The effects of iodoacetic acid on female reproduction in mice

Gonsioroski, Andressa Varella

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https://hdl.handle.net/2142/115515 Copy

Description

Title

The effects of iodoacetic acid on female reproduction in mice

Author(s)

Gonsioroski, Andressa Varella

Issue Date

2022-04-10

Director of Research (if dissertation) or Advisor (if thesis)

Flaws, Jodi A

Doctoral Committee Chair(s)

Flaws, Jodi A

Committee Member(s)

• Bagchi, Indrani
• Mahoney, Megan
• Nowak, Romana
• Plewa, Michael J

Department of Study

Comparative Biosciences

Discipline

VMS - Comparative Biosciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

disinfection byproducts, reproduction

Abstract

Disinfection byproducts (DBPs) are compounds formed during the process of water disinfection. Disinfectants such as chlorine, chloramines, or chlorine dioxide can react with organic or inorganic matter that is normally found in the source water to form DBPs .Studies have shown that DBP exposure is associated with an increased risk of cancer and poor reproductive outcomes. For this reason, the presence of DBPs in drinking water has become a public health concern. Currently, more than 700 DBPs were discovered in drinking water; however, only 11 of them have maximum contaminant levels in water. Iodoacetic acid (IAA) is one unregulated DBP because limited information exists about its toxicity. IAA can be found in treated water in levels up to 2.18 μg/L. Some studies also report that the levels of haloacetic acids can reach up to 136 μg/L in drinking water. Therefore, people are exposed to this compound by ingesting treated water or by consuming food and beverages that were prepared with treated water. IAA can also be formed during cooking. The reaction of iodide in iodized table salt with chlorine in tap water forms hypoiodous acid, which can react with residual organic matter from tap water or food to form IAA. Other forms of exposure are inhalation and dermal exposure. Moreover, the presence of IAA in drinking water can be higher in coastal regions, where source waters are significantly impacted by halide salts, including iodide. Anthropogenic activities can also elevate downstream halide levels in surface waters. For example, hydraulic fracturing can release mg/L levels of iodide. In addition, iodinated X-ray contrast media and iodine-based sanitizers used in the dairy industry can be sources of iodide in source water. Because of the many potential routes of exposure to IAA, the exact human exposure to this compound has not been established. IAA is known to be more cytotoxic and genotoxic than other DBPs. Further, IAA has been shown to be toxic in different cell lines. Specifically, IAA inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in Chinese hamster ovarian (CHO) cells, reducing pyruvate and ATP levels in these cells. Ali et al. showed that IAA exposure caused DNA damage in human lymphocytes and sperm. Toxicogenomic and reporter gene analyses demonstrated that in non-transformed human FHs 74 Int cells, IAA altered gene expression in DNA repair and oxidative stress pathways. IAA interacted with catalase inhibited catalase activity inducing cytotoxicity in mouse primary hepatocytes. Moreover, IAA exposure activated Nrf2-mediated antioxidant response of HepG2 cells in vitro and in rat liver, showing that oxidative stress plays a role in IAA toxicity. IAA also has been shown to be an ovarian toxicant in vitro. IAA exposure altered the ability of cultured antral follicles to produce sex steroid hormones important for reproductive function. IAA exposure also interfered with mouse oocyte maturation by elevating reactive oxygen species levels, disrupting spindle assembly, inducing DNA damage, and causing metaphase I arrest in vitro. Additionally, IAA exposure reduced ovarian weight compared to control in rats. This is concerning for public health because compounds that disrupt ovarian function could cause adverse reproductive outcomes and infertility. Thus, the objective of my dissertation work was to investigate the effects of IAA exposure on the female reproductive function. Specifically, I examined the effects of IAA exposure on ovarian follicle growth, estrous cyclicity, folliculogenesis, steroidogenesis, ovarian and follicular gene expression, fertility outcomes, and reproductive outcomes in the F0 and F1 generation of female mice. First, I tested the hypothesis that IAA exposure affects ovarian follicle growth, gene expression, and steroidogenesis in vitro. I found that IAA inhibits follicle growth, dysregulates steroidogenesis, and alters the expression of estrogen receptors, and genes involved in apoptosis and the cell cycle in mouse ovarian follicles. Next, I tested the hypothesis that iodoacetic acid exposure affects the number of ovarian follicles, ovarian gene expression, and steroidogenesis in mice. I found that IAA exposure did not alter the number of ovarian follicles. However, IAA exposure altered ovarian expression of genes involved in the cell cycle, apoptosis, oxidative stress, and steroidogenesis. I also determined that IAA exposure in vivo decrease the levels of estradiol. Moreover, IAA exposure reduced the time the animals spent in the proestrus stage of the estrous cycle. Based on these results, I found that IAA affects the function, but not the structure of the ovaries. Further, I tested the hypothesis that IAA exposure alters the transcriptome in mouse ovarian follicles. I found that IAA exposure altered gene expression of 1063 genes in antral follicles of animals treated with IAA compared to controls. Specifically, IAA exposure altered expression of genes involved with RNA processing, regulation of angiogenesis, cell cycle, cell division, phosphatidylinositol 3-kinase and protein kinase B signaling pathway, gonadotropin-releasing hormone (GnRH) signaling pathway, estrogen signaling pathways, and insulin signaling pathways. In addition, differentially expressed genes were involved with oocyte meiosis and oxytocin signaling pathway. Each one of these molecular processes and pathways are important for normal follicle function and alterations in the expression of these genes can cause adverse reproductive outcomes and infertility. Finally, I tested the hypothesis that IAA exposure affects fertility parameters in F0 female mice and impairs reproductive outcomes in F0 and F1 generation of female mice. I found that IAA exposure caused a borderline decrease in the gestation length but did not alter other fertility parameters compared to control in the F0 generation. In addition, IAA exposure decreased vaginal opening rate, increased the relative weight of the ovaries, increased anogenital index, and decreased the percentage of atretic follicles of female pups at postnatal day 21 compared to control. IAA exposure caused a borderline decrease in the levels of progesterone and follicle-stimulating hormone (FSH) and increased levels of testosterone in the female pups at postnatal day 21 compared to control. Collectively, my doctoral research shows that IAA exposure is an ovarian follicular toxicant in vitro. Additionally, IAA exposure via drinking water impairs estrous cyclicity, steroidogenesis, ovarian and follicular gene expression, and affects reproductive outcomes in F0 and F1 generation of female mice.

Graduation Semester

2022-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Andressa Varella Gonsioroski

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