Blood Metal Concentrations and Timing of Pubertal Onset in a Longitudinal Cohort of Girls, Northern California, 20062011 Open Access
Wilken, Jason Andrew (2016)
Published
Abstract
Background: Endocrinedisruptive 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 20042011, 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 6.510.1 (median 7.6) years, and 10% and 12% had attained thelarche and pubarche, respectively. Participants were followed 05 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 followup 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 1log 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 followup exam at which pubertal onset was observed was the followup 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: KaplanMeier 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 Pvalues 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 Pvalues predicting thelarche and pubarche by covariates. Intervaltime of blood draw to pubertal onset 83
Table 6. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and Pvalues predicting thelarche and pubarche by covariates. Intervalbirth to pubertal onset 84
Table 7: Distribution of blood metals 85
Table 8: Pearson coefficients (and Pvalues) 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 Pvalues 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 Pvalues predicting thelarche and pubarche by metals. Intervaltime 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. Intervaltime of blood draw to pubertal onset 93
Table 16. Crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and Pvalues predicting thelarche and pubarche by metals. Intervalbirth 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. Intervalbirth to pubertal onset 96
Table 18. Adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and Pvalues predicting pubarche, modeling for covariates and multiple metals simultaneously. Intervaltime of blood draw to pubertal onset 98
Table 19. Adjusted hazard ratios (aHRs), 95% confidence intervals (CIs) and Pvalues predicting pubarche, modeling for covariates and multiple metals simultaneously. Intervalbirth to pubertal onset 99
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