓雯. (2019). 食品汙染物單氯丙二醇及縮水甘油誘發腎臟毒性機轉並開發預防策略之研究. (碩士). 國立成功大學, 台南市. Retrieved from https://hdl.handle.net/11296/2pt95z
賴筱姍. (2021). 探討食品汙染物三單氯丙二醇藉由粒線體自體吞噬作用誘導之腎臟毒性機制. (碩士). 國立成功大學, 台南市. Retrieved from https://hdl.handle.net/11296/cnj4tv
Abdelsalam, N. A., Ramadan, A. T., ElRakaiby, M. T., & Aziz, R. K. (2020). Toxicomicrobiomics: The Human Microbiome vs. Pharmaceutical, Dietary, and Environmental Xenobiotics. Front Pharmacol, 11, 390. doi:10.3389/fphar.2020.00390
Abraham, K., Appel, K. E., Berger-Preiss, E., Apel, E., Gerling, S., Mielke, H., . . . Lampen, A. (2013). Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats. Archives of Toxicology, 87(4), 649-659. doi:10.1007/s00204-012-0970-8
Acharjee, A., Ament, Z., West, J. A., Stanley, E., & Griffin, J. L. (2016). Integration of metabolomics, lipidomics and clinical data using a machine learning method. BMC bioinformatics, 17(15), 37-49.
Appel, K. E., Abraham, K., Berger-Preiss, E., Hansen, T., Apel, E., Schuchardt, S., . . . Lampen, A. (2013). Relative oral bioavailability of glycidol from glycidyl fatty acid esters in rats. Archives of Toxicology, 87(9), 1649-1659. doi:10.1007/s00204-013-1061-1
Auerbach, S. (2017). Toxicogenomics. In M. Schwab (Ed.), Encyclopedia of Cancer (pp. 4589-4597). Berlin, Heidelberg: Springer Berlin Heidelberg.
Baer, I., de la Calle, B., & Taylor, P. (2010). 3-MCPD in food other than soy sauce or hydrolysed vegetable protein (HVP). Anal Bioanal Chem, 396(1), 443-456. doi:10.1007/s00216-009-3177-y
Bamalan, O. A., & Al Khalili, Y. (2022). Physiology, Serotonin. In StatPearls. Treasure Island (FL): StatPearls Publishing
Copyright © 2022, StatPearls Publishing LLC.
Barocelli, E., Corradi, A., Mutti, A., & Petronini, P. G. (2011). Comparison between 3-MCPD and its palmitic esters in a 90-day toxicological study. EFSA Supporting Publications, 8(9), 187E. doi:https://doi.org/10.2903/sp.efsa.2011.EN-187
Berg, G., Rybakova, D., Fischer, D., Cernava, T., Verges, M. C., Charles, T., . . . Schloter, M. (2020). Microbiome definition re-visited: old concepts and new challenges. Microbiome, 8(1), 103. doi:10.1186/s40168-020-00875-0
Braeuning, A., Sawada, S., Oberemm, A., & Lampen, A. (2015). Analysis of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes in rat liver. Food Chem Toxicol, 86, 374-384. doi:10.1016/j.fct.2015.11.010
Breault, D. T., & Majzoub, J. A. (2003). Corticotropin-Releasing Hormone (CRH). In H. L. Henry & A. W. Norman (Eds.), Encyclopedia of Hormones (pp. 297-305). New York: Academic Press.
