CYP19A1 promoter methylation in saliva associated with milestones of pubertal timing in urban girls

BMC Pediatrics

Jia Chen¹  Susan L Teitelbaum¹  Ashley Pajak¹  Mary S Wolff¹  Theresa Ryan Stueve² 

[1] Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

关键词: Puberty;    PPAR;    Obesity;    Methylation;    Aromatase;   

Others  :  1138944
DOI  :  10.1186/1471-2431-14-78

 received in 2013-07-24, accepted in 2014-03-18,  发布年份 2014

【 摘 要 】

Background

Childhood obesity and early puberty are intermediate risk factors for later metabolic and reproductive disorders including diabetes, polycystic ovarian syndrome (PCOS), and breast cancer. Atypical methylation patterns in genes related to hormone and adipose metabolism, such as CYP19A1 (aromatase) and PPARG (peroxisome proliferator-activated receptor gamma), are associated with alterations in gene expression which may contribute to pathogenesis of these diseases. If present in early life, it is conceivable similar methylation aberrations may result in hormone perturbations that alter pubertal timing.

Methods

We used Cox proportional hazard models to investigate whether promoter methylation of CYP19A1 and PPARG, independently or in concert with body weight, was associated with age at breast (B2) or pubic hair development (PH2) when assayed in saliva DNA collected from a cohort of New York City, Black and Hispanic girls (N = 130) enrolled in a study of pubertal timing between 6–8 years of age.

Results

An inverse association between CYP19A1 methylation and risk of early PH2 was suggested (HR = 0.95, 95% CI = 0.90-1.00, p = 0.05). CYP19A1 methylation also appeared to modify risk of early B2 associated with body weight. Specifically, compared to normal weight girls with ‘high’ CYP19A1 methylation, significantly increased risk of early B2 was observed in overweight girls with ‘low’ but not ‘high’ CYP19A1 methylation (HR = 2.15; 95% CI = 1.23- 3.76). However, in formal tests for effect modification, the interaction between body weight and methylation did not reach statistical significance (p for interaction = 0.085). PPARG methylation was not significantly associated with PH2 or B2.

Conclusions

Though limited by sample size, our findings suggest methylation of CYP19A1, a critical gene in estrogen biosynthesis, may influence timing of breast development in overweight girls. Consistent with emerging reports, these data support the notion that epigenetic marks in surrogate tissues may improve risk prediction when added to standard plasma and anthropometric indicators, and warrant further study.

