Female reproductive status and circulating blood leukocyte expression of selected metabolic or signaling genes involved in sex steroid metabolism.

OBJECTIVE: To examine the blood leukocyte expression of 22 sex steroid metabolic/signaling genes according to female reproductive status. METHODS: Michigan Fisheaters' Cohort participants underwent blood collection during the luteal phase of the menstrual cycle or randomly in non-menstruating participants. Gene expression (GE) was measured using Taqman hydrolysis probes and quantitative RT-PCR. Repeatability of four genes was determined in a subgroup. RESULTS: Five premenstrual, 57 premenopausal (20 users of systemic hormonal contraception), and 43 postmenopausal females participated. After Bonferroni correction for multiple comparisons of median GE between groups, three findings remained significant: greater GE of AhR in postmenopausal women than in premenopausal non-users of systemic hormonal contraception; and greater GE of ESR2 and HSD17B7 in premenstrual girls compared to postmenopausal women. Modest intra-class correlations were identified for CYP 19, ESR1, and ESR2 GE measured both in 2007 and 2010, but no intra-class correlation over the same time period was found for CYP17. CONCLUSIONS: There was little differential variation of blood leukocyte sex steroid ge between premenopausal women in the luteal phase of the menstrual cycle and postmenopausal women for most genes analyzed, but it will be necessary to make statistical adjustments in future epidemiologic studies in two circumstances: 1) when comparing AhR GE in premenopausal women non-users of systemic hormone contraception with postmenopausal women and 2) when comparing ESR2 and HSD17B7 GE in studies that include premenstrual girls. Developmental differences may explain the differential GE found in ESR2 and HSD17B7 in premenstrual girls compared with postmenopausal women.

Common classification schemes for PCB congeners and the gene expression of CYP17, CYP19, ESR1 and ESR2.

BACKGROUND: Reliable techniques to measure polychlorinated biphenyl (PCB) congeners make the clearer definition of their effects on human health possible. Given that PCBs are classified as endocrine disrupters, we sought to explore the expression of some key genes involved in sex steroid metabolism. OBJECTIVES: To examine common classification schemes of PCB congeners and determine whether exposure to groups classified by mechanism of action alter the gene expression (GE) of CYP17, CYP19, and ESR1 and ESR2. METHODS: GE and exposure to various classifications of lipid-adjusted PCB congeners were examined in 139 daughters of the Michigan Fisheaters' Cohort. Using mixed models analyses and adjusting for age, menopausal status, and current use of oral contraceptives and hormone replacement therapy, GE data were regressed on exposure to PCB congener groupings based on mechanism of action. RESULTS: Three novel findings are elucidated: first, that up-regulation of CYP19 expression is associated with exposure to PCB groupings containing dioxin-like, potentially anti-estrogenic, immunotoxic congeners, including PCB IUPAC #74, #105, #118, #138, #156, #157, #158, #167, and #170 from this cohort. Second, that exposure to similar congeners (PCB IUPAC #105, #156, #157, #158, and #167 in this cohort) but using a classification based solely on hormonal mechanisms of action is associated with increased expression of ESR2. Third, that increased expression of CYP17 is of borderline significance when associated with exposure to PCB IUPAC #118, #138, and #156. CONCLUSIONS: These findings are both counter-intuitive and intriguing. Rather than exhibiting anti-estrogenic effects alone, they suggest that these congeners up-regulate the major enzyme involved in estrogen synthesis and tend to confirm previous findings of links between AhR and ER signaling pathways. Replication of these findings, expansion of the number of genes examined, exploration of mixtures of environmental chemicals, and subsequent study of health outcomes in a larger cohort are future priorities.

Prenatal and concurrent exposure to halogenated organic compounds and gene expression of CYP17A1, CYP19A1, and oestrogen receptor alpha and beta genes.

