Postnatal exposure to environmental contaminants affects uterine development and produced subfertility

MILESI MM; RAMOS J; INGARAMO P; GUERRERO SCHIMPF M; MUÑOZ-DE-TORO M; LUQUE EH; VARAYOUD J

Buenos Aires

Congreso; 11th SETAC Latin America Biennial Meeting "The role of science in environmental decision-making"; 2015

Sociedad de Toxicología y Química Ambiental

The uterus completes its development during postnatal life. Our main objective was to investigate if a brief postnatal exposure to environmental contaminants affects uterine development and could be associated with reproductive pathologies, such as infertility. We studied environmental contaminants extensively used, such as endosulfan, glyphosate and bisphenol A. Female pups of Wistar rats were exposed to low doses of these environmental contaminants during the first week of life (critical period of reproductive tract development) according to National Toxicological Program?s recommendations. The results showed that all studied-compounds disrupt the uterine organogenetic differentiation in prepubertal rats, affecting the expression of proteins that regulate uterine development. Then, we studied long-term effects on: 1) reproductive performance, 2) implantation and post-implantation processes, and 3) hormone dependent-genes expression to identify epigenetic marks as mechanism of action of environmental contaminants. In relation to the reproductive performance, we detected a decrease in fertility rate and in the number of implantation sites (produced by endosulfan and bisphenol A), and an increase in the number of resorption sites (produced by glyphosate). To assay the molecular effects, we evaluated the endometrial cell proliferation and the expression of implantation and decidualization-associated genes during the pre- and post-implantation periods. We detected that endocrine-related pathways that regulate endometrial proliferation were affected in pregnant rats, both during the pre and post-implantation periods. In addition, we determined if changes in DNA methylation level could be an epigenetic mechanism to explain the aberrant expression of key uterine genes. We detected that the DNA methylation status of estrogen receptor alpha was affected in endosulfan-treated rats, and that this epigenetic mark could explain the changes in steroid hormone receptor expression. Our and other results indicate that a brief postnatal exposure to environmental contaminants affects the uterine organogenetic and functional differentiation, and might contribute to the increasing impaired fertility reported over the last decade.