Elsevier

Reproductive Toxicology

Volume 67, January 2017, Pages 56-64
Reproductive Toxicology

Associations of urinary phthalate and phenol biomarkers with menarche in a multiethnic cohort of young girls

https://doi.org/10.1016/j.reprotox.2016.11.009Get rights and content

Highlights

  • Two phenol and one phthalate urinary biomarker were associated with age of menarche.

  • Later menarche related to two exposures was more pronounced among normal-BMI girls.

  • Six-to-tenfold exposure ranges were associated with 4–7 month changes in menarche age.

Abstract

To study potential environmental influences on puberty in girls, we investigated urinary biomarkers in relation to age at menarche. Phenols and phthalates were measured at baseline (6–8 years of age). Menarche was ascertained over 11 years for 1051 girls with menarche and biomarkers. Hazards ratios were estimated from Cox models adjusted for race/ethnicity and caregiver education (aHR, 95% confidence intervals [CI] for 5th vs 1st quintile urinary biomarker concentrations). 2,5-Dichlorophenol was associated with earlier menarche (aHR 1.34 [1.06–1.71]); enterolactone was associated with later menarche (aHR 0.82 [0.66–1.03]), as was mono-3-carboxypropyl phthalate (MCPP) (aHR 0.73 [0.59–0.91]); the three p-trends were <0.05. Menarche differed by 4–7 months across this range. Enterolactone and MCPP associations were stronger in girls with below-median body mass index. These analytes were also associated with age at breast development in this cohort. Findings from this prospective study suggest that some childhood exposures are associated with pubertal timing.

Introduction

Menarche, or the first menstrual period, marks the beginning of a woman’s reproductive life. Earlier or later onset has been linked with risk of chronic disease in adulthood. Its decline from about 18–12 years of age over 300 years is explained by lifestyle changes that accompanied industrialization. Primary factors are a girl’s age, adiposity, and race. Individual factors such as race and body mass index (BMI) account for 6–12 months difference in menarche [1], [2]. Racial differences may reflect both genetic and environmental factors. Much but not all of variation in menarche is explained by genetics, perhaps 70% [3]. These observations, in combination with strong experimental evidence that some chemical exposures alter pubertal timing, have triggered research regarding whether environment influences menarche [4]. Most research has come from cross-sectional investigations that assess environmental exposures among girls over a range of ages. Cross-sectional designs may not be able to address adequately the question of temporality needed to evaluate exposures in relation to menarche.

We are interested in highly prevalent hormonally active environmental exposures that have been identified in the past 20 years [5]. Common sources are diet and the physical environment, including household and personal care products. Among these, a number of phthalates and phenols, including phytoestrogens, have exhibited agonist and antagonistic hormone activity as well as possible obesogenic and anti-obesogenic effects. Estrogen, androgen, thyroid, and peroxisome proliferator-activated receptor (PPAR) activity has been observed [6].

To examine relationships between such exposures and pubertal onset, the NCI and NIEHS established the Breast Cancer and Environment Research Program (BCERP) cohort of girls to enable longitudinal study during childhood [7]. Here we report associations of 19 urinary biomarkers of environmental exposures with menarche in the BCERP cohort.

Section snippets

Study design and data collection

The BCERP Puberty Study is a cohort that enrolled girls between 2004 and 2007, concluding in 2015 (up to eleven years’ follow-up or 9 annual visits). Study sites included Icahn School of Medicine at Mount Sinai (NYC) that recruited black or Hispanic girls mainly from East Harlem in New York City; Cincinnati Children’s Hospital (Cincinnati) that recruited from the greater Cincinnati metropolitan area; and Kaiser Permanente Northern California (California) that recruited members of the KPNC

Results

The BCERP cohort is a culturally diverse group of girls who were enrolled at 6–8 years of age and followed through 2015, for eight-to-eleven years depending on year of enrolment. Of the 1051 girls in our analysis, menarche occurred at 12.2 years of age among 912 girls (median 146 months, IQR 135–156). Girls who reported menarche were 137 months old at the pre-menarche visit immediately before (median, IQR 126–148; n = 912). Girls who never reported having a period (n = 139) were somewhat younger at

