Age-dependent vulnerability of the ovary to AhR-mediated TCDD action before puberty: Evidence from mouse models

Chemosphere. 2020 Nov;258:127361. doi: 10.1016/j.chemosphere.2020.127361. Epub 2020 Jun 10.


In female mammals, puberty and fertility are regulated by the synthesis of estradiol (E2) by the ovaries at the infantile stage and at the approach of puberty, a process which may be affected by endocrine disrupting chemicals (EDC)s acting through the Aryl hydrocarbon receptor (AhR). However, there is no information on AhR-mediated regulation of ovarian estrogenic activity during these developmental periods. Here, we assessed in mouse models, the intrinsic and exogenous ligand-induced AhR action on E2 synthesis at the infantile stage (14 days postnatal (dpn)) and at the approach of puberty (28 dpn). Intrinsic AhR pathway became activated in the ovary at the approach of puberty, as suggested by the decreased intra-ovarian expression in prototypical and steroidogenesis-related AhR targets and E2 contents in Ahr knockout (Ahr-/-) mice versus Ahr+/+ mice exclusively at 28 dpn. Accordingly, AhR nuclear localization in granulosa cells, reflecting its activity in cells responsible for E2 synthesis, was much lower at 14 dpn than at 28 dpn in C57BL/6 mice. However, AhR signaling could be activated by exogenous ligands at both ages, as revealed by FICZ- and TCDD-induced Ahrr and Cyp1a1 expression in C57BL/6 mice. Nevertheless, TCDD impacted ovarian estrogenic activity only at 28 dpn. This age-related AhR action may be ligand-dependent, since FICZ had no effect on E2 synthesis at 28 dpn. In conclusion, AhR would not regulate ovarian estrogenic activity before the approach of puberty. Its activation by EDCs may be more detrimental to reproductive health at this stage than during infancy.

Keywords: AhR; Estradiol; Fertility; Ovary; Puberty.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP1A1 / metabolism
  • Endocrine Disruptors / metabolism
  • Estradiol / metabolism
  • Estrogens / pharmacology
  • Female
  • Granulosa Cells / drug effects
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Ovary / drug effects
  • Ovary / physiology*
  • Polychlorinated Dibenzodioxins / metabolism
  • Polychlorinated Dibenzodioxins / toxicity*
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Sexual Maturation / drug effects
  • Signal Transduction / drug effects


  • Endocrine Disruptors
  • Estrogens
  • Ligands
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Estradiol
  • Cytochrome P-450 CYP1A1