No abstract

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5-untranslated region T3 C), CYP19 [intron 4 (TTTA) n ‫؍‬ 7-13 and a 3-bp deletion (؊3)], CYP1B1 (Val 432 Leu), and COMT (Val 108/158 Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2-and 16␣-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(؊3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P ‫؍‬ 0.01), 23% lower free estradiol (P ‫؍‬ 0.01), and 22% higher sex hormone-binding globulin concentrations (P ‫؍‬ 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P ‫؍‬ 0.003), 18% higher estradiol (P ‫؍‬ 0.02), and 21% higher free estradiol concentrations (P ‫؍‬ 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P ‫؍‬ 0.08) and 31% higher 16␣-hydroxyestrone concentrations (P ‫؍‬ 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Metals such as copper disrupt olfactory function in fish. Unfortunately, little is understood of the molecular consequences of copper olfactory impairment, thus hindering the development of relevant diagnostic tools of olfactory injury. To address this critical data gap, we analyzed gene expression within olfactory tissues of adult zebrafish exposed to CuCl2 (6, 16, 40 ppb) for 24 hrs. Transcriptional markers of copper impairment within the entire olfactory system were identified and specific genes of interest (e.g. S100a, parvalbumin 8, olfactory marker protein, and calbindin 2-like protein) were confirmed with quantitative real-time PCR. In addition, we performed gene set analysis (GSA) using both a-priori and custom pathways of gene sets specifically targeting the olfactory signal transduction (OST) pathway. These analyses revealed down-regulated gene sets related to calcium channels and ion transport, g-proteins, and olfactory receptors. Collectively, these data demonstrate that copper causes a depression of transcription of key genes within the OST pathway and elsewhere within olfactory tissues, likely resulting in an olfactory system less responsive to odorants. Further, these data provide a mechanistic explanation in support of earlier studies of functional olfactory impairment in fish following copper exposure.