Pesticides and fertility: the effects of a brief postnatal exposure on uterine development and female fertility

JORGELINA VARAYOUD; MARÍA MERCEDES MILESI; PAOLA I INGARAMO; MARLISE GUERRERO SCHIMPF; JORGE G. RAMOS; MARÍA PAULA GASTIAZORO; VIRGINIA LORENZ; MÓNICA MUÑOZ-DE-TORO; ENRIQUE H. LUQUE

Mar del Plata

Congreso; LXI ANNUAL MEETING ARGENTINE SOCIETY FOR CLINICAL INVESTIGATION (SAIC); 2016

Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Farmacología Experimental (SAFE)

The developmental programming hypothesis suggests that abnormal stimuli that occur during critical periods of development can permanently reprogram normal physiological responses and, consequently, give rise to reproductive health effects later in life. Early life exposures to chemicals in general, and pesticides in particular, have been associated with reproductive pathologies such as infertility and gynecologic tumors. Our research focuses on the effects of pesticides exposure on uterine development and their lasting consequences manifested later in life. The pesticides that we evaluated are the insecticide endosulfan and the herbicide glyphosate. In Argentina, glyphosate-based herbicides are the most commonly used, and although endosulfan has been banned in 2013, large quantities of this chemical continue to contaminate the environment because of its high persistence and lipophilicity. Using a rat model of early postnatal exposure we observed that low doses of endosulfan and low doses of a glyphosate-based herbicide disrupt the expression of genes that regulate uterine development and differentiation during the pre-pubertal period. In addition, we studied long-term effects on: 1) reproductive performance, 2) implantation and post-implantation processes, and 3) epigenetic modifications of endocrine-dependent genes. The results showed that both pesticides affected female fertility but in different ways. Low doses of endosulfan decreased the number of implantation sites. In the case of the glyphosate-based herbicide, there was an increased number of resorption sites. To address the effects of postnatal pesticide exposure on the pregnant uterus at the molecular level, we evaluated the endometrial proliferation and the expression of implantation and decidualization-associated genes. Both pesticides impaired endometrial proliferation and altered the expression of endocrine-regulated gene pathways. In addition, we found modifications on DNA methylation status of uterine genes, showing evidence of epigenetic regulation of altered gene expression due to a postnatal pesticide exposure. Based on the evidence presented here and previously published data, we conclude that some pesticides are likely to diminish fertility in a laboratory animal model. More studies are needed to identify whether these or other pesticides may contribute to the decline in human fertility observed in the past decades.