Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus

Neurotoxicology. 2008 Nov;29(6):988-97. doi: 10.1016/j.neuro.2008.06.008. Epub 2008 Jul 6.


It is well established that estrogen administration during neonatal development can advance pubertal onset and prevent the maintenance of regular estrous cycles in female rats. This treatment paradigm also eliminates the preovulatory rise of gonadotropin releasing hormone (GnRH). It remains unclear, however, through which of the two primary forms of the estrogen receptor (ERalpha or ERbeta) this effect is mediated. It is also unclear whether endocrine disrupting compounds (EDCs) can produce similar effects. Here we compared the effect of neonatal exposure to estradiol benzoate (EB), the ERalpha specific agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), the ERbeta specific agonist diarylpropionitrile (DPN) and the naturally occurring EDCs genistein (GEN) and equol (EQ) on pubertal onset, estrous cyclicity, GnRH activation, and kisspeptin content in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. Vaginal opening was significantly advanced by EB and GEN. By 10 weeks post-puberty, irregular estrous cycles were observed in all groups except the control group. GnRH activation, as measured by the percentage of immunopositive GnRH neurons that were also immunopositive for Fos, was significantly lower in all treatment groups except the DPN group compared to the control group. GnRH activation was absent in the PPT group. These data suggest that neonatal exposure to EDCs can suppress GnRH activity in adulthood, and that ERalpha plays a pivotal role in this process. Kisspeptins (KISS) have recently been characterized to be potent stimulators of GnRH secretion. Therefore we quantified the density of KISS immunolabeled fibers in the AVPV and ARC. In the AVPV, KISS fiber density was significantly lower in the EB and GEN groups compared to the control group but only in the EB and PPT groups in the ARC. The data suggest that decreased stimulation of GnRH neurons by KISS could be a mechanism by which EDCs can impair female reproductive function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Estrous Cycle / drug effects
  • Female
  • Gonadotropin-Releasing Hormone / metabolism*
  • Hypothalamus / drug effects*
  • Kisspeptins
  • Nerve Fibers / metabolism*
  • Phenols / pharmacology*
  • Proteins / metabolism*
  • Pyrazoles / pharmacology*
  • Rats
  • Receptors, Estrogen / agonists
  • Reproductive Physiological Phenomena / drug effects*


  • Kiss1 protein, rat
  • Kisspeptins
  • Phenols
  • Proteins
  • Pyrazoles
  • Receptors, Estrogen
  • 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
  • estradiol 3-benzoate
  • Gonadotropin-Releasing Hormone
  • Estradiol