Cadmium, Age at Menarche, and Early Puberty in Girls

Institution: Cancer Prevention Institute of California
Investigator(s): Pamela Horn-Ross, Ph.D. -
Award Cycle: 2011 (Cycle 17) Grant #: 17IB-0016 Award: $204,553
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

Initial Award Abstract (2011)

Non-technical overview of the research topic and relevance to breast cancer:
Women who experience their first menstrual period (i.e., menarche) before the age of 12 years have an increased risk of breast cancer. This association is consistent with the hypothesis that women who experience menarche at an earlier age experience a longer period during which susceptible breast cells are exposed to carcinogens, which may induce these cells to become cancerous. Over the past two decades the average age at menarche has been declining in the US and Europe. While the causes of early menarche and puberty are largely unknown, emerging evidence from animal studies suggest that increasing exposures to environmental chemicals that act as estrogens in the body may be contributing to this trend. Cadmium (Cd), a trace metal released into air and soil as a byproduct of industrial processes, is perhaps the most potent of these estrogenic chemicals. While the major sources of non-occupational exposure to Cd in adults include cigarette smoke, diet, and inhalation of air contaminated by industrial processes and combustion of fossil fuels, recent discoveries of Cd in children’s toys and jewelry have led to public concern about potential children’s exposure from ingestion and hand-to-mouth activity. Having a higher level of Cd in the body has been previously associated with breast cancer risk. It is possible that early-life exposure to this estrogenic metal may contribute to earlier age at menarche and pubertal development and thus also contribute to the risk of breast cancer.

The question(s) or central hypotheses of the research:
The primary hypothesis of this proposal is that the measured concentration of Cd in urine, an indicator of lifetime exposure to this metal, is associated with an earlier age at menarche and early onset of pubertal development.

The general methodology:
This proposed study will utilize existing data and urine specimens from the GRowth and LifeStyle Study (GRLS), a prospective cohort study of girls. A total of 214 girls, aged 10-13 years at the start of the study, provided overnight urine specimens that will be used to measure urinary Cd levels, completed an interview, provided a self-assessment of breast development and public hair growth based on standard pictorial depictions and verbal descriptions, and had their height and weight measured. A total of 87 girls had their first menstrual period prior to the start of the study, while 134 girls had not yet attained menarche at the start of the study and followed for up to two years using monthly questionnaires to ascertain the onset of menarche and pubertal development and an additional urine specimen was collected. Laboratory assays will measure urinary levels of Cd in the urine specimens. These indicators of Cd exposure will be compared with girls’ age at menarche and stage of breast and pubic hair development.

Innovative elements of the project:
Given the estrogenic potential of Cd, this proposed study would be one of the first evaluations of Cd and its role in the timing of menarche and pubertal development. One of the innovative aspects of this project is the fact that urine specimens were collected at the start of study from 134 girls who had not yet attained of menarche. Thus, we will be able to evaluate prospectively whether measured Cd levels from the beginning of follow-up predict the timing of menarche.

Advocacy involvement and relevance to the human issues associated with breast cancer:
As Cd exposures are potentially modifiable, this proposed study offers tremendous potential to contribute to our knowledge about the prevention of early menarche, a known risk factor for breast cancer. This project has high potential for meaningful translation into the reduction of children’s exposures to this estrogenic metal. If this study finds an association between early pubertal development and cadmium exposure, it could provide a major impetus for further regulatory actions to reduce the use of cadmium in industrial processes and the development of public health strategies to reduce exposures. To ensure our results are translated into actions aimed at mitigating the burden of exposure, we will disseminate our results to the scientific and lay communities, as well as to policy makers, using both a scientific manuscripts and lay-friendly fact sheet. Breast cancer and environmental advocacy organizations will play a critical role in the translation of findings from our study into meaningful and measurable interventions.

Final Report (2014)

Emerging evidence from animal and in vitro studies suggest that increasing exposures to estrogenic environmental chemicals may be contributing to the trend of earlier menarche and pubertal development that has been observed in many populations. Cadmium (Cd), a trace metal released into air and soil as a byproduct of industrial processes, is perhaps the most potent of these estrogenic contaminants. The primary hypothesis of this study was that urinary Cd concentration, a marker of lifetime body burden, is associated with an earlier age at menarche and earlier onset of pubertal development in girls. We tested this hypothesis using existing data and urine specimens from the GRowth and LifeStyle Study (GRLS), a prospective cohort study of 211, primarily Chinese and Caucasian, girls, aged 10-13 years at the start of the study.

We have successfully completed the project aims, which were to:
1. Determine the urinary concentrations of Cd in cohort participants and evaluate whether concentrations differ by age and race/ethnicity, and among Chinese girls, by nativity and generational status.
2. Evaluate whether urinary Cd concentration is associated with early age at menarche.
3: Evaluate whether urinary Cd concentration is associated with earlier estrogen-based or androgen-based pubertal development.

The baseline mean creatinine-adjusted cadmium concentration was 0.24 µg/g creatinine (SD=0.11 µg/g) in this cohort and none of the girls had excessive Cd levels. Cd was highest among 10-year olds (0.29 µg/g creatinine) and decreased with increasing age (to 0.23 µg/g creatinine among 13 year olds; p-trend=0.05). Chinese girls had higher Cd levels than non-Latina Whites (0.30 vs. 0.23 µg/g creatinine, respectively; p=0.006). Taking into account differences in age, race/ethnicity, and body size, and adjusting for creatinine, girls with the highest Cd levels (= 0.4 vs. <0.2 µg/L) experienced later menarche (hazard ratio=0.42; 95% confidence interval=0.23-0.78) but earlier androgenic development, as measured by self-identified Tanner's stage of pubic hair growth (odds ratio=0.21; 95% confidence interval=0.06-0.72). The timing of breast development was not associated with Cd concentration. Our findings are contrary to our a priori hypothesis that urinary Cd would be associated with earlier onset of menarche and pubertal development since it had been identified as an endocrine disruptor. However, a review of rodent studies revealed that Cd exposure is associated with delayed estrus (puberty), which is consistent with our findings.

These results have been presented in a number of venues, including oral presentations at the California Breast Cancer Research Program Symposium in Costa Mesa, CA, and the Nevada Public Health Association Annual Meeting in Reno, NV, and a poster at the International Society for Environmental Epidemiology Annual Meeting in Basel, Switzerland. In March 2014, we will also present these results as an oral presentation at the Society for Adolescent Health and Medicine Annual Meeting in Austin, Texas. Currently, we are developing a manuscript summarizing the findings of this study.