Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Environmental Health, Occupational Health, and Toxicology

First Advisor

Eleanor G. Rogan, Ph.D

Second Advisor

Alan Kolok, Ph.D

Third Advisor

Oksana Lockridge, Ph.D.

Fourth Advisor

Muhammad Zahid, Ph.D.

Abstract

Estrogens have been implicated in non-cancerous pathologies such as Fuchs Endothelial Corneal Dystrophy (FECD), and accumulating evidence suggests estrogen genotoxicity leads to initiation of multiple types of cancer among Caucasian populations. These studies were mono-racial, and restoration of estrogen metabolism imbalance using naturally occurring compounds were not definitive. Therefore, the role of estrogen metabolism in FECD, in cancer initiation among African American (AA) populations, its modulation by environmental toxicant arsenic trioxide (As2O3), and by antioxidants polydatin (PD) and resveratrol were explored.

In human breast epithelial non-transformed MCF10A cells, As2O3 – induced cytotoxicity was partially ameliorated by 25 μM resveratrol. Both 25 μM resveratrol and As2O3 induced NQO1, possibly via Nrf2 stabilization. As2O3 suppressed CYP1B1 expression whereas 25 μM resveratrol restored it to basal levels – rendering the As2O3 + resveratrol combination a little less effective than As2O3 alone in lowering estrogen-DNA adduct formation. Therefore, we cannot conclude that resveratrol co-treatment with As2O3 has any beneficial roles on estrogen metabolism, although resveratrol might provide some chemical protection as well as the protection from As2O3-cytotoxicity might stem from other cellular pathways.

PD was found to be safer than resveratrol. In MCF10A cells, PD was found to be less efficacious than resveratrol in inducing NQO1 or repressing CYP1B1, although this difference was abolished in human prostate epithelial non-transformed RWPE-1 cells – rendering both the antioxidants equally effective in lowering estrogen-DNA adduct formation. This indicates PD could be a less toxic alternative for resveratrol in chemo-preventing estrogen-induced cancer initiation in prostate cells.

AA women with breast cancer, and AA men at high risk for or with prostate cancer, exhibited higher estrogen-DNA adduct ratios than the controls. This suggests loss of estrogen metabolism balance might be instrumental in breast and prostate cancer initiation in AA populations.

In the menadione-induced FECD model of HCEnC-21T cells, N-acetylcysteine (NAC) was observed to ameliorate estrogen-DNA adduct formation, and this effect was sustained even in NQO1 KO cells. Therefore, NAC can be a promising therapeutic modality for FECD where loss of NQO1 has been reported. This needs to be replicated in animal models.

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