Buesen, R., Chorley, B. N., da Silva Lima, B., Daston, G., Deferme, L., Ebbels, T., . . . Poole, A. (2017). Applying 'omics technologies in chemicals risk assessment: Report of an ECETOC workshop. Regulatory Toxicology and Pharmacology, 91, S3-S13. doi:https://doi.org/10.1016/j.yrtph.2017.09.002
Buhrke, T., Voss, L., Briese, A., Stephanowitz, H., Krause, E., Braeuning, A., & Lampen, A. (2018). Oxidative inactivation of the endogenous antioxidant protein DJ-1 by the food contaminants 3-MCPD and 2-MCPD. Archives of Toxicology, 92(1), 289-299. doi:10.1007/s00204-017-2027-5
Cai, N., Gomez-Duran, A., Yonova-Doing, E., Kundu, K., Burgess, A. I., Golder, Z. J., . . . Soranzo, N. (2021). Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases. Nat Med, 27(9), 1564-1575. doi:10.1038/s41591-021-01441-3
Canzler, S., Schor, J., Busch, W., Schubert, K., Rolle-Kampczyk, U. E., Seitz, H., . . . Hackermuller, J. (2020). Prospects and challenges of multi-omics data integration in toxicology. Arch Toxicol, 94(2), 371-388. doi:10.1007/s00204-020-02656-y
Chain, E. Panel o. C. i. t. F. (2016). Risks for human health related to the presence of 3- and 2-monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food. Efsa Journal, 14(5), e04426. doi:https://doi.org/10.2903/j.efsa.2016.4426
Chain, E. Panel o. C. i. t. F., Knutsen, H. K., Alexander, J., Barregård, L., Bignami, M., Brüschweiler, B., . . . Hogstrand, C. (2018). Update of the risk assessment on 3-monochloropropane diol and its fatty acid esters. Efsa Journal, 16(1), e05083. doi:https://doi.org/10.2903/j.efsa.2018.5083
Cheng, W., Liu, G., & Liu, X. (2016). Formation of Glycidyl Fatty Acid Esters Both in Real Edible Oils during Laboratory-Scale Refining and in Chemical Model during High Temperature Exposure. J Agric Food Chem, 64(29), 5919-5927. doi:10.1021/acs.jafc.6b01520
Cheng, W. W., Liu, G. Q., Wang, L. Q., & Liu, Z. S. (2017). Glycidyl Fatty Acid Esters in Refined Edible Oils: A Review on Formation, Occurrence, Analysis, and Elimination Methods. Compr Rev Food Sci Food Saf, 16(2), 263-281. doi:10.1111/1541-4337.12251
Collier, P. D., Cromie, D. D. O., & Davies, A. P. (1991). Mechanism of Formation of Chloropropanols Present in Protein Hydrolysates. Journal of the American Oil Chemists Society, 68(10), 785-790. doi:Doi 10.1007/Bf02662173
Commission, E. (2020). Commission Regulation (EU) 2020/1322 of 23 September 2020 amending Regulation (EC) No 1881/2006 as regards maximum levels of 3-monochloropropanediol (3-MCPD), 3-MCPD fatty acid esters and glycidyl fatty acid esters in certain foods. Off J Eur Union L, 310, 2-5.
Council, N. R. (2007). Applications of toxicogenomic technologies to predictive toxicology and risk assessment.
Crews, C. (2014). Processing Contaminants: Chloropropanols and Related Esters. In Y. Motarjemi (Ed.), Encyclopedia of Food Safety (pp. 392-398). Waltham: Academic Press.
Dikeocha, I. J., Al-Kabsi, A. M., Miftahussurur, M., & Alshawsh, M. A. (2022). Pharmacomicrobiomics: Influence of gut microbiota on drug and xenobiotic metabolism. FASEB J, 36(6), e22350. doi:10.1096/fj.202101986R
Dos Santos, B. S., da Silva, L. C., da Silva, T. D., Rodrigues, J. F., Grisotto, M. A., Correia, M. T., . . . Paiva, P. M. (2016). Application of Omics Technologies for Evaluation of Antibacterial Mechanisms of Action of Plant-Derived Products. Front Microbiol, 7, 1466. doi:10.3389/fmicb.2016.01466
Dvorakova, M., & Landa, P. (2017). Anti-inflammatory activity of natural stilbenoids: A review. Pharmacol Res, 124, 126-145. doi:10.1016/j.phrs.2017.08.002
Ellinger-Ziegelbauer, H., & Ahr, H.-J. (2014a). Omics in Toxicology. In F.-X. Reichl & M. Schwenk (Eds.), Regulatory Toxicology (pp. 173-179). Berlin, Heidelberg: Springer Berlin Heidelberg.
Ellinger-Ziegelbauer, H., & Ahr, H.-J. (2014b). Omics in Toxicology. In (pp. 173-179): Springer Berlin Heidelberg.
