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Title:Prenatal exposure to phthalates accelerates reproductive aging in multiple generations of female mice
Author(s):Brehm, Emily
Director of Research:Flaws, Jodi A
Doctoral Committee Chair(s):Flaws, Jodi A
Doctoral Committee Member(s):Bagchi, Indrani C; Nowak, Romana A; Reddi, Prabhakara P
Department / Program:Comparative Biosciences
Discipline:VMS - Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):phthalates
aging
reproductive toxicology
female reproduction
reproductive aging
ovary
folliculogenesis, transgenerational
mixture
Abstract:Phthalates are a group of chemicals that are ubiquitously used in many different consumer products. Phthalates are widely used because of their stability and flexibility in products such as paints, personal care products like perfume, building materials, PVC pipes, children’s toys, car seats, and medical bags and IV tubing. Because phthalates are non-covalently bound to products, they can leach out due to cleaning and heating. Therefore, due to the vast use of products containing phthalates and their leaching capabilities, humans are exposed via ingestion, inhalation, and dermal contact. Phthalates and their metabolites have been found in urine, blood, semen, breast milk, amniotic fluid, umbilical cord blood, and follicular fluid. Additionally, studies have shown that women are exposed to higher levels of phthalates compared to men, most likely from their increased use of personal care products compared to men. Studies have shown that phthalates are endocrine-disrupting chemicals that can cause detrimental effects on reproduction in males and females. Specifically, in females, phthalates have been shown to accelerate primordial follicle recruitment, disrupt estrous cyclicity, inhibit ovarian steroidogenesis, and disrupt fertility. Furthermore, these effects have been observed in a multiple and transgenerational manner in female mice. Recent studies have also shown that phthalates may accelerate reproductive aging. Reproductive aging in females is characterized by biomarkers including a drastic decrease in the ovarian follicle pool, dysregulation of hormones involved in the hypothalamic-pituitary-gonadal (HPG) axis including sex steroids, gonadotropin, and peptide hormones, irregular estrous/menstrual cycles, and together this can lead to infertility. Moreover, the ovary has been shown to exhibit direct signs of aging, including increases in inflammation, oxidative stress, fibrosis, and in rodents an increase in cystic ovaries. This is of concern because if a chemical causes an early depletion of the follicle pool, this would lead to early reproductive senescence or menopause in women. Early reproductive senescence would have negative effects on the overall health of a female, leading to dysregulation of the HPG axis, acyclicity, and decreased time for the possibility of pregnancy. Additionally, dysregulation of the hypothalamic-pituitary-gonadal axis leads to decreased levels of estradiol, and estradiol is vital to cognitive function, cardiovascular health, and bone health. Many studies focus on exposure to single phthalates, but humans are exposed to mixtures of many different chemicals, including phthalates, on a daily basis. Therefore, studies are needed to examine if an environmentally relevant phthalate mixture may be negatively affecting female reproduction. Also, studies are needed to examine if phthalate mixtures cause multigenerational and transgenerational effects on female reproduction. Lastly, minimal studies have examined if phthalates accelerate reproductive aging and if this can occur in multiple generations. Thus, the goal of my dissertation work was to examine if phthalate exposure accelerates reproductive aging and if this occurs in a multigenerational and transgenerational manner in female mice. Specifically, I examined if prenatal exposure to the single phthalate di(2-ethylhexyl) (DEHP) or an environmentally relevant phthalate mixture accelerated biomarkers of reproductive aging in a multiple and/or transgenerational manner in female mice. Further, I investigated if prenatal exposure to a relevant phthalate mixture accelerated the natural decline in fertility and the direct aging of the ovary in a multigenerational manner in female mice. First, I tested the hypothesis that prenatal exposure to the single phthalate, DEHP, accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice. Biomarkers of reproductive aging in females include a decrease in the ovarian follicle pool, acyclicity, and dysregulation of the HPG axis. Early reproductive aging can lead to accelerated infertility and detrimental effects on non-reproductive health like bone and cardiovascular health. I found that prenatal DEHP exposure altered estrous cyclicity, increased the percentage of cystic ovaries, decreased the primordial follicle pool, and altered hormones involved in the HPG axis in the F1 generation. DEHP exposure altered follicle numbers and decreased sex steroid hormone levels in the F2 generation. Last, I found that prenatal DEHP exposure altered estrous cyclicity, decreased the percentage of ovarian follicles, and dysregulated hormones in the HPG axis in the F3 generation. Next, I tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice. Due to humans being exposed to mixtures of chemicals on a daily basis, it is vital to examine if a phthalate mixture may be accelerating reproductive aging. I found that the phthalate mixture dysregulated hormones involved in the HPG axis in the F1 generation. Next, I found that the mixture decreased the percent of antral follicles and testosterone hormone levels in the F2 generation. Last, I found that prenatal mixture exposure caused irregular estrous cyclicity, altered follicle numbers, and decreased luteinizing hormone levels in the F3 generation. Finally, I tested the hypothesis that prenatal exposure to the phthalate mixture accelerates the natural decline in reproductive capacity and the aging of the ovary in the F1 generation of female mice. Women become infertile as they age, and chemical exposure could accelerate the onset of infertility. Further, the ovary displays direct signs of aging including increased oxidative stress, cell death, and fibrosis. I found that prenatal phthalate exposure decreased the ability of females to carry out their pregnancies and produce pups at 11 and 13 months of age. Further, I found that the phthalate mixture decreased the time spent in proestrus at 11 and 13 months. Last, I found that the mixture did not significantly affect the levels of fibrosis, antioxidants, or apoptotic factors that could contribute to the direct aging of the ovary. Collectively, the research from my doctoral studies shows that prenatal exposure to the single phthalate DEHP or an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging and causes an early decline in reproductive capacity in a multiple and transgenerational manner in female mice.
Issue Date:2021-04-06
Type:Thesis
URI:http://hdl.handle.net/2142/110791
Rights Information:Copyright 2021 Emily Brehm
Date Available in IDEALS:2021-09-17
Date Deposited:2021-05


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