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Polluants environnementaux et développement du testicule foetal humain : effets et mécanismes des phtalates

Abstract : Since the last decades, an increase in several abnormalities of the male reproductive function has been progressively evidenced in industrialized countries. According to these observations, it was hypothesized that exposure to some environmental pollutants may impair the fetal testis development, and therefore be at the origins of those abnormalities. Among incriminated compounds, phthalates are molecules highly produced worldwide. These compound are classified as reprotoxic molecules, as they disrupt the development of the germ cell lineage in different species and lead to a decrease in testosterone production in rat. Nevertheless, very few data are available concerning their effects in human. In this study we analyzed the effects of one phthalate, the MEHP, on the human fetal testis development during the first trimester of pregnancy. It was performed using an organotypic culture system that allows the preservation of the different testis structures. We first demonstrated that MEHP (10-4M) does not affect testosterone production of the human fetal testis, in opposition to the results described in rat. We also have demonstrated that MEHP exposure triggers apoptosis in the fetal germ cells, leading to a quick decrease in the total number of these cells. Following those results, we tested the effects of lower doses of MEHP that are close to the highest doses measured in human biological fluids. We therefore demonstrated that fetal germ cells are altered by exposure to this dose of MEHP (10-5M). Finally, in the third part of this work, we focused on the mechanisms of action of phthalate toxicity. Different studies, mostly in the liver, report the involvement of the nuclear receptor superfamilly in the effect of those compounds. Thus, it seemed important to investigate their implication in the effect of phthalates on the human fetal testis. We demonstrated that LXRα is certainly implicated in these effects as its transcriptional level is increased. Moreover, this nuclear receptor regulates two metabolic pathways: Cholesterol and fatty acid synthesis pathways, that seemed to by both modulated by phthalate exposure in the human fetal testis. We also showed that the modulation of these two metabolic pathways is a common process to both the male and female gonads. Nevertheless, the germ cell decrease we evidenced in the human fetal testis was never observable in the fetal ovary. In conclusion, this work contributed to improve our knowledge about the effects of phthalate exposure on the establishment and the development of the human fetal reproductive system. We also have evidenced a new mechanism of these compounds that involves members of the nuclear receptors superfamilly, as well as cholesterol and fatty acid synthesis.
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Vincent Muczynski. Polluants environnementaux et développement du testicule foetal humain : effets et mécanismes des phtalates. Sciences agricoles. Université Paris Sud - Paris XI, 2011. Français. ⟨NNT : 2011PA11T011⟩. ⟨tel-00631554⟩

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