Invited Perspective: Metals and Menarche

Menarche marks the start of the reproductive life span and has implications for chronic disease and mortality. Earlier age at menarche is a recognized risk factor for breast cancer.1,2 Mortality and cardiovascular disease have also been associated with age at menarche.3 Age at menarche has decreased globally over the last several decades4–9; these temporal changes underscore the likely influence of environmental factors, such as endocrine disrupting chemicals.10 Metals may also act as endocrine disruptors.11 In this issue of Environmental Health Perspectives, Malin Igra et al. have advanced the understanding of how three nonessential metals— cadmium, lead, and arsenic—potentially affect menarche in a longitudinal cohort with the measurement of those metals during fetal development and at 5 and 10 years of age.12 The main study finding of later age at menarche being associated with maternal blood arsenic during pregnancy is notable.12 Evidence of arsenic’s influence on menarche and pubertal markers is lacking in prospective epidemiologic studies, apart from an earlier finding of delayed menarche with increased in utero exposure to arsenic reported from this mother–child cohort in rural Bangladesh,13 underscoring the need for further prospective research on this toxic metal with widespread exposure. A body of ecologic and experimental evidence suggests that arsenic exposure may delay menarche.14–19 This evidence supports the findings by Malin Igra et al. of prenatal arsenic exposure with later age at menarche.12 Of note, urinary arsenic in childhood was not associated with age at menarche. This suggests that arsenic exposure in utero, a critical period of development, but not later life levels, can influence timing of menarche. Cadmium, too, was associated with later age at menarche but only for childhood exposures. This is in line with a few studies on this topic20,21 although the evidence is mixed.22 The variety of methodological approaches makes comparisons of these studies challenging. Longitudinal studies with multiple individual exposure biomarkers of metals are needed to confirm these findings by Malin Igra et al.12 Other studies have reported that blood iron is inversely associated with cadmium exposure.23–25 This may help explain why cadmium exposure later in childhood, but not in utero, was associated with later menarche given that in utero cadmium exposure was attenuated by iron supplementation.23–25 There is limited evidence of lead’s effect on menarche. Although Malin Igra et al. reported no association between lead and menarche, the point estimates consistently indicated earlier menarche during childhood.12 Evidence for an association is mixed.26–28 Again, the lack of consistency of these findings and the various approaches to lead measurement—in bone, blood, and urine—underscore the need for further studies on this topic with consistent exposure measurement approaches. The study byMalin Igra et al.12 advances thefield in several important ways. The longitudinal design hadmultiple exposuremeasurements (one prenatal and twice in childhood), a key strength. This captures exposure at critical stages of development in the life course. Of note, the childhood biomarkers of different urinary metals reflect exposure over different time periods, depending on the metal. Urinary cadmium reflects long-term exposure, on the order of years.29 In contrast, urinary lead and arsenic reflect short-term exposure, on the order of days or weeks.30 Although this study is an important contribution, some important gaps should be addressed in future work in metals and pubertal development. Because of the time span of follow-up in this cohort, participants were <14 years of age. However, clinically delayed menarche is considered the absence of menses after 15 years of age31; therefore, additional follow-up is warranted. This study also had some variability around the preparation of maternal biospecimens. The method for maternal erythrocyte preparation differed for the 34.8% of the samples that had acid digestion instead of alkali dilution prior to inductively coupled plasma mass spectrometry (ICP-MS). 12 Values for samples prepared using acid digestion were consistently lower than for samples prepared via alkali dilution, although samples prepared by these two methods were highly correlated in another cohort.32 In addition, correlated exposures that differ from the true exposure of interest introduce a source of measurement error from the true exposure.33,34 The correction approach applied here is helpful. However, an additional approach that excludes the one-third of samples prepared via acid digestion method would have better evaluated how this correction may have influenced the findings. Finally, additionalmetals exposure followingmenarchemay come from the use ofmenstrual products, an important and understudied exposure route for menstruators.35,36 The analysis by Malin Igra et al. evaluated how specific time points in development and metal concentrations differed by age. There was moderate correlation between urine concentration of cadmium at 5 and 10 years of age (rho= 0:40) but weaker correlation with maternal erythrocyte cadmium (rho= 0:10). Urine concentrations of lead at 5 years of age was approximately double the concentrations at 10 years of age.12 Future studies should evaluate the trajectory of exposure over time using longitudinal methods that appropriately address correlated measures over time. One recent study implemented a longitudinal approach incorporating multiple exposure measures to metals in relation to menarche and pubertal measures.37 Measurement of lead using blood or bone also should be a priority in children because these tissues better reflect childhood lead exposure compared with urine.38 Consideration of linear associations or splines for nonlinear approaches should be considered in future studies. In addition, exposures do not occur in isolation, so future studies should evaluate exposure mixtures.39–41 Considering the role that societal factors contribute along with environmental exposures is key.42 In particular, social norms can influence exposure to beauty products, which contain metals and other chemicals.43–45 Leveraging pregnancy cohort studies with follow-up of children Address correspondence to Anna Z. Pollack, 4400 University Dr., MS5B7, Fairfax, VA 22030 USA. Email: Apollac2@gmu.edu The authors declare they have nothing to disclose. Received 7 December 2022; Revised 3 January 2023; Accepted 4 January 2023; Published 2 February 2023. Note to readers with disabilities: EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact ehpsubmissions@niehs.nih. gov. Our staff will work with you to assess and meet your accessibility needs within 3 working days.