Discussion

Age of menarche in the BCERP cohort was associated with two urinary phenols and one phthalate metabolite which had been measured several years earlier. Menarche on average occurred 7 months younger with higher 2,5-dichlorophenol and 4–5 months older with enterolactone and MCPP. Exposure effects were similar for age at first breast development (adjusted; Table 5) but not pubarche, which is not estrogen dependent. Pubertal changes associated with these exposures were reflected in hazards ratios

Conclusion

In this prospective study of environmental biomarkers measured as long as ten years before puberty, we find three to be associated with timing of both breast development and menarche; two others were associated with breast development but not menarche. Six other biomarkers or composite indices were associated with neither. Little is known about the relative biological effects and exposure thresholds that govern the pubertal trajectory. The timing of exposure measurement in this study may

Funding

This research was supported by the Breast Cancer and the Environment Research Program (BCERP) award numbers U01ES012770, U01ES012771, U01ES012800, U01ES012801, U01ES019435, U01ES019453, U01ES019454, U01ES019457, and by R827039, P01ES009584, P30ES006096, P30ES023515 from the National Institute of Environmental Health Sciences (NIEHS), the National Cancer Institute (NCI), EPA, NIH, DHHS, CSTA-UL1RR029887, NYS Empire Clinical Research Investigator Program, Pediatric Environmental Health Fellowship

Acknowledgments

We gratefully acknowledge our collaborators at the centers involved in this research including Jessica Montana, Nancy Mervish, Cheryl Stein, Rochelle Osborne, Lisa Boguski, Joel Forman, and Barbara Brenner (MSSM); Gayle Greenberg, Peggy Monroe, Bob Bornschein (Cincinnati); Robert Hiatt, Louise Greenspan, Julie Deardorff, Janice Barlow (Kaiser Permanente). We also thank Daniel L. Parker, Amber Bishop, Ella Samandar, Jim Preau and Tao Jia for measurement of the environmental biomarkers.

References (47)

  • M. Lorber et al.

    Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)

    Environ. Int.

    (2013)
  • N. Mervish et al.

    Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004–2007

    Environ. Res.

    (2014)
  • S.Y. Euling et al.

    Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings

    Pediatrics

    (2008)
  • R.L. Rosenfield et al.

    Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index

    Pediatrics

    (2009)
  • S.M. van den Berg et al.

    The familial clustering of age at menarche in extended twin families

    Behav. Genet.

    (2007)
  • G. Schoeters et al.

    Endocrine disruptors and abnormalities of pubertal development

    Basic Clin. Pharmacol. Toxicol.

    (2008)
  • M.S. Wolff

    Endocrine disruptors: challenges for environmental research in the 21st century

    Ann. N. Y. Acad. Sci.

    (2006)
  • E. Diamanti-Kandarakis et al.

    Endocrine-disrupting chemicals: an Endocrine Society scientific statement

    Endocr. Rev.

    (2009)
  • F.M. Biro et al.

    Pubertal assessment methods and baseline characteristics in a mixed longitudinal study of girls

    Pediatrics

    (2010)
  • CDC

    200 CDC Growth Charts: United States

    (2000)
  • M.S. Wolff et al.

    Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls

    Environ. Health Perspect.

    (2010)
  • M.S. Wolff et al.

    Phthalate exposure and pubertal development in a longitudinal study of US girls

    Hum. Reprod.

    (2014)
  • N.A. Mervish et al.

    Thyroid antagonists (Perchlorate, thiocyanate, and nitrate) and childhood growth in a longitudinal study of U.S. girls

    Environ. Health Perspect.

    (2015)
  • Cited by (56)

    • Personal care products and cosmetics

      2022, Reproductive and Developmental Toxicology
    • Concentrations of urinary parabens and reproductive hormones in girls 6–17 years living in Canada

      2021, International Journal of Hygiene and Environmental Health
      Citation Excerpt :

      Only a handful of human studies have examined the association between paraben exposure and reproductive development, and most have reported no association. A longitudinal cohort of girls living in the U.S. showed that urinary parabens at 6–8 years old were not associated with age at breast or pubic hair development (Wolff et al., 2015) or age at menarche (Wolff et al., 2017). Another longitudinal cohort, conducted in Chile, showed that urinary parabens measured prior to the onset of breast development and during adolescence was not associated with the age of menarche (Binder et al., 2018).

    View all citing articles on Scopus
    View full text