Blood Metal Concentrations and Timing of Pubertal Onset in a Longitudinal Cohort of Girls, Northern California, 2006-2011 Pubblico

Abstract

Background: Endocrine-disruptive toxicants might alter the complex interplay of hormones that regulates timing of pubertal onset. The few studies of metals as potential disruptors of pubertal timing have yielded inconsistent results. We investigated the associations between blood concentrations of arsenic, cadmium, lead, manganese, mercury, and uranium and pubertal onset among girls.

Methods: Study participants included 313 Kaiser Permanente Northern California members followed at annual intervals during 2004-2011, who provided a blood specimen during their first, second, or third annual clinical visit. Metal concentrations were measured in serum from the first blood specimen available for each participant. Pubertal onset was defined as Tanner stage ≥2 for breast (thelarche) or pubic hair (pubarche) development. Associations between blood metals concentrations and pubertal onset were assessed by multivariable logistic regression and Cox proportional hazards modeling, controlling for age at blood draw, race, body mass index, annual family income, and primary caregiver's educational attainment.

Results: At blood draw, participants were age 6.5-10.1 (median 7.6) years, and 10% and 12% had attained thelarche and pubarche, respectively. Participants were followed 0-5 years (median 4). Most (91% and 88%) had attained thelarche and pubarche, respectively, at most recent clinical visit. Median ages of attaining thelarche and pubarche were 10.3 and 10.6 years, respectively. Odds of having achieved thelarche or pubarche at time of blood draw were not associated with metal concentrations after adjusting for covariates. Using time of blood draw to time of exam at which pubertal onset was observed as the follow-up interval, decreased risk of pubarche was associated with blood concentrations of arsenic (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.71, 1.00, P=0.05; per 1-log increase), cadmium (aHR 0.71, 95% CI 0.55, 0.92, P<0.01; cadmium >limit of detection), and manganese (aHR 0.94, 95% CI 0.91, 0.98, P<0.01; per μg/L); similar associations were observed when birth to time of follow-up exam at which pubertal onset was observed was the follow-up interval.

Summary: Higher prepubertal blood concentrations of arsenic, cadmium, and manganese are associated with later pubarche.

Table of Contents

CHAPTER I:INTRODUCTION 4

Puberty and the mechanisms regulating pubertal onset 4

Stages of puberty 5

Secular trends in pubertal timing 6

Consequences of altered pubertal timing 7

Posited factors influencing pubertal timing 8

Summary of current problem 12

Thesis purpose statement 13

CHAPTER II: METHODOLOGY 14

Introduction 14

Population and sample 14

Research design and methods 16

CHAPTER III: RESULTS 25

Introduction 25

Participant anthropometrics and demographics 25

Timing of pubertal onset 27

Pubertal status at time of blood draw by demographics and anthropometric measurements 28

Risk of pubertal onset by demographic and anthropometric measurements measurements 34

Distribution of blood metals 40

Research question #1: do blood metal concentrations vary by pubertal status at time of blood draw? 44

Research question #2: are blood metal concentrations associated with risk of puberty? 47

Results summary 52

CHAPTER IV: DISCUSSION 55

REFERENCES 61

FIGURES

Figure 1: Tanner stages of breast and pubic hair development 71

Figure 2: Kaplan-Meier curves of attainment of thelarche and pubarche 72

Figure 3: Distribution of blood arsenic concentrations among girls 73

Figure 4: Distribution of blood cadmium concentrations among girls 74

Figure 5: Distribution of blood lead concentrations among girls 75

Figure 6: Distribution of blood manganese concentrations among girls 76

Figure 7: Distribution of blood mercury concentrations among girls 77

Figure 8: Distribution of blood uranium concentrations among girls 78

TABLES

Table 1: Demographic and anthropometric characteristics of girls at time of blood draw 79

Table 2: Timing of pubertal onset and participation in CYGNET study over time 80

Table 3: Pubertal status at time of blood draw by covariates 81

Table 4: Crude odds ratios (cORs) and adjusted odds ratios (aORs), 95% confidence intervals (CIs) and P-values of having achieved thelarche and pubarche at time of blood draw by covariates 82

Table 5. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting thelarche and pubarche by covariates. Interval--time of blood draw to pubertal onset 83

Table 6. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting thelarche and pubarche by covariates. Interval--birth to pubertal onset 84

Table 7: Distribution of blood metals 85

Table 8: Pearson coefficients (and P-values) of metal concentrations 86

Table 9: Mean blood metals by cadmium < vs. ≥LOD 87

Table 10: Mean blood metal concentration by covariate category 88

Table 11: Mean blood metal concentrations by pubertal status at time of blood draw draw 89

Table 12. Crude odds ratios (cORs) and adjusted odds ratios (aORs), 95% confidence intervals (CIs) and P-values of having achieved thelarche and pubarche at time of blood draw by metals 90

Table 13. Crude odds ratios (cORs) and 95% confidence intervals (CIs) of having achieved thelarche and pubarche at time of blood draw, by metals categorized into quartiles 91

Table 14. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting thelarche and pubarche by metals. Interval--time of blood draw to pubertal onset 92

Table 15. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) predicting thelarche and pubarche, by metals categorized into quartiles. Interval--time of blood draw to pubertal onset 93

Table 16. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting thelarche and pubarche by metals. Interval--birth to pubertal onset 95

Table 17. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) predicting thelarche and pubarche, by metals categorized into quartiles. Interval--birth to pubertal onset 96

Table 18. Adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting pubarche, modeling for covariates and multiple metals simultaneously. Interval--time of blood draw to pubertal onset 98

Table 19. Adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and P-values predicting pubarche, modeling for covariates and multiple metals simultaneously. Interval--birth to pubertal onset 99

About this Master's Thesis

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School	Rollins School of Public Health
Department	Executive Masters of Public Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Parola chiave	Metals Puberty Epidemiology
Committee Chair / Thesis Advisor	Darrow, Lyndsey, Emory University
Committee Members	Windham, Gayle, California Department of Public Health Barr, Dana Boyd, Emory University
Partnering Agencies	State or local health department (not in Georgia) Hospital or other health care provider

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