【 授权许可】

   
2014 Stueve et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Relton CL, Groom A, St Pourcain B, Sayers AE, Swan DC, Embleton ND, Pearce MS, Ring SM, Northstone K, Tobias JH, Trakalo J, Ness AR, Shaheen SO, Davey Smith G: DNA methylation patterns in cord blood DNA and body size in childhood. PLoS One 2012, 7(3):e31821.
• [2]Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, Rodford J, Slater-Jefferies JL, Garratt E, Crozier SR, Emerald BS, Gale CR, Inskip HM, Cooper C, Hanson MA: Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 2011, 60(5):1528-1534.
• [3]Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, Kaidar G, Knoll JG, Wright H, Pfeifer GP, Ojeda SR: Epigenetic control of female puberty. Nat Neurosci 2013, 16(3):281-289.
• [4]Ibanez L, Jimenez R, de Zegher F: Early puberty-menarche after precocious pubarche: relation to prenatal growth. Pediatrics 2006, 117(1):117-121.
• [5]Nader PR, O’Brien M, Houts R, Bradley R, Belsky J, Crosnoe R, Friedman S, Mei Z, Susman EJ: National Institute of Child Health and Human Development Early Child Care Research Network: identifying risk for obesity in early childhood. Pediatrics 2006, 118(3):e594-e601.
• [6]American Diabetes Association: Type 2 diabetes in children and adolescents. Pediatrics 2000, 105(3 Pt 1):671-680.
• [7]Ibanez L, Valls C, Marcos MV, Ong K, Dunger DB, De Zegher F: Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. J Clin Endocrinol Metab 2004, 89(9):4331-4337.
• [8]Must A, Phillips SM, Naumova EN: Occurrence and timing of childhood overweight and mortality: findings from the Third Harvard Growth Study. J Pediatr 2012, 160(5):743-750.
• [9]Qu F, Wang FF, Yin R, Ding GL, El-Prince M, Gao Q, Shi BW, Pan HH, Huang YT, Jin M, Leung PC, Sheng JZ, Huang HF: A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells. J Mol Med (Berl) 2012, 90(8):911-923.
• [10]Tessitore L, Vizio B, Pesola D, Cecchini F, Mussa A, Argiles JM, Benedetto C: Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. Int J Oncol 2004, 24(6):1529-1535.
• [11]Geisler J: Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol 2003, 86(3–5):245-253.
• [12]Smith JT: Sex steroid regulation of kisspeptin circuits. Adv Exp Med Biol 2013, 784:275-295.
• [13]Jasik CB, Lustig RH: Adolescent obesity and puberty: the “perfect storm”. Ann N Y Acad Sci 2008, 1135:265-279.
• [14]Biro FM, Greenspan LC, Galvez MP: Puberty in girls of the 21st century. J Pediatr Adolesc Gynecol 2012, 25(5):289-294.
• [15]Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M: A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci U S A 1997, 94(17):9372-9377.
• [16]Fujiki K, Kano F, Shiota K, Murata M: Expression of the peroxisome proliferator activated receptor gamma gene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes. BMC Biol 2009., 387007-7-38
• [17]Meng L, Zhou J, Sasano H, Suzuki T, Zeitoun KM, Bulun SE: Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction. Cancer Res 2001, 61(5):2250-2255.
• [18]Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A: History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 2009, 30(4):343-375.
• [19]Bulun SE, Chen D, Lu M, Zhao H, Cheng Y, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Su E, Marsh E, Hakim A, Yin P, Ishikawa H, Amin S, Imir G, Gurates B, Attar E, Reierstad S, Innes J, Lin Z: Aromatase excess in cancers of breast, endometrium and ovary. J Steroid Biochem Mol Biol 2007, 106(1–5):81-96.
• [20]Rubin GL, Duong JH, Clyne CD, Speed CJ, Murata Y, Gong C, Simpson ER: Ligands for the peroxisomal proliferator-activated receptor gamma and the retinoid X receptor inhibit aromatase cytochrome P450 (CYP19) expression mediated by promoter II in human breast adipose. Endocrinology 2002, 143(8):2863-2871.
• [21]Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER: A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 1993, 77(6):1622-1628.
• [22]Agarwal VR, Bulun SE, Leitch M, Rohrich R, Simpson ER: Use of alternative promoters to express the aromatase cytochrome P450 (CYP19) gene in breast adipose tissues of cancer-free and breast cancer patients. J Clin Endocrinol Metab 1996, 81(11):3843-3849.
• [23]Clyne CD, Speed CJ, Zhou J, Simpson ER: Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem 2002, 277(23):20591-20597.
• [24]Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S: Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 2005, 57(3):359-383.
• [25]Demura M, Bulun SE: CpG dinucleotide methylation of the CYP19 I.3/II promoter modulates cAMP-stimulated aromatase activity. Mol Cell Endocrinol 2008, 283(1–2):127-132.
• [26]Pancione M, Sabatino L, Fucci A, Carafa V, Nebbioso A, Forte N, Febbraro A, Parente D, Ambrosino C, Normanno N, Altucci L, Colantuoni V: Epigenetic silencing of peroxisome proliferator-activated receptor gamma is a biomarker for colorectal cancer progression and adverse patients’ outcome. PLoS One 2010, 5(12):e14229.
• [27]Biro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, Teitelbaum S, Windham GC, Kushi LH, Wolff MS: Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics 2010, 126(3):e583-e590.
• [28]Wolff MS, Teitelbaum SL, Pinney SM, Windham G, Liao L, Biro F, Kushi LH, Erdmann C, Hiatt RA, Rybak ME, Calafat AM: Investigation of Relationships between Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols and Pubertal Stages in Girls. Environ Health Perspect 2010, 118(7):1039-1046.
• [29]Davison KK, Susman EJ, Birch LL: Percent body fat at age 5 predicts earlier pubertal development among girls at age 9. Pediatrics 2003, 111(4 Pt 1):815-821.
• [30]Ibanez L, Lopez-Bermejo A, Diaz M, Marcos MV, de Zegher F: Metformin treatment for four years to reduce total and visceral fat in low birth weight girls with precocious pubarche. J Clin Endocrinol Metab 2008, 93(5):1841-1845.
• [31]Janfaza M, Sherman TI, Larmore KA, Brown-Dawson J, Klein KO: Estradiol levels and secretory dynamics in normal girls and boys as determined by an ultrasensitive bioassay: a 10 year experience. J Pediatr Endocrinol Metab 2006, 19(7):901-909.
• [32]Landrigan P, Garg A, Droller DB: Assessing the effects of endocrine disruptors in the National Children’s Study. Environ Health Perspect 2003, 111(13):1678-1682.
• [33]Subbaramaiah K, Howe LR, Zhou XK, Yang P, Hudis CA, Kopelovich L, Dannenberg AJ: Pioglitazone, a PPARgamma agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1. Cancer Prev Res (Phila) 2012, 5(10):1183-1194.
• [34]Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Giri D, Kopelovich L, Hudis CA, Dannenberg AJ: Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discov 2012, 2(4):356-365.
• [35]Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, Du B, Brogi E, Crawford CB, Kopelovich L, Subbaramaiah K, Dannenberg AJ: Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 2011, 4(7):1021-1029.
• [36]Bremer AA: Polycystic ovary syndrome in the pediatric population. Metab Syndr Relat Disord 2010, 8(5):375-394.
• [37]Gemma C, Sookoian S, Alvarinas J, Garcia SI, Quintana L, Kanevsky D, Gonzalez CD, Pirola CJ: Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns. Obesity (Silver Spring) 2009, 17(5):1032-1039.
• [38]Michael MD, Michael LF, Simpson ER: A CRE-like sequence that binds CREB and contributes to cAMP-dependent regulation of the proximal promoter of the human aromatase P450 (CYP19) gene. Mol Cell Endocrinol 1997, 134(2):147-156.
• [39]Liu E, Samad F, Mueller BM: Local adipocytes enable estrogen-dependent breast cancer growth: Role of leptin and aromatase. Adipocyte 2013, 2(3):0-4.
• [40]Bulun SE, Chen D, Moy I, Brooks DC, Zhao H: Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 2012, 23(2):83-89.