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Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone.
Aquat Toxicol 2019; 214:105242AT

Abstract

Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex differentiation disturbance by progestins, particularly from the metabolic aspect. We thus aimed to examine the sex changes by exposing zebrafish embryos to 4.4 (L), 44 (M) and 440 (H) ng/L DDG for up to 140 days, and investigated metabolomic profile changes during the critical period of sex differentiation at fry stage (35 dpf). DDG increased the percentage of male zebrafish in a dose-dependent manner, with 98% male fish in the high concentration group. In zebrafish fry, DDG increased the levels of some free fatty acids, monoglycerides, acylcarnitines, organic acids, free amino acids, while decreased lysophospholipids, uric acid and bile acids. DDG exposure also decreased the nucleoside monophosphates and UDP-sugars while increased nucleosides and their bases. These metabolite changes, namely increase in n-3 PUFAs (polyunsaturated fatty acids), myo-inositol, taurine, palmitoleic acid, oleic acid, lactic acid, fumaric acid, and uracil, and decrease in uric acid and bile acids, might account for the male-biased sex ratio in zebrafish. It appears that many of these metabolites could inhibit several pathways that regulate zebrafish gonad differentiation, including NF-κB/COX-2 and Wnt/β-catenin pathways, and activate p53 pathway. Thus we proposed a hypothesis that DDG might induce oocytes apoptosis through the above pathways and finally lead to female-to-male sex reversal. The results from this study suggest that DDG at environmentally relevant concentrations could affect zebrafish metabolomic profiles and finally disturb fish sex differentiation.

Authors+Show Affiliations

State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China; SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; University of Chinese Academy of Sciences, Beijing 100049, China.SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China.SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China.State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China; SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; University of Chinese Academy of Sciences, Beijing 100049, China.SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China. Electronic address: guangguo.ying@m.scnu.edu.cn.NUS Environmental Research Institute, National University of Singapore, 117411, Singapore.School of Public Health, National University of Singapore, 117547, Singapore. Electronic address: ephocn@nus.edu.sg.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31319296

Citation

Jiang, Yu-Xia, et al. "Male-biased Zebrafish Sex Differentiation and Metabolomics Profile Changes Caused By Dydrogesterone." Aquatic Toxicology (Amsterdam, Netherlands), vol. 214, 2019, p. 105242.
Jiang YX, Shi WJ, Ma DD, et al. Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone. Aquat Toxicol. 2019;214:105242.
Jiang, Y. X., Shi, W. J., Ma, D. D., Zhang, J. N., Ying, G. G., Zhang, H., & Ong, C. N. (2019). Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone. Aquatic Toxicology (Amsterdam, Netherlands), 214, p. 105242. doi:10.1016/j.aquatox.2019.105242.
Jiang YX, et al. Male-biased Zebrafish Sex Differentiation and Metabolomics Profile Changes Caused By Dydrogesterone. Aquat Toxicol. 2019 Jul 11;214:105242. PubMed PMID: 31319296.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Male-biased zebrafish sex differentiation and metabolomics profile changes caused by dydrogesterone. AU - Jiang,Yu-Xia, AU - Shi,Wen-Jun, AU - Ma,Dong-Dong, AU - Zhang,Jin-Na, AU - Ying,Guang-Guo, AU - Zhang,Hui, AU - Ong,Choon-Nam, Y1 - 2019/07/11/ PY - 2019/04/03/received PY - 2019/07/05/revised PY - 2019/07/07/accepted PY - 2019/7/19/pubmed PY - 2019/7/19/medline PY - 2019/7/19/entrez KW - Dydrogesterone KW - Fish KW - Metabolites KW - Metabolomics KW - Oocyte apoptosis KW - Sex differentiation SP - 105242 EP - 105242 JF - Aquatic toxicology (Amsterdam, Netherlands) JO - Aquat. Toxicol. VL - 214 N2 - Some progestins, including the widely used dydrogesterone (DDG), have been shown to cause male-biased sex ratio in teleost. However, there is a gap to fully understand the mechanisms of the sex differentiation disturbance by progestins, particularly from the metabolic aspect. We thus aimed to examine the sex changes by exposing zebrafish embryos to 4.4 (L), 44 (M) and 440 (H) ng/L DDG for up to 140 days, and investigated metabolomic profile changes during the critical period of sex differentiation at fry stage (35 dpf). DDG increased the percentage of male zebrafish in a dose-dependent manner, with 98% male fish in the high concentration group. In zebrafish fry, DDG increased the levels of some free fatty acids, monoglycerides, acylcarnitines, organic acids, free amino acids, while decreased lysophospholipids, uric acid and bile acids. DDG exposure also decreased the nucleoside monophosphates and UDP-sugars while increased nucleosides and their bases. These metabolite changes, namely increase in n-3 PUFAs (polyunsaturated fatty acids), myo-inositol, taurine, palmitoleic acid, oleic acid, lactic acid, fumaric acid, and uracil, and decrease in uric acid and bile acids, might account for the male-biased sex ratio in zebrafish. It appears that many of these metabolites could inhibit several pathways that regulate zebrafish gonad differentiation, including NF-κB/COX-2 and Wnt/β-catenin pathways, and activate p53 pathway. Thus we proposed a hypothesis that DDG might induce oocytes apoptosis through the above pathways and finally lead to female-to-male sex reversal. The results from this study suggest that DDG at environmentally relevant concentrations could affect zebrafish metabolomic profiles and finally disturb fish sex differentiation. SN - 1879-1514 UR - https://www.unboundmedicine.com/medline/citation/31319296/Male-biased_zebrafish_sex_differentiation_and_metabolomics_profile_changes_caused_by_dydrogesterone L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-445X(19)30258-9 DB - PRIME DP - Unbound Medicine ER -