Etxeberria, U., Hijona, E., Aguirre, L., Milagro, F. I., Bujanda, L., Rimando, A. M., . . . Portillo, M. P. (2017). Pterostilbene-induced changes in gut microbiota composition in relation to obesity. Mol Nutr Food Res, 61(1). doi:10.1002/mnfr.201500906
Gao, B., Li, Y., Huang, G., & Yu, L. (2019). Fatty Acid Esters of 3-Monochloropropanediol: A Review. Annu Rev Food Sci Technol, 10, 259-284. doi:10.1146/annurev-food-032818-121245
Gao, B., Liu, M., Huang, G., Zhang, Z., Zhao, Y., Wang, T. T., . . . Yu, L. (2017). Absorption, Distribution, Metabolism and Excretion of 3-MCPD 1-Monopalmitate after Oral Administration in Rats. J Agric Food Chem, 65(12), 2609-2614. doi:10.1021/acs.jafc.7b00639
Giuliani, C., Iezzi, M., Ciolli, L., Hysi, A., Bucci, I., Di Santo, S., . . . Napolitano, G. (2017). Resveratrol has anti-thyroid effects both in vitro and in vivo. Food and Chemical Toxicology, 107, 237-247. doi:https://doi.org/10.1016/j.fct.2017.06.044
Giulivo, M., Lopez de Alda, M., Capri, E., & Barceló, D. (2016). Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review. Environ Res, 151, 251-264. doi:10.1016/j.envres.2016.07.011
Gómez-Zorita, S., Milton-Laskibar, I., Macarulla, M. T., Biasutto, L., Fernández-Quintela, A., Miranda, J., . . . Portillo, M. P. (2021). Pterostilbene modifies triglyceride metabolism in hepatic steatosis induced by high-fat high-fructose feeding: a comparison with its analog resveratrol. Food & Function, 12(7), 3266-3279. doi:10.1039/D0FO03320K
Groopman, E. E., Rasouly, H. M., & Gharavi, A. G. (2018). Genomic medicine for kidney disease. Nat Rev Nephrol, 14(2), 83-104. doi:10.1038/nrneph.2017.167
Ham, J., You, S., Lim, W., & Song, G. (2020). Bifenthrin impairs the functions of Leydig and Sertoli cells in mice via mitochondrion-endoplasmic reticulum dysregulation. Environ Pollut, 266(Pt 3), 115174. doi:10.1016/j.envpol.2020.115174
Horgan, R. P., & Kenny, L. C. (2011). ‘Omic’ technologies: genomics, transcriptomics, proteomics and metabolomics. The Obstetrician & Gynaecologist, 13(3), 189-195. doi:https://doi.org/10.1576/toag.13.3.189.27672
Jones, A. R., Milton, D. H., & Murcott, C. (1978). The oxidative metabolism of alpha-chlorohydrin in the male rat and the formation of spermatocoeles. Xenobiotica, 8(9), 573-582. doi:10.3109/00498257809061257
Jones, A. R., & Porter, L. M. (1995). Inhibition of glycolysis in boar spermatozoa by alpha-chlorohydrin phosphate appears to be mediated by phosphatase activity. Reprod Fertil Dev, 7(5), 1089-1094. doi:10.1071/rd9951089
Joseph, D. N., & Whirledge, S. (2017). Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci, 18(10). doi:10.3390/ijms18102224
Kalkhof, S., Dautel, F., Loguercio, S., Baumann, S., Trump, S., Jungnickel, H., . . . von Bergen, M. (2015). Pathway and time-resolved benzo[a]pyrene toxicity on Hepa1c1c7 cells at toxic and subtoxic exposure. J Proteome Res, 14(1), 164-182. doi:10.1021/pr500957t
Kim, H., Seo, K. H., & Yokoyama, W. (2020). Chemistry of Pterostilbene and Its Metabolic Effects. J Agric Food Chem, 68(46), 12836-12841. doi:10.1021/acs.jafc.0c00070
Kosyakovsky, L. B. (2017). The emerging role of the microbiome in precision medicine: An overview. UBC Medical Journal, 9(1).
