The effects of environmentally relevant toxicants on female reproduction and embryo development

Phthalates;Toxicants;Uterus;Embryos;DEHP, ,

Richardson, Kadeem Anthony

关键词: Phthalates;    Toxicants;    Uterus;    Embryos;    DEHP, ,;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/106206/RICHARDSON-DISSERTATION-2019.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Becoming pregnant and carrying to term is undeniably a very complicated process. Unfortunately, reproductive failure is widespread among many women globally. There are a plethora of problems that can lead to reproductive failure among women such as, but not limited to, sexually transmitted infections (STI), hormone imbalance, body weight, stress, alcohol, drug abuse, diets, and genetics. A novel culprit that is now associated with reproductive failure is exposure to endocrine disrupting chemicals (EDCs). These chemical compounds can interact with the endocrine systems in humans and animals by influencing hormone metabolism. EDCs can disrupt the synthesis, secretion, transport, binding, action, or elimination of hormones, including hormones that are responsible for behavior and fertility, resulting in severe consequences for the reproductive and endocrine systems. One group of EDCs which gained interest are phthalates. Phthalates are a family of chemicals that are colorless, odorless, have lipophilic properties, and low solubility in water. Phthalates are used as plasticizers and additives in a variety of products such as polyvinyl chloride (PVC), cosmetics, adhesives, flooring, and medical supplies. However, phthalates leach from these products and enter the environment.Animals and humans are exposed to a variety of phthalates daily due to high production and leaching of phthalates.Phthalates are classified as reproductive toxicants because have they been shown to impair normal reproduction function in males and females. However, studies have primarily focused on male reproduction. Studies have shown that phthalates are detected in both female reproductive organs and fluids. Measurable amounts of phthalates are present in human blood, urine, amniotic fluid, ovarian follicular fluid, breast milk, and umbilical cord blood. However, there is limited research on the effects of phthalates on the female reproduction system, including the uterus. Specifically, it is unknown if environmentally and occupationally relevant doses of phthalates affect uterine morphology and function. Also, there are limited studies on the effects of phthalates on preimplantation embryos. Of these studies, most have shown that exposure to a single phthalate such as Di (2-ethylhexyl) phthalate (DEHP) and other EDCs have adverse effects on proper embryo development. However, there are limited data on the effects of exposure to relevant phthalate mixtures on preimplantation embryos.In this dissertation, I first examined whether adult exposure to environmentally and occupationally relevant doses of di (2-ethylhexyl) phthalate (DEHP) for 30 days in vivo alters uterine function and morphology. To determine whether the uterus was affected, the morphology, cellular proliferation, uterine glands, and steroid hormone levels were analyzed after exposure to DEHP for 30 days. Uterine morphology was evaluated by measuring the thickness of the myometrial layers (inner and outer), luminal epithelium height, counting the number of glands and finding the percentage of proliferating cells within the uterus. The results from this study demonstrated that exposure to DEHP decreased cellular proliferation in the luminal epithelium; however, increased cellular proliferation of the stromal cells. I also observed that exposure to an occupational dose of DEHP for 30 days increased the total number of glands present in the uterus. Exposure to DEHP for 30 days dilated blood vessels in the endometrium at both environmental and occupational doses. However, DEHP exposure did not cause any significant difference in the myometrial layers or luminal epithelium layer compared to control. Also, DEHP exposure for 30 days did not alter sex steroid levels. These results demonstrate that exposure to specific doses of DEHP for 30 days can have adverse effects on reproductive function of the uterus.Lastly, in my dissertation, I examined whether relevant phthalate mixture altered preimplantation embryo development. The mixture used in this study is composed of the following chemicals: 35% diethyl phthalate (DEP), 21% di (2-ethylhexyl) phthalate (DEHP), 15% di-n-butyl phthalate (DBP), 15% di-isononyl phthalate (DiNP), 8% di-isobutyl phthalate (DiBP), and 5% benzyl butyl phthalate (BBzP). Theses phthalates and percentages were from measurements obtained from pregnant women in the UIUC iKids study. To determine whether exposure to a phthalate mixture affects preimplantation and embryo development, embryos exposed to vehicle or mixture were observed at the 2-cell, 8-cell, morula, blastocyst, and hatched blastocyst stages. Also, embryo fragmentation was assessed. Oct-4 expression (4 cell stage), E-cadherin (8-cell and blastocyst), micronucleation (4-cell, 8-cell, blastocyst), and blastocyst cell populations of the inner cell mass (ICM) and trophectoderm (TE) was analyzed by immunofluorescence (IF) staining to observe protein expression and accurately count the number of ICM and TE cells within the blastocyst. The results from this study show that exposure to a relevant phthalate mixture greatly reduces the percentage of embryos which developed to the hatched blastocyst stage, increased fragmentation, increased Oct-4 expression, and reduced E-cadherin expression at the 8-cell stage and increased the percentage of micronucleation at the 4-cell stage. The results demonstrate that exposure to a relevant phthalate mixture affects preimplantation embryos.