Genetic predisposition to ovotoxic effects of smoking may hasten time to menopause.

T obacco use, particularly smoking, has deleterious effects on the ovary and is a risk factor for reaching menopause approximately 2 years earlier than those who do not use tobacco products. It has been known for decades that smoking hastens time to menopause, with perhaps the earliest discussion published in 1949. Two later studies provided the first statistics (20% of smokers entered menopause early, whereas less than 2% of nonsmokers had early menopause) linking smoking to early menopause. Early menopause is associated with higher mortality, increased incidence of cardiovascular diseases, and increased incidence of other menopausal symptoms such as hot flashes, osteoporosis, and memory decline. It is well recognized that age at menopause is established in part by genetic factors but also by environmental influences such as smoking, alcohol consumption, social status, age at menarche, number of offspring born, and body mass index. A number of toxic substances found in cigarette smoke contribute to reproductive problems in women. Nicotine, for example, impacts negatively on the uterine vasculature during gestation. Among the most damaging classes of chemicals found in cigarette smoke, however, are polycyclic aromatic hydrocarbons (PAHs). Benzo[a]pyrene and 9,10-dimethylbenz[a]anthracene are among the most wellstudied PAHs; these toxicants have been shown primarily in rodent models to cause ovarian senescence through depletion of primordial follicles. It is probable that the complex mixture of chemicals in cigarette smoke activates a number of pathways that interfere with female reproduction, but four such pathways have been studied in more detail. First, smoking is associated with increased activation of the 2-hydroxylation pathway in the liver, which results in the conversion of highly bioactive estrogens (eg, 17A-estradiol) into 2-hydroxyestrogens, which have minimal activity in peripheral tissues. Second, PAHs induce other hepatic enzymes such as monooxygenases and transferases, which enhance steroid metabolism and clearance. Third, cigarette smoking increases adrenal production of androgens, which can counter or blunt the actions of estrogens. Fourth, PAHs induce or up-regulate the expression of cytochrome P450 enzymes in an effort to solubilize such chemicals for excretion. The cytochrome P450 enzymes CYP1A1 and CYP1B1 become elevated in human and rodent tissues in response to PAHs, in turn leading to metabolism of PAHs within the liver and target tissues such as the ovary. Metabolized PAHs form DNA, protein, and lipid adducts that wreak havoc on cells. This ultimately leads to activation of autophagic and apoptotic pathways. With regard to apoptosis, a molecular circuit in which PAHs activate the aryl hydrocarbon receptor (AHR) has been studied in reasonable detail. This PAHactivated transcription factor up-regulates not only the PAHmetabolizing enzymes CYP1A1 and CYP1B1 but also the proapoptotic gene Bax in the ovary. Metabolism of PAHs causes formation of DNA adducts, which results in genotoxic stress and subsequent activation of apoptosis. The proapoptotic gene Bax has been shown in murine and human ovaries to be essential for PAH-induced apoptosis. Activation of apoptotic cascade in the ovary by PAH exposure is far more extensive than transcriptional up-regulation of Bax alone. At least two studies provided evidence that PAH-induced follicle depletion associates with the transcriptional up-regulation of a large cassette of at least 17 proapoptotic genes that exist at multiple levels within the cell death signaling cascade. Not surprisingly, many of these genes, as with Bax, harbor consensus AHR response elements within their promoter regions and are therefore direct transcriptional targets of PAH-activated AHR. Some of these proapoptotic genes include Harakiri, Mtd, Bmf, Noxa, and Trp53. Like Bax and Ahr, Harakiri and Trp53 genes were shown in mouse mutagenesis studies to be essential for mediating the ovotoxic effects of PAHs in vivo. The apoptotic cascade activated by PAH exposure seems to be evolutionarily conserved in that the human ovary responds to PAHs in much the same way that the mouse ovary does. Here, human ovarian cortical strips implanted into immunocompromised mice showed the detrimental effects of PAH treatment by causing complete destruction of human oocytes. Although it is probable that PAHs negatively impact on several cell populations within ovarian follicles, PAHs directly activate apoptosis in oocytes. Interestingly, the study by Jurisicova et al demonstrated that maternal exposure to PAHs before pregnancy or during lactation causes ovotoxicity in female offspring. This finding highlights the potential for transgenerational effects of maternal cigarette smoking on humans, as has been shown for other environmental toxicants or endocrine disruptors. The ovotoxic effects of cigarette smoking on the human ovary probably stem from the direct activation of apoptosis genes by PAHs and from genotoxic PAH derivatives generated by CYP1A1 and CYP1B1 metabolism. In this issue of Menopause, Butts et al present new findings wherein a single nucleotide polymorphism in the CYP1B1 gene was found to