Disruption of developmental programming with long-term consequences after exposure to a glyphosate-based herbicide in a rat model

Marlise Guerrero Schimpf, María M. Milesi, María Victoria Zanardi, Jorgelina Varayoud

Research output: Contribution to journalArticlepeer-review

Abstract

Glyphosate-based herbicides (GBHs) have been associated with endocrine disrupting effects on reproductive organs. We examined whether postnatal exposure to GBH affects developmental programming of the uterus with long-term consequences. Female Wistar pups received vehicle (control) or GBH (2 mg of glyphosate/kg/day) from postnatal day (PND) 1 to PND7, where the developing uterus is highly sensitive to endocrine disruption. Short-, mid- and long-term effects were evaluated on PND8, PND120 and PND600, respectively. GBH induced hyperplasia and epigenetic alterations in the uterus of neonatal females (PND8). DNA hypermethylation, enrichment of H3K9me3 and reductions of H3K27me3 at regulatory regions of the morphoregulatory gene Hoxa10 resulted in gene downregulation. In young adult females (PND120), GBH increased 17β-estradiol (E2) and decreased progesterone (P4) serum levels, altering estrous cyclicity. Aged females (PND600) exposed to GBH developed leiomyoma and pre-neoplastic glandular lesions in the uterus. Vaginal rhabdomyosarcoma and intrahepatic bile duct adenoma were also observed. In conclusion, neonatal exposure to GBH altered the expression and induced hypermethylation of the Hoxa10 gene in uterine tissue at early life, and increased E2/P4 ratio serum level at middle-age. We propose that epigenetic reprogramming of Hoxa10 in association with hormonal imbalance could be among the possible mechanisms underlying the long-term adverse effects detected in GBH-exposed rats.

Original languageEnglish (US)
Article number112695
JournalFood and Chemical Toxicology
Volume159
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Endocrine disruptor
  • Epigenetic reprogramming
  • Glyphosate-based herbicide
  • Hoxa10
  • Uterine development

ASJC Scopus subject areas

  • Food Science
  • Toxicology

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