Disruption of developmental programming with long-term consequences after exposure to a glyphosate-based herbicide in a rat model. (January 2022)

• Record Type: Journal Article
• Authors: Guerrero Schimpf, Marlise; Milesi, María M.; Zanardi, María Victoria; Varayoud, Jorgelina
• Is Part Of: Food and chemical toxicology. Volume 159(2022)
• Publication Date: 2022-01
• Subjects: Glyphosate-based herbicide -- Hoxa10 -- Epigenetic reprogramming -- Uterine development -- Endocrine disruptor; BPA bisphenol A -- DES diethylstilbestrol -- E2 17β-estradiol -- EDC endocrine disruptor chemical -- EFSA European Food Safety Authority -- ER estrogen receptor -- GBH Glyphosate-based herbicide -- Hoxa10 homeobox A10 -- IARC International Agency for Research on Cancer -- LECH luminal epithelial cell height -- P4 progesterone -- PND postnatal day -- U. S. EPA U.S. Environmental Protection Agency; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112695
• Languages: English
• ISSNs: 0278-6915

Abstract

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. Highlights: Uterine hyperplasia is observed after exposure to glyphosate-based herbicide (GBH). Hoxa10 undergoes epigenetic reprogramming in uterine tissue after exposure to GBH. GBH increases 17β-estradiol and decreases progesterone serum levels at middle age. Neoplastic and pre-neoplastic lesions are found in the uteri of aged GBH animals.