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Title:The effects of an environmentally relevant phthalate mixture on female reproduction
Author(s):Zhou, Changqing
Director of Research:Flaws, Jodi A
Doctoral Committee Chair(s):Flaws, Jodi A
Doctoral Committee Member(s):Bagchi, Indrani C; Mahoney, Megan M; Raetzman, Lori T
Department / Program:Comparative Biosciences
Discipline:VMS - Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Phthalate mixture
Environmentally relevant
Female reproduction
Abstract:Phthalates are a category of chemicals that are commonly used in a wide range of consumer products, including plastics, building materials, medical devices, and personal care products. As a result, humans and animals are constantly exposed to phthalates daily. Metabolites of multiple phthalates frequently have been detected in human urine and blood samples, suggesting ubiquitous exposure to different phthalates. Studies have shown that women are exposed to phthalates at higher levels compared to men, likely due to the higher use of products by women compared to men. This ubiquitous exposure to phthalates is of great concern because several phthalates have been shown to have endocrine disrupting abilities. The developing ovary is thought to be extremely vulnerable to toxicants. In mammals, females are born with a finite pool of primordial follicles, and the size of primordial follicle pool determines the reproductive lifespan. To form the finite pool of primordial follicles, germ cells must undergo mitosis, formation of germ cell nests, meiosis, and germ cell nest breakdown. Any disruption in the formation of the primordial follicle pool can affect female reproductive ability. In the mouse, the ovaries begin to develop around embryonic day (E) 10.5 and the pool of primordial follicles starts to form around birth. During the reproductive life span, some primordial follicles grow into primary follicles, then pre-antral follicles, and subsequently into antral follicles. The antral follicle is the major follicle type that is capable releasing an egg for fertilization and synthesizing sex steroid hormones such as estrogens. Thus, female fertility depends on normal prenatal ovarian development, the maintenance of a constant stream of growing follicles from the primordial to antral stage postnatally, and the health of antral follicles. Chemicals that interfere with developing ovaries, formation of a normal number of primordial follicles, and the quality of antral follicles will cause infertility. Very limited information is available on the effects of phthalate mixtures on female reproduction, and even less information is available on the effects of an environmentally relevant phthalate mixture on female reproduction. Thus, the goal of my doctoral dissertation work was to examine the effects of an environmentally relevant phthalate mixture on female reproduction. Specifically, I examined the direct effect of in vitro phthalate mixture exposure on mouse antral follicles. Further, I examined the effects of in vivo prenatal phthalate mixture exposure on the first and subsequent generation of mice in a transgenerational study design. First, I tested the hypothesis that phthalate mixture exposure decreases antral follicle growth, compromises steroidogenic capacity, and induces atresia. Normal antral follicle growth, steroidogenic capacity, intact oocyte and somatic cells, and undisrupted cell cycles are important for female reproductive health and fertility. I found that the phthalate mixture decreased antral follicle growth starting at 24 hours compared to controls. The mixture also decreased several hormone levels in the steroidogenic pathway compared to control. Further, the mixture reduced atresia rating, but it induced more oocyte fragmentation compared to control. Additionally, the phthalate mixture adversely affected antioxidant enzymes, apoptotic factors, steroidogenic enzymes, and receptors. Interestingly, the mixture adversely affected several cell cycle regulators to induce cell cycle arrest, which in turn reduced atresia. Next, I tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects female reproduction in mice. Developing sex organs are very sensitive to chemical challenges. For example, prenatal exposure to several phthalates induces “phthalate syndrome” in male rodents to disrupt male reproduction. Similar in females, disrupting the developing female reproductive organs can result in disrupted puberty, irregular cyclicity, subfertility, or infertility. I found that prenatal exposure to the phthalate mixture significantly increased uterine weight and decreased anogenital distance at early ages, disrupted estrous cyclicity at multiple time points, and induced cystic ovaries at an old age. These observed adverse effects are probably the reason for the observed reduced fertility and increased breeding complications in phthalate mixture treated mice compared to controls. Further, I tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture induces transgenerational disruption on female reproduction in mice. Multigenerational effects occur when the effects of a chemical are observed in more than one generation (F1 and F2). Transgenerational effects occur when the effects of a chemical is transmitted to the generations that are not directly exposed to the chemical, such as the F3 generation. I found that prenatal exposure to the phthalate mixture induced multigenerational and transgenerational effects in female mice. Specifically, the phthalate mixture significantly increased body weight at different ages in F2 and F3 females, increased liver weights in F2 females, decreased anogenital distance in F2 and F3 females, increased uterine weight in F2 females, induced cystic ovaries in F2 females, and caused breeding complications in F2 and F3 females. Taken together, these data suggest that prenatal exposure to an environmentally relevant phthalate mixture disrupts many aspects of female reproduction in F2 and F3 female mice. Collectively, my doctoral dissertation data suggest that exposure to an environmentally relevant phthalate mixture directly acts on antral follicles to reduce the health and function of antral follicles, and exposure to this mixture prenatally causes fertility problems in the first and the subsequent generations of female mice.
Issue Date:2017-03-10
Type:Thesis
URI:http://hdl.handle.net/2142/97266
Rights Information:Copyright 2017 Changqing Zhou
Date Available in IDEALS:2017-08-10
Date Deposited:2017-05


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