Common Childhood Viruses and Pubertal Timing: The LEGACY Girls Study.

Earlier pubertal development is only partially explained by childhood body mass index (BMI); the role of other factors like childhood infections is less understood. Using data from the LEGACY Girls Study (2011 - 2016), we prospectively examined the associations between childhood viral infections (Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus 1 (HSV1), HSV2 and pubertal timing. We measured exposures based on seropositivity in pre-menarcheal girls (n=490). Breast and pubic hair development were classified based on mother-reported Tanner Stage (TS: TS2+ compared with TS1), adjusting for age, BMI, and sociodemographic factors. The average age at first blood draw was 9.8 years (Stdev=1.9 years). The prevalences were 31% CMV+, 37% EBV+, 14% HSV1+, 0.4% HSV2+, and 16% for both CMV+/EBV+. CMV+ infection without co-infection was associated with developing breasts an average of 7 months earlier (Hazard Ratio (HR)=2.12, 95% CI 1.32, 3.40). CMV+ infection without co-infection and HSV1+ and/or HSV2+ infection were associated with developing pubic hair 9 months later (HR 0.41, 95% CI 0.24, 0.71, HR 0.42, 95% CI 0.22, 0.81, respectively). Infection was not associated with menarche. If replicated in larger cohorts with blood collection prior to any breast development, this study supports that childhood infections may play a role in altering pubertal timing.

[1]  K. Hayashi,et al.  Estradiol Affects Epstein–Barr Virus Reactivation-Induced Thyrotropin Receptor Antibody and Immunoglobulin Production in Graves’ Disease Patients and Healthy Controls , 2018, Viral immunology.

[2]  S. Sehrawat,et al.  Herpesviruses: Harmonious Pathogens but Relevant Cofactors in Other Diseases? , 2018, Front. Cell. Infect. Microbiol..

[3]  W. Chung,et al.  Comparison of methods to assess onset of breast development in the LEGACY Girls Study: methodological considerations for studies of breast cancer , 2018, Breast Cancer Research.

[4]  J. Kwekkeboom,et al.  Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation , 2018, Front. Immunol..

[5]  E. Fuentes-Pananá,et al.  Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System , 2018, Front. Microbiol..

[6]  R. Hiatt,et al.  Age at Pubertal Onset in Girls and Tobacco Smoke Exposure During Pre- and Postnatal Susceptibility Windows , 2017, Epidemiology.

[7]  A. Whittemore,et al.  Pubertal development in girls by breast cancer family history: the LEGACY girls cohort , 2017, Breast Cancer Research.

[8]  A. Bertke,et al.  Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons , 2017, Journal of Virology.

[9]  C. Schooling,et al.  Infection and pubertal timing: a systematic review. , 2016, Journal of developmental origins of health and disease.

[10]  Zhongheng Zhang,et al.  Parametric regression model for survival data: Weibull regression model as an example. , 2016, Annals of translational medicine.

[11]  M. Schleiss,et al.  Cytomegalovirus Vaccines: Current Status and Future Prospects , 2016, Drugs.

[12]  G. Windham,et al.  Residential proximity to traffic and female pubertal development. , 2016, Environment international.

[13]  J. Persson,et al.  Associations between EBV and CMV Seropositivity, Early Exposures, and Gut Microbiota in a Prospective Birth Cohort: A 10-Year Follow-up , 2016, Front. Pediatr..

[14]  W. Chung,et al.  Comparison of Clinical, Maternal, and Self Pubertal Assessments: Implications for Health Studies , 2016, Pediatrics.

[15]  Sheida Nabavi,et al.  Epstein–Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation , 2016, EBioMedicine.

[16]  A. Whittemore,et al.  The LEGACY Girls Study: Growth and Development in the Context of Breast Cancer Family History , 2016, Epidemiology.

[17]  Justin M. Reitsma,et al.  Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication , 2016, PLoS pathogens.

[18]  A. Calafat,et al.  Environmental phenols and pubertal development in girls. , 2015, Environment international.

[19]  T. Rebbeck,et al.  Distinct microbiological signatures associated with triple negative breast cancer , 2015, Scientific Reports.

