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University of Macau / Institute of Chinese Medical Sciences

The basis for the species difference between B6C3F1 mice (susceptible) and Fischer 344 rats (resistant) to 4- vinylcyclohexene (VcH)-induced ovarian tumorigenicity was investigated. Greater than 95% of a single oral 400 mg/kg dose of [¹⁴C]VCH was eliminated in 48 hr by mice and rats. Approximately 50-60% of the administered dose was excreted in the urine, while the remaining 30-40% of the dose was expired as organically soluble radioactivity. VCH-treated mice had dramatically higher blood concentrations of the VCH metabolite VCH-1,2-epoxide compared to VCH-treated rats. Furthermore, mouse hepatic microsomes catalyzed the conversion of VCH to VCH-1,2-epoxide at greater rates than rat hepatic microsomes. The destruction of oocytes was used as an index of ovarian toxicity to compare the potency of VCH and VCH epoxides in the mouse and rat. VCH markedly reduced the number of small oocytes in mice while no detectable change in oocyte number occurred in rats. Epoxide metabolites of VCH destroyed oocytes in both species at lower doses than VCH. Inhibition of VCH epoxidation reduced VCH-1,2-epoxide blood levels and partially protected mice from VCH-induced ovarian toxicity. Thus, the conversion of VCH to epoxides and the subsequent destruction of oocytes are critical steps in the induction of ovarian tumors by VCH. Rats may be resistant because the amount of VCH converted to epoxides is insufficient to destroy oocytes. The biochemical basis for the species difference in the rate of VCH epoxidation by hepatic microsomes from mice and rats was investigated. studies using inducers and inhibitors of certain cytochrome(s) P450 showed that hepatic microsomes of female mice perform VCH epoxidation at greater rates than rats because of the constitutive expression of P450 IIA and lIB forms. Hepatic microsomes of human females perform VCH epoxidation at lower rates than rats. This suggests that if the rate of epoxidation of VCH by the liver is the most important factor determining susceptibility to VCH toxicity then the rat may better model the response of humans exposed to VCH than mice.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [202]-262).

Ovarian cancer is the fifth most common cause of cancer death in females and the most lethal gynecologic cancer. Globally, an estimated 240,000 people are diagnosed with ovarian cancer each year, with 22,530 new cases in the United States in 2019. Parity, oral contraceptive use, and lactation are protective, while early menarche, late menopause, and nulliparity have opposite effects. The “incessant ovulation” theory has thus emerged, in which a higher number of ovulations may be a cause of epithelial ovarian cancer (EOC). However, the mechanisms of this theory are unknown; one possibility is that the chance of acquiring a cancer-initiating pathogenic variant increases with each ovulatory cycle because of a microenvironment that promotes DNA damage. In this dissertation, we aimed to leverage genetic epidemiologic data to test this potential mechanism by evaluating the presence of gene-environment interaction between DNA repair capacity (measured through the presence of pathogenic variants in DNA repair genes) and lifetime ovulatory years (LOY). In the first aim of this dissertation, we conducted a systematic review and meta-analysis, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to formally evaluate the strength of evidence and to generate summary point estimates for the association between LOY and EOC. We then executed two analytic aims to evaluate if the presence of pathogenic variants in DNA repair genes exacerbated the increase in ovarian cancer risk associated with LOY. In Aim 2, we evaluated interaction on the additive scale in the United Kingdom (UK) Biobank through use of a novel DNA repair capacity score developed in this dissertation, measured by quantifying the number of pathogenic variants present per individual from a list of 163 DNA repair genes, using whole exome sequencing (WES) data. In Aim 3, we evaluated the presence of interaction between pathogenic BRCA1/2 status and LOY in the Breast Cancer Family Registry (BCFR), a cohort enriched for familial risk. In both empirical aims, we assessed the presence of interaction on the additive scale using the relative excess risk due to interaction (RERI) formula. We compared results across the two empirical aims. We found the relationship between lifetime ovulations and ovarian cancer risk to be consistent and replicable in the published literature. In pooled estimates from 22 published studies, a one-year increase in LOYs was associated with a 4% (3-6%) increased risk of ovarian cancer and those with a high number of ovulations (compared to low LOYs) had a 2.15-fold (95% CI 1.82, 2.54) increased risk of ovarian cancer. We also confirmed the positive association between increasing LOYs and ovarian cancer risk in the UK Biobank and the BCFR cohorts. Although interaction on the additive scale was not detected, there were strong positive associations between pathogenic variants in DNA repair genes and ovarian cancer risk. In the UK Biobank, the presence of at least one pathogenic variant in a DNA repair gene was associated with a significant 27% increased risk of epithelial ovarian cancer (EOC) (95% CI 5-55%). Among women at high risk of ovarian cancer due to family history of breast and/or ovarian cancer, there was a strong relationship between BRCA1/2 pathogenic variants and ovarian cancer, regardless of the number of ovulations experienced. The association between LOY and ovarian cancer was found to be consistent and replicable, despite differences in study design, covariates, and measurement. We also detected robust evidence that increasing lifetime ovulations and pathogenic DNA repair variants were associated with ovarian cancer risk. Such variants were exceedingly rare in both cohorts, which limited power to detect interaction in an already rare cancer. Despite such associations, there was no evidence of synergy between LOY and impaired DNA repair capacity, but rather, high LOY and impaired DNA repair capacity may be independent risk factors of ovarian cancer. Each exposure may describe a separate class of women at increased risk of ovarian cancer that should be targeted for future prevention and screening strategies.

Call number: LD2668 .T4 1937 K51

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

In chapter one, the existing literature on ovarian ageing and fertility is reviewed. In it I (a) discuss the natural history and the potential causes of ovarian ageing (b) assess available tests of ovarian ageing and their limitations (c) discus the trends in the age of first childbirth, its causes and health service consequences. In chapter two, I explore women’s awareness of issues associated with delayed childbearing, including their social and medical implications and the limitations of available treatment. In chapter three, I surveyed IVF clinics throughout the United Kingdom, to determine (1) proportion of women aged 40 or more in each clinic (2) attitudes of clinicians towards older women and (3) clinicians’ views on an upper age limit for IVF. In chapter four, I investigated trends in the age at which women present to general infertility clinics (a step prior to IVF) in Grampian region. Women were grouped according to their age at first presentation to the infertility clinic (&lt;30, 30-34, 35-39 and ≥40 years). I tested the hypothesis that women of advanced reproductive age have a different diagnostic profile than younger women (&lt;30 years). In particular older women are more likely to be diagnosed with unexplained sub-fertility, probably due to ovarian ageing. This hypothesis was tested based on routinely collected data from a single secondary care centre. In chapter five, a systematic review of currently available dynamic tests of ovarian reserve assesses their power to predict fertility outcomes. In chapter six, I calculated the costs of achieving a live birth in different age groups (< 30, 30-34, 35-39 and ≥40 years) following IVF. In chapter seven, I summarize the results of the studies reported in this thesis and consider how they have improved our understanding of various aspects of delayed childbearing.

Thesis (M.Sc.)--University of the Witwatersrand, Faculty of Science, 1950.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.