Hypermethylation of Hoxa10 by neonatal endosulfan exposure: an epigenetic mechanism for impaired embryo implantation

MILESI MM; GUERRERO SCHIMPF ML; LUQUE EH; VARAYOUD J

Congreso; SAIC 2016; 2016

Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds in the environment and exposure during fetal or early postnatal life can induce developmental and reproductive disturbance. Among these chemicals, organochlorine pesticides are of great concern as they accumulate in the human tissues because of their high lipophilicity and resistance to metabolism. Human and animal studies have reported developmental and reproductive disorders caused by endosulfan exposure.A classical target of EDCs? action is the homeobox gene, Hoxa10. Hoxa10 directs embryonic uterine development and is also dynamically expressed in adult endometrium, where it is necessary for embryo implantation. In the last decade, aberrant DNA methylation has emerged as an important epigenetic mechanism resulting in long-term changes in gene expression and diseases. DNA methylation involves the covalent addition of a methyl group to a cytosine residue of a CpG dinucleotide by DNA methyltransferases enzymes (DNMTs). Alterations in Hoxa10 methylation have been associated with reproductive tract anomalies, such as endometriosis and endometrial cancer.In previous work we demonstrated that early postnatal exposure to low doses of endosulfan alters the uterine expression of Hoxa10 in prepubertal rats, and induces long-term adverse effects on female fertility characterized by a drop in the pregnancy rate and in the number of implanted embryos. Taking into account the crucial role of Hoxa10 on embryo implantation, in the present study we hypothesized that the endosulfan effects on fertility are mediated through aberrant methylation of the Hoxa10 gene. To evaluate this mechanism, we analyzed the DNA methylation status of the Hoxa10 gene, as well as the expression of the DNMTs in the pre-implantation uterus. These findings could contribute to the elucidation of the molecular mechanism underlying endosulfan induction of subfertility.