[20]  T. Lehtimäki,et al.  Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study , 2015, International Journal of Obesity.

[21]  R. Hiatt,et al.  Brominated Flame Retardants and Other Persistent Organohalogenated Compounds in Relation to Timing of Puberty in a Longitudinal Study of Girls , 2015, Environmental health perspectives.

[22]  W. Ingman,et al.  Hormonal Regulation of the Immune Microenvironment in the Mammary Gland , 2014, Journal of Mammary Gland Biology and Neoplasia.

[23]  S. P. Kachur,et al.  Investigating the important correlates of maternal education and childhood malaria infections. , 2014, The American journal of tropical medicine and hygiene.

[24]  Bin Huang,et al.  Hormone changes in peripubertal girls. , 2014, The Journal of clinical endocrinology and metabolism.

[25]  A. Calafat,et al.  Phthalate exposure and pubertal development in a longitudinal study of US girls. , 2014, Human reproduction.

[26]  Y. Tan,et al.  Epidermal growth factor receptor (EGFR) signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland. , 2014, Endocrinology.

[27]  Madeeha Kamal,et al.  Epstein Barr virus: a prime candidate of breast cancer aetiology in Sudanese patients , 2014, Infectious Agents and Cancer.

[28]  A. Busca,et al.  Innate immune responses in hepatitis B virus (HBV) infection , 2014, Virology Journal.

[29]  L. Kananen,et al.  Molecular mechanisms associated with the strength of the anti-CMV response in nonagenarians , 2014, Immunity & Ageing.

[30]  P. Griffiths,et al.  Priorities for CMV vaccine development. , 2013, Vaccine.

[31]  R. Hiatt,et al.  Onset of Breast Development in a Longitudinal Cohort , 2013, Pediatrics.

[32]  Paige L. Williams,et al.  Pubertal onset in children with perinatal HIV infection in the era of combination antiretroviral treatment , 2013, AIDS.

[33]  J. Belsky,et al.  Evo-devo of human adolescence: beyond disease models of early puberty , 2013, BMC Medicine.

[34]  D. Shukla,et al.  Recent advances in vaccine development for herpes simplex virus types I and II , 2013, Human vaccines & immunotherapeutics.

[35]  I. Camacho-Arroyo,et al.  Role of Sex Steroid Hormones in Bacterial-Host Interactions , 2012, BioMed research international.

[36]  Hiroko Masuda,et al.  Role of epidermal growth factor receptor in breast cancer , 2012, Breast Cancer Research and Treatment.

[37]  A. Wolk,et al.  Adenovirus-36 Is Associated with Obesity in Children and Adults in Sweden as Determined by Rapid ELISA , 2012, PloS one.

[38]  G. Weinstock,et al.  Emerging view of the human virome , 2012, Translational Research.

[39]  A. Juul,et al.  Recent Secular Trends in Pubertal Timing: Implications for Evaluation and Diagnosis of Precocious Puberty , 2012, Hormone Research in Paediatrics.

[40]  Qifeng Yang,et al.  Epstein-Barr Virus Infection and Sporadic Breast Cancer Risk: A Meta-Analysis , 2012, PloS one.

[41]  G. Leung,et al.  Lifecourse infectious origins of sexual inequalities in central adiposity. , 2011, International journal of epidemiology.

[42]  G. Leung,et al.  Early life infections and onset of puberty: evidence from Hong Kong's children of 1997 birth cohort. , 2011, American journal of epidemiology.

[43]  E. Walvoord The timing of puberty: is it changing? Does it matter? , 2010, The Journal of adolescent health : official publication of the Society for Adolescent Medicine.

[44]  T. Ley,et al.  Latent herpesvirus infection arms NK cells. , 2010, Blood.

[45]  Persephone Borrow,et al.  The immune response during acute HIV-1 infection: clues for vaccine development , 2009, Nature Reviews Immunology.

