title: Scrambled and fried: cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress.
abstract: Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.
authors.affiliation: Reproductive Science Group, School of Environmental & Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: A P
authors.initials: AP
authors.lastname: Sobinoff
authors.forename: E L
authors.initials: EL
authors.lastname: Beckett
authors.forename: A G
authors.initials: AG
authors.lastname: Jarnicki
authors.forename: J M
authors.initials: JM
authors.lastname: Sutherland
authors.forename: A
authors.initials: A
authors.lastname: McCluskey
authors.forename: P M
authors.initials: PM
authors.lastname: Hansbro
authors.forename: E A
authors.initials: EA
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005306:Fertilization / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007247:Infertility, Female / Q000139:chemically induced; D015227:Lipid Peroxidation / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects* / Q000473:pathology; D006080:Ovarian Follicle / Q000187:drug effects* / Q000473:pathology; D010053:Ovary / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D017382:Reactive Oxygen Species; D014028:Tobacco Smoke Pollution; D012313:RNA; D020169:Caspases
keywords: Atresia; Bioactivation; Cigarette; Infertility; Ovotoxicity; Oxidative stress