Invited Perspective: PFAS and Pubertal Timing in Girls—A Maturing Literature

In a downward global trend in timing of maturation, today’s children are reaching pubertal milestones earlier than prior generations.^1,2 The average age at onset of breast development (thelarche), for example, has dropped by 3 months per decade since the 1970s,² likely owing to higher energy intake and more sedentary lifestyles.^3,4 How do environmental pollutants, particularly those that disrupt the gonadal and adrenal hormone axes that regulate puberty, fit in? Although it may be convenient to speculate that the increasing production of synthetic endocrine-disrupting chemicals (EDCs) around the world has fueled the secular trend in pubertal timing, the reality is, of course, more complicated.⁵

Per- and polyfluoroalkyl substances (PFAS), a class of forever chemicals, are of particular concern in this context given their reproductive and developmental toxicity, their widespread use in industrial applications and consumer products, and their resistance to environmental and biological degradation.⁶ Data from the National Health and Nutrition Examination Survey indicate nearly 100% of Americans have measurable blood levels of PFAS, with exposure typically occurring through contaminated water and food, as well as via consumer products.^7,8 To date, results of epidemiological studies examining the impact of PFAS on pubertal outcomes have been inconsistent, likely owing to methodological differences and challenges.^9–12

Among those challenges is the variable timing of pubertal milestones, leading to mistiming of exposure and outcome assessment in some participants.^9,12 The widespread reliance on self- or parent-reported assessment of pubertal development, rather than gold-standard Tanner staging by a trained professional, can additionally introduce outcome misclassification and obscure true associations.^13,14 Finally, there remains controversy regarding the role of body size as a potential mediator in the association between PFAS and pubertal development; adjustment for body mass index (BMI) as a potential confounder may result in overadjustment bias.

In this issue, Pinney et al.¹⁵ overcome limitations and advance the field through a carefully and intentionally designed longitudinal study developed as part of the larger Breast Cancer and the Environmental Research Program.^16,17 PFAS were measured in middle childhood (6–8 years of age) reducing concerns regarding “late age at entry” that have hindered prior studies. Participants were followed through annual or semiannual visits, including comprehensive assessments of pubertal outcomes by trained examiners using gold-standard methods in addition to measurement of pubertal hormones. Sophisticated statistical approaches were used to estimate ages at thelarche and pubarche (first appearance of pubic hair) based on pubertal changes occurring between regular visits, thereby minimizing error in outcome timing,¹⁸ and mediation analyses were conducted to understand the role of BMI.

These considerable methodological advances make for the most rigorous analysis on this topic to date, and results indicated that girls with higher baseline perfluorooctanoic acid (PFOA) concentrations were significantly less likely to have reached pubarche and menarche (first occurrence of menstruation) by the end of follow-up, with similar patterns observed for perfluorooctane sulfonate (PFOS). PFOA concentrations 6 months prior to thelarche were additionally inversely associated with concentrations of the circulating hormones estrone and dehydoepiandrosterone sulfate, suggesting endocrine pathways through which PFAS exposures may delay puberty. The authors identified a “triangular relationship” between PFAS, BMI, and pubertal timing, moreover, such that PFOA was a significant predictor of lower BMI, as well as of later pubertal milestones, whereas higher BMI independently predicted earlier pubertal milestones. These results both complement and contrast with studies showing that prenatal PFAS exposures were associated with reduced fetal growth and birth weight followed by greater childhood adiposity.^19,20

Ultimately, the results of the study by Pinney et al. require deep reflection. Concerns about the acceleration of pubertal development in the modern era have been fueled by reports of the negative consequences of early pubertal development, including increased risks of cardiometabolic disease (reviewed by Prentice and Viner²¹) and reproductive cancers,^22–24 as well as mental health and behavioral concerns.^25–27 By contrast, far fewer studies have considered the implications of delayed pubertal development. Although delays in pubertal timing may have benefits in terms of reductions in risks of hormone-sensitive cancers,²⁸ there may also be adverse impacts on bone density and microstructure.²⁹ Furthermore, some seemingly protective impacts of delayed maturation may be limited; for instance, one study reported U-shaped associations between age at menarche and risks of coronary heart disease, whereby risks were highest in both early and late maturers.³⁰

The work by Pinney et al. improves upon key limitations of the prior literature and provides strong evidence that PFAS exposure in mid to late childhood is associated with delays in pubertal milestones. These compelling results, of course, lead to more questions in urgent need of answers. A clear next step is to query how exposures to mixtures of PFAS—as a class of compounds, as well as in combination with other classes of EDCs—impact pubertal milestones. How do PFAS, moreover, interact with dietary factors that can be both a source of exposure and independent predictors of body size and pubertal development? In addition, the critical and sensitive windows during which PFAS exposures are most impactful remain uncertain, and evaluating the contributions of exposures during multiple critical windows (a so-called “two hit” approach) is warranted.^31,32 Last, the landscape of PFAS contamination is evolving, with average blood levels of legacy PFAS (including PFOA and PFOS) declining even as a new generation of replacement PFAS is on the rise.^33,34 Unfortunately, precious little is known about the human health impacts of these newer contaminants. This important study reinforces the urgency of better understanding the impacts of these “forever chemicals” on child and adolescent health.

Refers to https://doi.org/10.1289/EHP11811