Lange, K. W., & Li, S. (2018). Resveratrol, pterostilbene, and dementia. Biofactors, 44(1), 83-90. doi:10.1002/biof.1396
Li, X., Ma, J., Shi, W., Su, Y., Fu, X., Yang, Y., . . . Yue, Z. (2016). Calcium oxalate induces renal injury through calcium-sensing receptor. Oxidative medicine and cellular longevity, 2016.
Liang, C., Gao, Y., He, Y., Han, Y., Manthari, R. K., Tikka, C., . . . Zhang, J. (2020). Fluoride induced mitochondrial impairment and PINK1-mediated mitophagy in Leydig cells of mice: In vivo and in vitro studies. Environ Pollut, 256, 113438. doi:10.1016/j.envpol.2019.113438
Lin, W. S., Leland, J. V., Ho, C. T., & Pan, M. H. (2020). Occurrence, Bioavailability, Anti-inflammatory, and Anticancer Effects of Pterostilbene. J Agric Food Chem, 68(46), 12788-12799. doi:10.1021/acs.jafc.9b07860
Liu, P. W., Li, C. I., Huang, K. C., Liu, C. S., Chen, H. L., Lee, C. C., . . . Chen, R. J. (2021). 3-MCPD and glycidol coexposure induces systemic toxicity and synergistic nephrotoxicity via NLRP3 inflammasome activation, necroptosis, and autophagic cell death. J Hazard Mater, 405, 124241. doi:10.1016/j.jhazmat.2020.124241
Ma, Y., Liu, H., Du, X., Shi, Z., Liu, X., Wang, R., . . . Zhang, H. (2021). Advances in the toxicology research of microcystins based on Omics approaches. Environ Int, 154, 106661. doi:10.1016/j.envint.2021.106661
Ma, Y.-B., Manzoor, R., Jia, P.-P., Bian, W.-P., Hamid, N., Xie, Z.-Y., & Pei, D.-S. (2021). Transcriptome and in silico approaches provide new insights into the mechanism of male reproductive toxicity induced by chronic exposure to DEHP. Environmental Pollution, 289, 117944. doi:https://doi.org/10.1016/j.envpol.2021.117944
Maruvada, P., Leone, V., Kaplan, L. M., & Chang, E. B. (2017). The Human Microbiome and Obesity: Moving beyond Associations. Cell Host Microbe, 22(5), 589-599. doi:10.1016/j.chom.2017.10.005
Mokhtari, P., Metos, J., & Anandh Babu, P. V. (2021). Impact of type 1 diabetes on the composition and functional potential of gut microbiome in children and adolescents: possible mechanisms, current knowledge, and challenges. Gut Microbes, 13(1), 1-18. doi:10.1080/19490976.2021.1926841
Morgan, E. W., Perdew, G. H., & Patterson, A. D. (2022). Multi-Omics Strategies for Investigating the Microbiome in Toxicology Research. Toxicol Sci, 187(2), 189-213. doi:10.1093/toxsci/kfac029
Nogacka, A. M., Gómez-Martín, M., Suárez, A., González-Bernardo, O., de Los Reyes-Gavilán, C. G., & González, S. (2019). Xenobiotics formed during food processing: Their relation with the intestinal microbiota and colorectal cancer. International journal of molecular sciences, 20(8), 2051.
Obrador, E., Salvador-Palmer, R., Jihad-Jebbar, A., Lopez-Blanch, R., Dellinger, T. H., Dellinger, R. W., & Estrela, J. M. (2021). Pterostilbene in Cancer Therapy. Antioxidants (Basel), 10(3). doi:10.3390/antiox10030492
Palmeira, C. M., & Ramalho-Santos, J. (2017). Chapter 53 - Mitochondrial Dysfunction in Reproductive and Developmental Toxicity. In R. C. Gupta (Ed.), Reproductive and Developmental Toxicology (Second Edition) (pp. 1023-1035): Academic Press.
