Endocrine Disruption throughout the Hypothalamus-Pituitary-Gonadal-Liver (HPGL) Axis in Marine Medaka (Oryzias melastigma) Chronically Exposed to the Antifouling and Chemopreventive Agent, 3,3'-Diindolylmethane (DIM).
Despite being proposed as a promising antifouling and chemopreventive agent, the environmental risks of 3,3'-diindolylmethane (DIM) are scarcely investigated. Therefore, this study used adult marine medaka (Oryzias melastigma) as a model organism to examine the toxicological effects and underlying mechanism of DIM throughout the hypothalamus-pituitary-gonadal-liver (HPGL) axis following 28 days of exposure to low DIM concentrations (0 and 8.46 μg/L). The results showed that altered gene transcription in the hypothalamus, pituitary, and gonads contributed to the great imbalance in hormone homeostasis. The lowered estradiol (E2)/testosterone (T) and E2/11-keto-testosterone (11-KT) ratios in female plasma resulted in decreased synthesis and levels of vitellogenin (VTG) and choriogenin in the liver and plasma, and vice versa in males. Subsequently, VTG and choriogenin deficiency blocked the reproductive function of the ovary as indicated by decreased fecundity and offspring viability, whereas in male medaka, DIM mainly targeted the liver and induced severe vacuolization. Proteomic profiling of plasma revealed that the sex-specific susceptibility to DIM could be attributed to the increased detoxification and oxidative defense in males. Overall, this study identified the endocrine disruption and reproductive impairment potency of DIM and first elucidated its mechanisms of action in medaka. The differential responses to DIM (estrogenic activities in the male but antiestrogenic activities in the female) provided sensitive biomarkers characteristic of each sex. Considering the chemical stability and potent endocrine disturbance at low concentration, the application of DIM either as an antifouling or chemopreventive agent should be approached with caution in marine environments.
HKUST Shenzhen Research Institute and Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong SAR, China.
Lianguo
L
Chen
Rui
R
Ye
HKUST Shenzhen Research Institute and Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong SAR, China.
Weipeng
W
Zhang
Chenyan
C
Hu
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences , Wuhan 430072, China.
Bingsheng
B
Zhou
Drew R
DR
Peterson
Doris W T
DW
Au
Paul K S
PK
Lam
HKUST Shenzhen Research Institute and Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong SAR, China.
Pei-Yuan
PY
Qian
D000818:Animals; D057219:Biofouling / Q000517:prevention & control*; D004527:Egg Proteins / Q000097:blood / Q000378:metabolism; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006066:Gonads / Q000187:drug effects* / Q000473:pathology; D007031:Hypothalamus / Q000187:drug effects* / Q000473:pathology; D007211:Indoles / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009990:Oryzias / Q000097:blood / Q000254:growth & development / Q000378:metabolism*; D010902:Pituitary Gland / Q000187:drug effects* / Q000473:pathology; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism; D014819:Vitellogenins / Q000097:blood / Q000378:metabolism
D004527:Egg Proteins; D052244:Endocrine Disruptors; D007211:Indoles; D011498:Protein Precursors; D014819:Vitellogenins; C104950:choriogenin H; C016392:3,3'-diindolylmethane