[46]  S. Montgomery,et al.  Epstein‐Barr virus and cytomegalovirus are differentially associated with numbers of cytokine‐producing cells and early atopy , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[47]  J. Dowd,et al.  Socioeconomic and race/ethnic patterns in persistent infection burden among U.S. adults. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[48]  J. Dowd,et al.  Early origins of health disparities: burden of infection, health, and socioeconomic status in U.S. children. , 2009, Social science & medicine.

[49]  L. Cooper,et al.  Induction of Pluripotent Protective Immunity Following Immunisation with a Chimeric Vaccine against Human Cytomegalovirus , 2008, PloS one.

[50]  S. Hong,et al.  Androgen‐dependent activation of human cytomegalovirus major immediate‐early promoter in prostate cancer cells , 2008, The Prostate.

[51]  M. Moasser,et al.  The epidermal growth factor receptor family: Biology driving targeted therapeutics , 2008, Cellular and Molecular Life Sciences.

[52]  P. Kaplowitz Link Between Body Fat and the Timing of Puberty , 2008, Pediatrics.

[53]  N. Khardori,et al.  Infection, immunity, and hormones/endocrine interactions. , 2007, Infectious disease clinics of North America.

[54]  M. Diamond,et al.  Herpesvirus latency confers symbiotic protection from bacterial infection , 2007, Nature.

[55]  D. Allison,et al.  Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids , 2005, International Journal of Obesity.

[56]  M. Wickman,et al.  Cytomegalovirus infection and development of allergic diseases in early childhood: interaction with EBV infection? , 2004, The Journal of allergy and clinical immunology.

[57]  B. Ellis Timing of pubertal maturation in girls: an integrated life history approach. , 2004, Psychological bulletin.

[58]  Darrell M. Wilson,et al.  Early sexual maturation, body composition, and obesity in African-American girls. , 2004, Obesity research.

[59]  R. Rabinovich,et al.  Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[60]  D. Gertig,et al.  Cytomegalovirus, Epstein–Barr virus and risk of breast cancer before age 40 years: a case–control study , 2004, British Journal of Cancer.

[61]  J. Toppari,et al.  The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. , 2003, Endocrine reviews.

[62]  N. Krieger,et al.  Breast cancer, birth cohorts, and Epstein-Barr virus: methodological issues in exploring the "hygiene hypothesis" in relation to breast cancer, Hodgkin's disease, and stomach cancer. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[63]  J. Bethel,et al.  Blood lead concentration and delayed puberty in girls. , 2003, The New England journal of medicine.

[64]  H. Ploegh,et al.  The Human Cytomegalovirus US10 Gene Product Delays Trafficking of Major Histocompatibility Complex Class I Molecules , 2002, Journal of Virology.

[65]  Youfa Wang Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. , 2002, Pediatrics.

[66]  E. Obarzanek,et al.  Impact of timing of pubertal maturation on growth in black and white female adolescents: The National Heart, Lung, and Blood Institute Growth and Health Study. , 2001, The Journal of pediatrics.

[67]  S. Klein,et al.  The effects of hormones on sex differences in infection: from genes to behavior , 2000, Neuroscience & Biobehavioral Reviews.

[68]  R. MacCallum,et al.  Hormonal modulation of Epstein-Barr virus replication. , 1995, Neuroendocrinology.

[69]  P. Mackowiak,et al.  Effect of human sex hormones on cytomegalovirus growth and Fc receptor expression. , 1987, The Journal of laboratory and clinical medicine.

[70]  R. Revelle,et al.  Height and Weight at Menarche and a Hypothesis of Critical Body Weights and Adolescent Events , 1970, Science.

[71]  J M Tanner,et al.  Variations in pattern of pubertal changes in girls. , 1969, Archives of disease in childhood.

[72]  F. Biro,et al.  Puberty as a Window of Susceptibility , 2011 .

[73]  R. Atkinson,et al.  Human adenovirus-36 antibody status is associated with obesity in children. , 2010, International journal of pediatric obesity : IJPO : an official journal of the International Association for the Study of Obesity.

[74]  J. Stanford,et al.  Breast cancer risk and "delayed" primary Epstein-Barr virus infection. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[75]  R. Lawrence,et al.  COMMITTEE TO STUDY PRIORITIES FOR VACCINE DEVELOPMENT , 2000 .