Pan, J., Shi, M., Li, L., Liu, J., Guo, F., Feng, Y., . . . Fu, P. (2019). Pterostilbene, a bioactive component of blueberries, alleviates renal fibrosis in a severe mouse model of hyperuricemic nephropathy. Biomed Pharmacother, 109, 1802-1808. doi:10.1016/j.biopha.2018.11.022
Rahn, A. K. K., & Yaylayan, V. A. (2011). What do we know about the molecular mechanism of 3-MCPD ester formation? European Journal of Lipid Science and Technology, 113(3), 323-329. doi:10.1002/ejlt.201000310
Redza-Dutordoir, M., & Averill-Bates, D. A. (2016). Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta, 1863(12), 2977-2992. doi:10.1016/j.bbamcr.2016.09.012
Reel, P. S., Reel, S., Pearson, E., Trucco, E., & Jefferson, E. (2021). Using machine learning approaches for multi-omics data analysis: A review. Biotechnology Advances, 49, 107739. doi:https://doi.org/10.1016/j.biotechadv.2021.107739
Rosato, A., Tenori, L., Cascante, M., De Atauri Carulla, P. R., Martins Dos Santos, V. A. P., & Saccenti, E. (2018). From correlation to causation: analysis of metabolomics data using systems biology approaches. Metabolomics, 14(4), 37. doi:10.1007/s11306-018-1335-y
Ruiz, M., Fernández, M., Pico, Y., Manes, J., Asensi, M., Carda, C., . . . Estrela, J. (2009). Dietary administration of high doses of pterostilbene and quercetin to mice is not toxic. Journal of agricultural and food chemistry, 57(8), 3180-3186.
Rysz, J., Gluba-Brzozka, A., Franczyk, B., Jablonowski, Z., & Cialkowska-Rysz, A. (2017). Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome. Int J Mol Sci, 18(8). doi:10.3390/ijms18081702
Sawada, S., Oberemm, A., Buhrke, T., Meckert, C., Rozycki, C., Braeuning, A., & Lampen, A. (2015). Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate toxicity in rat testis. Food Chem Toxicol, 83, 84-92. doi:10.1016/j.fct.2015.06.002
Scala, G., Kinaret, P., Marwah, V., Sund, J., Fortino, V., & Greco, D. (2018). Multi-omics analysis of ten carbon nanomaterials effects highlights cell type specific patterns of molecular regulation and adaptation. NanoImpact, 11, 99-108. doi:10.1016/j.impact.2018.05.003
Schilter, B., Scholz, G., & Seefelder, W. (2011). Fatty acid esters of chloropropanols and related compounds in food: Toxicological aspects. European Journal of Lipid Science and Technology, 113(3), 309-313. doi:10.1002/ejlt.201000311
Seefelder, W., Varga, N., Studer, A., Williamson, G., Scanlan, F. P., & Stadler, R. H. (2008a). Esters of 3-chloro-1,2-propanediol (3-MCPD) in vegetable oils: Significance in the formation of 3-MCPD. Food Additives and Contaminants Part a-Chemistry Analysis Control Exposure & Risk Assessment, 25(4), 391-400. doi:10.1080/02652030701385241
Seefelder, W., Varga, N., Studer, A., Williamson, G., Scanlan, F. P., & Stadler, R. H. (2008b). Esters of 3-chloro-1,2-propanediol (3-MCPD) in vegetable oils: significance in the formation of 3-MCPD. Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 25(4), 391-400. doi:10.1080/02652030701385241
Sengupta, K., Kolla, J. N., Bagchi, D., & Bagchi, M. (2011). Chapter 59 - Applications of toxicogenomics in reproductive and developmental toxicology. In R. C. Gupta (Ed.), Reproductive and Developmental Toxicology (pp. 793-799). San Diego: Academic Press.
