Exposure to a Glyphosate-based Herbicide Alters the Expression of Key Regulators of Mammary Gland Development on Pre-pubertal Male Rats

GOMEZ, AYELEN L.; ALTAMIRANO, GABRIELA A.; TSCHOPP, MARÍA V.; BOSQUIAZZO, VERÓNICA L.; MUÑOZ-DE-TORO, MÓNICA; KASS, LAURA

TOXICOLOGY

ELSEVIER IRELAND LTD

Año: 2020

0300-483X

We previouslyreported that exposure during gestation and lactation to a low dose ofglyphosate-based herbicide (GBH) reduced the area and perimeter of maleoffspring mammary gland at postnatal day 60 (PND60), whereas a higher doseincreased the longitudinal growth of the gland. Here, our aim was to assesswhether perinatal exposure to GBH exhibits endocrine disruptive action in male mammary glandat an early time point (pre-puberty), which could be related to thechanges observed after puberty. We also wanted to explore whether an early evaluation of themale rat mammary gland is appropriate to assess exposure to potential endocrinedisrupting chemicals (EDCs). Pregnant rats were orally exposed, throughthe diet, to vehicle (saline solution), 3.5 or 350 mg/kg/day of GBH fromgestational day 9 until weaning. At PND21, the male offspring were euthanized,and mammary gland samples were collected. The histology and proliferation indexof the mammary glands were evaluated, and the mRNA expression of estrogen (ESR1) and androgen (AR) receptors, cyclin D1(Ccnd1), amphiregulin (Areg), insulin-like growth factor 1 (IGF1), epidermalgrowth factor receptor (EGFR) and IGF1 receptor (IGF1R) were assessed.Moreover, the phosphorylated-Erk1/2 (p-ERK1/2) protein expression wasdetermined. No differences were observed in mammary epithelial structures andAR expression between experimental groups; however, the proliferation index wasreduced in GBH3.5-exposed males. This result was associated with decreasedESR1, Ccnd1, Areg, IGF1, EGFR and IGF1R mRNA expressions, as well as reducedp-Erk1/2 protein expression in these animals. ESR1, Ccnd1, IGF1R and EGFRexpressions were also reduced in GBH350-exposed males. In conclusion, themammary gland development of pre-pubertal male rats is affected by perinatalexposure to GBH. Although further studies are still needed to understand themolecular mechanisms involved in GBH350 exposure, the present results may explainthe alterations observed in mammary gland growth of post-pubertal males exposedto low doses of GBH. Our results also suggest that early evaluation of the malerat mammary gland is useful in assessing exposure to potential EDCs. However, analysis ofEDCs effects at later time points should not be excluded.