Issue 46 – Winter 2019

Stefano Cianfarani considers the complex effects of environmental factors on the timing of puberty.

Definition and implications The European Commission’s current definition of an endocrine disruptor (ED) is ‘an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations’. This includes a broad range of effects potentially affecting all endocrine functions. EDs interfere with the endocrine physiology at multiple target sites, from hormone secretion and transport to receptor binding and signalling. Although genetic factors account for 50–80% of the variance of age at puberty, the impact of environmental factors on pubertal timing has recently been proposed. The sensitivity to environmental cues is particularly high in specific critical periods characterised by biological plasticity, which ensures that the organism assumes the appropriate features to match the surrounding environment. Fetal and early postnatal life are classically considered the time windows with the maximum adaptation capacity. Exposure to adverse environmental cues, such as EDs, during critical periods of development can permanently programme pubertal timing and long term fertility. Evidence in animals Several animal studies suggest that environmental factors may interfere with pubertal timing by inducing biochemical, genetic and epigenetic changes. There is robust evidence in animals showing a close relationship between alterations of puberty and exposure to EDs, such as dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), phthalates, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Most EDs act as oestrogen and androgen agonists or antagonists, ultimately leading to a central (neuroendocrine) or peripheral disruption of the hypothalamus-pituitary gonadal axis. The results obtained in animals are, however, conflicting, showing normal, early and late initiation of puberty induced by the same ED in the same species. Furthermore, the findings from animal models can hardly be applied to humans, as the dynamics of puberty is species-specific and experimental data are obtained from exposure to one single ED. This is not the case in humans, who are exposed to a mixture containing multiple EDs at the same time Evidence in humans The report on the consequences of the accidental contamination of the Michigan food chain with polybrominated biphenyls (PBBs) in 1973 was a milestone in understanding the epidemiology of ED effects in human beings. In this report, an earlier age at menarche was observed in breastfed girls exposed to high levels of PBB in utero. Other observational studies have often, but not always, confirmed the association between exposure to EDs and alterations in pubertal timing. For instance, an outbreak of premature thelarche and ovarian cysts in Puerto Rico (1990−1995) was associated with exposure to phthalates and brominated flame retardants. Higher urinary concentrations of 2,5-dichlorophenol were associated with an earlier onset of menarche (by 7 months), whereas urinary levels of mono-3- carboxypropyl phthalate (MCPP) were associated with a 4- to 5-month greater age at both thelarche and menarche in a cohort of 1051 girls followed longitudinally. A number of case−control studies have been conducted, yielding conflicting results. Higher serum concentrations of PBDE have been reported in girls with premature thelarche but not in girls with precocious puberty. Overall, the prevailing opinion, stemming from early observational studies, is that exposure to EDs induces an advancement in female pubertal timing. However, recent evidence indicates that both boys and girls may experience alterations in pubertal timing, with early initiation but delayed completion of puberty. Conclusions Although EDs may interfere with several biological processes, including puberty, a number of factors affect the interpretation of data. (1) Each individual is exposed to many different EDs from conception to old age and always to a mixture rather than to a single substance. (2) The effects are often not dose-dependent and even exposure to ‘negligible’ doses of chemicals may be disrupting. (3) The effects are species-specific, making it impossible to reliably infer the biological consequences from observations of what occurs in wildlife to human beings. (4) Effects are age- and sex-dependent. (5) EDs may have transgenerational effects, probably due to epigenetic changes that transmit ED effects to subsequent generations even in the absence of direct exposure. Stefano Cianfarani Bambino Gesù Children’s Hospital, Tor Vergata University, Rome, Italy, and Karolinska Institutet and University Hospital, Stockholm, Sweden