OBJECTIVE: To determine whether prenatal exposure to dichlorodiphenyl ethylene (DDE) and polychlorinated biphenyls (PCBs) and concurrent exposure to DDE, PCBs and polybrominated diphenylethers (PBDEs) affect gene expression of aromatase (CYP19A1), 17-α-hydroxylase (CYP17A1), and oestrogen receptors α and ß (ESR 1 and ESR2). METHODS: Based on maternal PCB and DDE levels in the parent generation of the Michigan Fisheater Cohort determined between 1973 and 1991, individual prenatal exposures were estimated and have been published. In 2007, female adult offspring of this cohort were examined. Gene expression and concurrent lipid-adjusted exposures to DDE, PCBs and PBDEs were measured in blood and serum, respectively. Using mixed models and path analyses, gene-expression data were regressed on prenatal and concurrent exposures controlling for confounders. RESULTS: 139 daughters of Michigan fisheaters (65.3%) participated in the investigation. While prenatal PCB levels were statistically significantly associated with decreased expression of the aromatase and 17-α-hydroxylase genes, prenatal DDE levels were significantly related to increased gene expression of aromatase but not of 17-α-hydroxylase. The DDE association seems to be mediated by concurrent lipid-adjusted p,p'-DDE serum levels. Prenatal and concurrent exposure of both PCBs and DDE had comparable effects. No association was found for PBDEs or for the gene expression of ESR 1 and ESR2. CONCLUSIONS: A 40-year antecedent prenatal exposure and concurrent levels of PCBs and DDE are associated with the expression of aromatase and 17-α-hydroxylase genes. Prenatal exposures to organochlorines may instigate long-term alterations of gene expression. Mechanisms of prenatal induction of persistent gene-expression alterations are speculated to be epigenetic in nature.

Expression of CYP19 and CYP17 is associated with leg length, weight, and BMI.

This study investigates associations between gene expressions of aromatase (CYP19), 17α hydroxylase (CYP17), and estrogen receptors α and ß and anthropometric measurements in offspring of the Michigan fish eater cohort. Leg and trunk length, height, weight, and BMI and gene expression in peripheral blood cells were measured in offspring of the Michigan fish eater cohort. The parental generation was followed between 1973 and 1991, and maternal age, height, and weight data were collected. Female offspring were contacted in 2001/2002 and followed up in 2006/2007; offspring information included age, education, reproductive history, smoking, and exercise. Gene expression was standardized against 18S ribosomal ribonucleic acid (18SrRNA) and RNA polymerase II (RNA PolII) expressions. Mixed models assessed the statistical effect of gene expression on anthropometric outcomes, accounting for multiple offspring from one mother. Anthropometric measurements and gene expression were measured in 139 female offspring. The two length and the height measurements were correlated, as were BMI and weight. CYP19 expression was correlated with the other gene expressions and both estrogen receptor expressions were associated. For every 1 unit of ΔC(t) (18SrRNA - CYP19) or ΔC(t) (RNA PolII - CYP19), BMI was increased by 0.9 (P = 0.03) and 0.87 kg/m(2) (P = 0.04), respectively, and weight by 2.35 kg (P = 0.03) and 2.1 kg (P = 0.03), respectively. For every 1 unit of ΔC(t) (18SrRNA - CYP17), leg length was increased by 0.84 cm (P = 0.04). The results suggest that CYP17 gene expression may influence growth during childhood and adolescence while CYP19 may be associated with the concurrent measures of weight and BMI.

Association of age at menarche with adult leg length and trunk height: Speculations in relation to breast cancer risk.

BACKGROUND: It seems paradoxical that both increased height and earlier age at menarche (which predicts for shorter stature) are both associated with increased breast cancer risk. METHODS: Retrospective data from a parental cohort coupled with prospective interviews with and anthropometric measurements from their daughters were used. Multivariable linear regression analyses were conducted using mixed regression models to account for same-family participants. RESULTS: Controlling for birth weight, maternal height, and birth cohort, and analyzed as a group, a 1-year increase in the age at menarche predicted an increase in standing height, leg length, and trunk height of 0.76, 0.41, and 0.35 cm, respectively. However, when stratifying by birth year (prior to 1966 vs 1966 or after), these relationships were true only for those born prior to 1966. CONCLUSION: Given the height-breast cancer risk association, the emerging evidence linking breast cell proliferation to hormones associated with growth, and the finding in this study that the relationship between age at menarche and adult height no longer exists for women born in 1966 or later, it is possible that the long-established relationship between age at menarche and breast cancer risk may also no longer exist.