title: Linking genomic responses of gonads with reproductive impairment in marine medaka (Oryzias melastigma) exposed chronically to the chemopreventive and antifouling agent, 3,3'-diindolylmethane (DIM).
abstract: 3,3'-Diindolylmethane (DIM) has been promoted as an effective chemopreventive and antifouling additive. However, the concurrent risks or side effects of DIM are not fully understood, especially on tissues responsive to estrogen. Therefore, this study employed marine medaka (Oryzias melastigma) as a test model to evaluate relative safety and explore mechanisms of toxic action of DIM on development and function of gonad after chronic (28days) aqueous exposure to relatively low doses (0μg/L or 8.5μg/L). Integration of comprehensive toxicogenomic analysis at the transcriptome and proteome levels with apical endpoints, such as production of eggs and swimming performance of larvae, elucidated the molecular linkage in gonad from bottom up along the reproductive adverse outcome pathway. A series of sequential changes at the transcript and protein levels were linked to lesser fecundity and viability of larvae exposed to DIM. Anomalous production of vitellogenin (VTG) and eggshell proteins in testis confirmed the estrogenic potency of DIM. In the ovary, although storage of VTG was greater, lesser expressions of cathepsin enzymes blocked cleavage and incorporation of VTG into oocytes as yolk, which acted together with lower eggshell proteins to inhibit maturation of primary oocyte and thus contributed to impairment of fecundity. Overall, this study demonstrated that exposure to DIM impaired reproductive fitness. Diverse molecular initiating changes in gonads were linked to apical endpoints that could be used in assessment of risks posed by DIM on gametogenesis. In combination with chemical stability and potent endocrine disruption, the results of this study can inform decisions about the use of DIM either as chemopreventive or antifouling agent.
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
authors.forename: Lianguo
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory in Marine Pollution, Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
authors.forename: Doris W T
authors.initials: DWT
authors.lastname: Au
authors.affiliation: School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430072, China.
authors.forename: Chenyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Bingsheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Zoology, and Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China. Electronic address: boqianpy@ust.hk.
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Qian
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D004202:Disinfectants / Q000633:toxicity*; D004527:Egg Proteins / Q000378:metabolism; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects; D029941:Fish Proteins / Q000378:metabolism; D007211:Indoles / Q000633:toxicity*; D007814:Larva / Q000187:drug effects / Q000502:physiology; D008297:Male; D009990:Oryzias / Q000502:physiology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D014819:Vitellogenins / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D016588:Anticarcinogenic Agents; D004202:Disinfectants; D004527:Egg Proteins; D052244:Endocrine Disruptors; D029941:Fish Proteins; D007211:Indoles; D014819:Vitellogenins; D014874:Water Pollutants, Chemical; C015753:chorion proteins; C016392:3,3'-diindolylmethane
keywords: Adverse apical outcome; Endocrine disruption; Fish; Gonad; Toxicogenomic