title: Estrogens and Their Genotoxic Metabolites Are Increased in Obese Prepubertal Girls.
abstract: BACKGROUND
  Estrogen levels and their metabolites are higher in obese vs lean postmenopausal women, and obesity increases breast cancer risk. Quinone derivatives of 4-hydroxylated estrogen metabolites, independently of the estrogen receptor, cause depurination and impaired DNA repair (genotoxic). 16α-Hydroxy (16α-OH)-estrone (E1), eg, promotes tumor proliferation and 2-methoxy-estradiol (E2) may be chemoprotective. Childhood obesity increases breast cancer death risk in women, but levels of estrogen derivatives had not been previously studied in young children.
  
  
  OBJECTIVE
  The objective of the study was to investigate whether total and genotoxic estrogens are increased in prepubertal obese girls compared with lean controls.
  
  
  METHODS
  Stored sera from 12 lean and 23 obese prepubertal girls (Tanner stage I breast and pubic hair) studied previously were assayed for E1, E2, and their multiple metabolites (12 steroids total) using highly sensitive liquid chromatography and tandem mass spectrometry.
  
  
  RESULTS
  E2 concentrations were significantly higher in obese [3.45 (0.5, 4.65) pg/ml (median [quartile 1, quartile 3])] vs lean girls [0.5 (0.5, 2.37), P = .04], 57% of values upper quartile or greater (quartile 3) of controls. Concentrations of 16α-OH-E1 were higher in obese [7.17 (0.5, 9.64) pg/mL] vs lean girls [0.5 (0.5, 1.72, P = .007)], 65% of values quartile 3 or greater of controls. 2-Methoxy-E2 concentrations were lower in the obese group (P = .012). 16α-OH-E1 concentrations were positively correlated with body mass index, percentage fat mass, and IL-6 concentrations (P < .001).
  
  
  CONCLUSIONS
  E2 and genotoxic metabolites were higher in obese vs lean prepubertal girls. These data suggest that obesity is associated with an increased extraglandular estrogen production and metabolism before the onset of puberty in girls. Long-term epidemiological studies are needed to assess any potential increase in breast cancer risk.
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Nelly
authors: N
authors: Mauras
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Richard J
authors: RJ
authors: Santen
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Gerardo
authors: G
authors: Colón-Otero
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Jobayer
authors: J
authors: Hossain
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Qingqing
authors: Q
authors: Wang
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Clementina
authors: C
authors: Mesaros
authors: Division of Endocrinology, Diabetes, and Metabolism (N.M.), Nemours Children's Health System, Jacksonville, Florida 32207; Division of Endocrinology (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Division of Hematology and Oncology (G.C.-O.), Mayo Clinic, Jacksonville, Florida 32224; Department of Statistics and Bioinformatics (J.H.), Dupont Hospital for Children, Wilmington, Delaware 19803; and Center for Excellence in Environmental Toxicology (Q.W., C.M., I.A.B.), Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Ian A
authors: IA
authors: Blair
mesh_terms: D000077584:2-Methoxyestradiol; D016022:Case-Control Studies; D002648:Child; D004958:Estradiol / Q000031:analogs & derivatives / Q000097:blood; D045166:Estradiol Congeners / Q000097:blood* / Q000378:metabolism; D004964:Estriol / Q000097:blood; D004967:Estrogens / Q000097:blood* / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D006801:Humans; D009153:Mutagens / Q000378:metabolism*; D063766:Pediatric Obesity / Q000097:blood* / Q000378:metabolism; D011627:Puberty; D013851:Thinness / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D045166:Estradiol Congeners; D004967:Estrogens; D009153:Mutagens; D004970:Estrone; D004958:Estradiol; D000077584:2-Methoxyestradiol; D004964:Estriol