Norethindrone suppress the germ cell development via androgen receptor resulting in male bias.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier/North Holland Biomedical Press Country of Publication: Netherlands NLM ID: 8500246 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1514 (Electronic) Linking ISSN: 0166445X NLM ISO Abbreviation: Aquat Toxicol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam, Netherlands : Elsevier/North Holland Biomedical Press, c1981-
    • Subject Terms:
      Norethindrone*/pharmacology ; Water Pollutants, Chemical*/toxicity; Animals ; Male ; Female ; Progestins/pharmacology ; Receptors, Androgen ; Zebrafish/genetics ; Molecular Docking Simulation ; Flutamide/toxicity ; Sex Differentiation ; Germ Cells ; Cell Differentiation
    • Abstract:
      Progestins are widely used and detected in surface waters, and can affect gonad development and sexual differentiation in fish. However, the toxicological mechanisms of sexual differentiation induced by progestins are not well understood. Here, we investigated the effects of norethindrone (NET) and androgen receptor (AR) antagonist flutamide (FLU) on gonadal differentiation in zebrafish from 21 dpf (days post-fertilization) to 49 dpf. The results showed that NET caused male bias, while FLU resulted in female bias at 49 dpf. The NET and FLU mixtures significantly decreased the percentage of males compared to the NET single exposure. Molecular docking analysis showed that FLU and NET had similar docking pocket and docking posture with AR resulting in competitively forming the hydrogen bond with Thr334 of AR. These results suggested that binding to AR was the molecular initiating event of sex differentiation induced by NET. Moreover, NET strongly decreased transcription of biomarker genes (dnd1, ddx4, dazl, piwil1 and nanos1) involved in germ cell development, while FLU significantly increased transcription of these target genes. There was an increase in the number of juvenile oocytes, which was consistent with the female bias in the combined groups. The bliss independence model analysis further showed that NET and FLU had antagonistic effect on transcription and histology during gonadal differentiation. Thus, NET suppressed the germ cell development via AR, resulting in male bias. Understanding the molecular initiation of sex differentiation in progestins is essential to provide a comprehensive biological basis for ecological risk assessment.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2023 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Androgen receptor; Germ cells; Male bias; Molecular docking; Norethindrone
    • Accession Number:
      T18F433X4S (Norethindrone)
      0 (Progestins)
      0 (Receptors, Androgen)
      0 (Water Pollutants, Chemical)
      76W6J0943E (Flutamide)
    • Publication Date:
      Date Created: 20230613 Date Completed: 20230808 Latest Revision: 20230808
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.aquatox.2023.106604
    • Accession Number:
      37311377