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Title:The transgenerational effects of Di(2-ethylhexyl) phthalate on female reproduction in mice
Author(s):Rattan, Saniya
Director of Research:Flaws, Jodi A.
Doctoral Committee Chair(s):Flaws, Jodi A.
Doctoral Committee Member(s):Bagchi, Indrani C.; Li, Quanxi; Nowak, Romana; Yang, Jing
Department / Program:Comparative Biosciences
Discipline:VMS - Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):endocrinology
ovary
female reproduction
di(2-ethylhexyl) phthalate
DEHP
toxicology
Abstract:Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to confer flexibility and stability in common polyvinyl chloride products. DEHP can be found in numerous consumer products and is a ubiquitous chemical. Humans are exposed to DEHP daily due to its widespread use and ability to leach from out of products. DEHP and its bioactive metabolites are found in human tissues such as amniotic fluid, cord blood, breast milk, and human follicular fluid. Exposure to DEHP is a public health concern because DEHP is a known endocrine disrupting chemical and reproductive toxicant in females. The presence of DEHP in tissues vital for reproduction and development suggests that DEHP exposure occurs at various developmental stages; thus, posing as a potential toxicant for several generations. Multiple organs are required to facilitate healthy reproduction. Organs within the hypothalamic-pituitary-ovary axis consist of the hypothalamus, anterior pituitary, and the ovary and are vulnerable to toxicant exposure. Specifically, the ovary is a heterogeneous organ composed of follicles, oocytes, corpora lutea, and interstitial tissue. The primary roles of the ovary are to produce sex steroid hormones and maintain a steady stream of growing follicles. Normal sex steroid hormone production by the mature follicles is essential for the maintenance of normal menstrual/estrous cyclicity, reproductive tract tissues, and non-reproductive tissues such as bones, the heart, and the brain. In addition, the mature antral follicle is the only follicle type capable of ovulating and releasing an oocyte for potential fertilization. Therefore, female fertility is dependent on the maintenance of a constant stream of growing follicles and sex steroid hormone secretion throughout the reproductive lifespan. The ability of endocrine disruptors to cause disease and infertility is a major concern, but even more troubling is that some of the effects of DEHP may be multigenerational or transgenerational in nature. To obtain a multigenerational or transgenerational effect, the phenotype or the effect must be passed from one generation to a subsequent generation. During prenatal exposure, the F0 generation is exposed to DEHP during pregnancy. The F1 generation is exposed as a developing fetus and the F2 generation is exposed as the developing germ cells inside the fetus. Both the F1 and F2 generations are directly exposed and effects observed in these generations are considered multigenerational effects. The subsequent generation, the F3 generation, is the first generation that is not directly exposed to DEHP and any effects observed are considered transgenerational effects. The transgenerational phenomena does not involve direct exposure and usually involves epigenetic changes induced in the germline. Limited information is available on the effects of environmentally relevant DEHP exposure on female reproduction and even less information is available on the effects of DEHP on female reproduction across generations. Therefore, the goal of my doctoral dissertation work was to investigate the multigenerational and transgenerational toxicant effects of DEHP on female reproduction. Specifically, I investigated the effects of prenatal and ancestral DEHP on ovarian steroidogenesis and folliculogenesis and how DEHP exposure affects female reproductive outcomes in the F1 – F3 generation of mice. Additionally, I investigated how prenatal and ancestral DEHP exposure disrupts gene expression and DNA methylation in juvenile mouse ovaries across generations. First, I tested the hypothesis that prenatal and ancestral exposure to environmentally relevant doses of DEHP decreases folliculogenesis and impairs steroidogenesis in the F1 – F3 generations. Folliculogenesis is the process in which follicles in the ovary develop and mature towards ovulation to release the oocyte for fertilization. Steroidogenesis involves the production of sex steroid hormones by the mature follicle type. I found that prenatal DEHP exposure decreased folliculogenesis and the percentage of atretic follicles in adult ovaries the F1 generation. DEHP exposure disrupted folliculogenesis in adult ovaries in the F2 generation. Ancestral DEHP exposure accelerated germ cell transition into primordial follicles in neonatal ovaries in the F3 generation. I also found that prenatal DEHP exposure increases serum 17β-estradiol levels in the F1 generation and altered serum progesterone levels in the F2 generation. Next, I tested the hypothesis that prenatal and ancestral DEHP exposure to environmentally relevant doses impair reproductive outcomes in the F1 – F3 generations of female mice. Sex organs are particularly sensitive to endocrine disruptors and during a developmental window of exposure. I found that prenatal and ancestral DEHP exposure caused precocious puberty and disrupted normal estrous cyclicity in all three generations of mice. I also observed changes in birth outcomes such as increased litter size in the F2 generation and increased percentage of female pups per litter in the F3 generation. Additionally, I found that prenatal DEHP exposure decreased fertility in the F1 and F2 generations. Specifically, prenatal DEHP exposure decreased the mating index and pregnancy rate in the F1 generation and decreased the gestational index in the F2 generation. Further, I tested the hypothesis that prenatal and ancestral exposure to environmentally relevant doses of DEHP differentially expressed genes in pathways critical for ovarian functions and increased DNA methylation in whole ovaries in the F1 – F3 generations. I found that prenatal and ancestral DEHP exposure disrupted gene expression in various pathways in the ovary. In the F1 generation, prenatal DEHP exposure increased the expression of Dnmt1 and increased the percentage of 5-mC in the whole ovary. In the F2 generation, DEHP exposure decreased the expression of Tets. In the F3 generation, ancestral DEHP exposure decreased the expression of Dnmts, Tets, and decreased the percentage of 5-mC in the whole ovary. Collectively, my doctoral dissertation work shows that prenatal and ancestral exposure to environmentally relevant doses of DEHP cause multigenerational and transgenerational impairment of ovarian health and function, female reproductive outcomes, ovarian gene expression, and ovarian DNA methylation levels.
Issue Date:2019-04-11
Type:Text
URI:http://hdl.handle.net/2142/104976
Rights Information:© 2019 Saniya Rattan
Date Available in IDEALS:2019-08-23
Date Deposited:2019-05


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