Abstract
Di (2-ethylhexyl) phthalate (DEHP), is the most common member of the class of phthalates that are used as plasticizers and have become common environmental contaminants. A number of studies have shown that DEHP exposure impacts reproductive health in both male and female mammals by acting as an estrogen analog. Here, we investigated the effects of DEHP on meiotic progression of fetal mouse oocytes by using an in vitro model of ovarian tissue culture. The results showed that 10 or 100 μM DEHP exposure inhibited the progression of oocytes throughout meiotic prophase I, specifically from the pachytene to diplotene stages. DEHP possibly impairs the ability to repair DNA double-strand breaks induced by meiotic recombination and as a consequence activates a pachytene check point. At later stages, such defects led to an increased number of oocytes showing apoptotic markers (TUNEL staining, expression of pro-apoptotic genes), resulting in reduced oocyte survival, gap junctions, and follicle assembly in the ovarian tissues. Microarray analysis of ovarian tissues exposed to DEHP showed altered expression of several genes including some involved in apoptosis and gonad development. The expression changes of some genes clustered in cell-cell communication and signal transduction, along with plasma membrane, extracellular matrix and ion channel function classes, were dependent on the DEHP concentration. Together, these results bring new support to the notion that exposure to DEHP during gestation might exert deleterious effects on ovary development, perturbing germ cell meiosis and the expression of genes involved in a wide range of biological processes including ovary development.
Highlights
Di (2-ethylhexyl) phthalate (DEHP), is a compound largely used in plasticizing polyvinyl chloride resin (PVC) products worldwide.[1]
In order to explore the effects of DEHP exposure on the progression of meiotic prophase I in female germ cells, 12.5 dpc fetal mouse ovarian tissues were cultured in vitro and exposed to DEHP for 6 days as the first meiotic prophase I accomplished at 18.5 dpc in vivo, relative to day 6 in vitro (Supplementary Figure S1)
Since the DEHPinduced meiotic delay reported above resembles the meiotic arrest occurring in a variety of species as a consequence of the pachytene checkpoint triggered by defects in DNA double-strand break (DSB) repair,[13] we decided to investigate the status of DNA breaks and repair in DEHP treated oocytes
Summary
Di (2-ethylhexyl) phthalate (DEHP), is a compound largely used in plasticizing polyvinyl chloride resin (PVC) products worldwide.[1]. DEHP effects on early postnatal and adult ovaries appear to be a consequence of activation of PPAR and/or ER-dependent pathways. Effects are seen during several developmental waypoints including during the formation and development of PGCs, entrance and progression of oocytes into meiotic prophase I, germ cell cyst breakdown during the prenatal or early postnatal period, along with primordial follicle activation and development in the adult ovary.[10,11]. We utilized an in vitro ovarian tissue culture system, developed in our lab, to study the effects of DEHP on prenatal or early postnatal oogenesis.[12] While it has been reported that DEHP effects folliculogenesis through impairment of oocyte meiosis, survival, and follicle assembly,[10] the mechanisms involved remain largely unknown. Using our in vitro system we investigated the mechanisms of such effects and identified the gene expression profile induced by DEHP in the fetal ovary
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