Song, D., Xu, C., Holck, A. L., & Liu, R. (2021). Acrylamide inhibits autophagy, induces apoptosis and alters cellular metabolic profiles. Ecotoxicol Environ Saf, 208, 111543. doi:10.1016/j.ecoenv.2020.111543
Suez, J., Korem, T., Zilberman-Schapira, G., Segal, E., & Elinav, E. (2015). Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microbes, 6(2), 149-155. doi:10.1080/19490976.2015.1017700
Tan, Y. Q., Zhang, X., Zhang, S., Zhu, T., Garg, M., Lobie, P. E., & Pandey, V. (2021). Mitochondria: The metabolic switch of cellular oncogenic transformation. Biochim Biophys Acta Rev Cancer, 1876(1), 188534. doi:10.1016/j.bbcan.2021.188534
Trinh, P., Zaneveld, J. R., Safranek, S., & Rabinowitz, P. M. (2018). One Health Relationships Between Human, Animal, and Environmental Microbiomes: A Mini-Review. Front Public Health, 6, 235. doi:10.3389/fpubh.2018.00235
Tsai, H. J., Tsai, W. C., Hung, W. C., Hung, W. W., Chang, C. C., Dai, C. Y., & Tsai, Y. C. (2021). Gut Microbiota and Subclinical Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus. Nutrients, 13(8). doi:10.3390/nu13082679
van Breda, S. G. J., Claessen, S. M. H., van Herwijnen, M., Theunissen, D. H. J., Jennen, D. G. J., de Kok, T., & Kleinjans, J. C. S. (2018). Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology, 393, 160-170. doi:10.1016/j.tox.2017.11.013
Van Den Wijngaard, A. J., Janssen, D. B., & Witholt, B. (1989). Degradation of Epichlorohydrin and Halohydrins by Bacterial Cultures Isolated from Freshwater Sediment. Microbiology, 135(8), 2199-2208. doi:https://doi.org/10.1099/00221287-135-8-2199
Wang, W., Ding, X. Q., Gu, T. T., Song, L., Li, J. M., Xue, Q. C., & Kong, L. D. (2015). Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. Free Radic Biol Med, 83, 214-226. doi:10.1016/j.freeradbiomed.2015.02.029
Waters, M. D. (2016). Chapter 1. Introduction to Predictive Toxicogenomics for Carcinogenicity. In (pp. 1-38): Royal Society of Chemistry.
Waters, M. D., & Fostel, J. M. (2004). Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet, 5(12), 936-948. doi:10.1038/nrg1493
Xiao, Y., Bi, M., Guo, H., & Li, M. (2022). Multi-omics approaches for biomarker discovery in early ovarian cancer diagnosis. EBioMedicine, 79, 104001. doi:10.1016/j.ebiom.2022.104001
Xing, H. Z., Fang, B., Pang, G. F., & Ren, F. Z. (2019). 3-Monochloropropane-1, 2-diol causes irreversible damage to reproductive ability independent of hormone changes in adult male rats. Food Chem Toxicol, 124, 10-16. doi:10.1016/j.fct.2018.11.023
Ye, J., Zhao, Y., Chen, X., Zhou, H., Yang, Y., Zhang, X., . . . Xiao, M. (2021). Pu-erh tea ameliorates obesity and modulates gut microbiota in high fat diet fed mice. Food Res Int, 144, 110360. doi:10.1016/j.foodres.2021.110360
Zelinkova, Z., Novotny, O., Schurek, J., Velisek, J., Hajslova, J., & Dolezal, M. (2008). Occurrence of 3-MCPD fatty acid esters in human breast milk. Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 25(6), 669-676. doi:10.1080/02652030701799375
Zhang, Q., Luo, P., Chen, J., Yang, C., Xia, F., Zhang, J., . . . Wang, J. (2022). Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics. Int J Biol Sci, 18(5), 2003-2017. doi:10.7150/ijbs.69618
Zhao, L., Zhang, Q., Ma, W., Tian, F., Shen, H., & Zhou, M. (2017). A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota. Food Funct, 8(12), 4644-4656. doi:10.1039/c7fo01383c
Zhao, W. P., Wang, H. W., Liu, J., Zhang, Z. H., Zhu, S. Q., & Zhou, B. H. (2019). Mitochondrial respiratory chain complex abnormal expressions and fusion disorder are involved in fluoride-induced mitochondrial dysfunction in ovarian granulosa cells. Chemosphere, 215, 619-625. doi:10.1016/j.chemosphere.2018.10.043
Zhou, X.-J., Zhong, X.-H., & Duan, L.-X. (2022). Integration of artificial intelligence and multi-omics in kidney diseases. Fundamental Research. doi:https://doi.org/10.1016/j.fmre.2022.01.037