Over the last decades, the onset of puberty in girls has occurred earlier, but the tempo of pubertal progression has been relatively slower, resulting in a younger age at puberty onset without a change in age at menarche. Sufficient energy availability and adiposity contribute to early pubertal development, and environmental factors, such as endocrine-disrupting chemicals (EDCs), may affect not only the control of energy balance, but also puberty and reproduction. EDCs are hormonally active substances that can perturb puberty by acting both peripherally on target organs, such as adipose tissue or adrenal glands, and/or centrally on the hypothalamic-pituitary-gonadal (HPG) axis. Depending on whether the exposure takes place earlier during fetal and neonatal life or later during early childhood, EDCs can lead to different outcomes through different mechanisms. Evidence of associations between exposures to EDCs and altered pubertal timing makes it reasonable to support their relationship. However, human epidemiologic data are limited or inconsistent and cannot provide sufficient evidence for a causal relationship between EDC exposure and changes in pubertal timing. Further investigation is warranted to determine the overall or different effects of EDCs exposure during prenatal or childhood windows on pubertal milestones and to reveal the underlying mechanisms, including epigenetic marks, whereby early-life exposure to EDCs affect the HPG-peripheral tissue axis.
Puberty begins with the release of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator from central nervous system inhibition after a quiescent period during childhood [1]. The age of menarche has definitely decreased from 16 years in the 1800s to 13 years in the 1960s, after which this downward trend seems to have slowed or even stopped [2]. The trend for earlier age at menarche has also been reported in Korea, from 16.6 years for females born between 1925 and 1929 to 12.6 years for females born between 1990 and 1994 [3,4]. While the onset of puberty has been occurring earlier, the overall tempo of pubertal progression is reported to be relatively slower, resulting in skewing towards younger ages for the onset of puberty and towards older ages for the completion of puberty [2]. Such increased duration of the pubertal transition may result from gonadotropin-independent estrogenic action at the level of the breast which may originate from peripheral tissues [5].
Although genetic factors remain the major determinant of pubertal timing [6], the secular trend for earlier onset of puberty has coincided with improved public health and nutrition [7-9]. Sufficient energy availability and early adiposity rebound contribute to early pubertal development. Endocrine-disrupting chemicals (EDCs) may affect not only the control of energy balance and adiposity, but also puberty and reproduction [2]. EDCs can act at any level in the 'hypothalamic-pituitary-gonadal (HPG)-peripheral tissues' axis [10]. Their effects can manifest right before puberty as well as much earlier, during fetal and neonatal life [2]. We reviewed the genetic and environmental factors that have been implicated in pubertal timing. We present the current evidence for the roles of EDCs on pubertal timing in girls based on human epidemiologic data and introduce potential mechanisms depending on the timing of exposure.
Factors implicated in pubertal timing by affecting the hypothalamic-pituitary-gonadal-peripheral tissues axis
Pubertal onset appears to be a highly heritable trait, but earlier sexual maturation in girls may be linked to environmental factors. Some genes implicated in precocious puberty (DLK1, MKRN3, and KISS1) and in delayed puberty (TACR3) are associated with variations in pubertal onset. The childhood GnRH pulse generator may be inhibited, in part, by MKRN3. Disinhibition of the HPG axis leads to the progressive amplification of pulsatile GnRH secretion which may be mediated by leptin levels and increased expression of neuropeptides, such as neurokinin B and kisspeptin, and their receptors [1]. In addition to central signals, peripheral metabolic and nutritional signals, such as leptin and insulin, play a permissive role in the proper function of the HPG axis [11].
Genes involved in pubertal timing or menarche reported by Elks et al. [12] and Perry et al. [13] include those related to hypothalamic GnRH secretion, pituitary development and function, hormone synthesis and bioactivity, energy homeostasis and growth, and potential peripheral feedback from sex steroids [13]. The overlap of genes involved in pubertal onset and obesity from genome wide association studies and human epidemiological data suggests a common pathway connecting early infancy weight gain, earlier pubertal onset, and later obesity in adulthood, although mechanisms whereby early-life changes in adiposity affect growth acceleration and early pubertal onset remain to be determined [14,15].
Obese girls are at risk for early pubertal development. Girls maturing at earlier ages have higher body mass index (BMI) z-scores with advanced Tanner stages [16]. Obesity-induced hyperinsulinemia and hyperleptinemia can affect linear growth and advance puberty [17]. Since adrenarche starts earlier as childhood BMI and insulin levels gradually increase, the increased adrenal androgen levels in obese children may also be responsible for accelerated growth before puberty [17]. In addition, hyperinsulinemia can increase sex steroid bioavailability via stimulation of ovarian growth and steroidogenesis, reduction of sex hormone binding globulin, and increased conversion of androgens to estrogens by stimulating aromatase activity in adipose tissues [2]. Breast development can occur from the gonadotropin-independent release of estrogen by peripheral tissues, such as the adrenal glands and adipose tissue. Finally, increased sex steroid levels in obese girls can induce gonadotropin-independent or dependent precocious puberty.
Gene-to-environment interactions during critical periods of development could alter gene expression in the HPG-peripheral tissue axis through epigenetic mechanisms [18]. While recent data have started to reveal the epigenetic regulation of KISS1 expression [18,19], epigenetic mechanisms that affect the HPG-peripheral tissue axis remain to be discovered. The intrauterine environment, birth size, nutrition, and (potentially) EDCs can affect adiposity and the timing of puberty. EDCs and adiposity may be the most concerning contributors to changes in puberty and reproduction. While sufficient energy availability provides clues to the mechanism of early pubertal development, changes in the control of both energy balance and reproduction may vary under the influence of common determinants, such as EDCs. These effects can manifest right before puberty as well as much earlier during fetal and neonatal life [20,21]. Although the link between EDCs and pubertal timing does not prove causality, their association is highly suggestive [22].
Possible mechanisms for the effect of EDCs on pubertal timing in girls
EDCs are defined as "an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action" by the Endocrine Society’s second scientific statement published in 2015 [10]. Endocrine disruptors can be naturally occurring or synthetic. This section reviews the effects of synthetic EDCs on pubertal timing in girls.
EDCs can act through several mechanisms at any level in the 'HPG-peripheral tissues' endocrine axis. Directly, EDCs may affect genes or HPG pathways unique to puberty. Indirectly, EDCs can act as obesogens and change metabolic programming during fetal and early childhood development, resulting in alterations in the metabolic and peripheral hormones associated with the onset of puberty [15]. A variety of chemical toxins that are ubiquitously present in our environment exert antagonistic and agonistic actions on hormonal axes and pathways at low versus high concentrations, and they demonstrate nonmonotonic dose-response curves [10]. Since many EDCs can act as agonists of estrogen receptors (ERs) or antagonists of androgen receptors (ARs), EDCs may mimic naturally occurring estrogens and androgens. In addition, EDCs might bind to a receptor within a cell and block the functions of endogenous hormones, thus acting as antiestrogens and antiandrogens [10,23].
Low-level exposures to a mixture of EDCs may mask the effect of an individual compound. Moreover, interindividual and interspecies variation in susceptibility may be present due to differences in pharmacokinetics and/or genetic polymorphisms in key genes, complicating our ability to translate data from animal studies to human health [20]. In humans, the long interval from exposure to endpoints (latent effects) and the setting of mixed exposures over a lifetime make it difficult to analyze the health outcomes of EDCs [20]. Furthermore, it is difficult to distinguish the influence of nutrition and adiposity on pubertal outcomes from that of EDCs. Since the prenatal, neonatal, infancy, early childhood and peripubertal periods are critical windows of development, EDCs may have different effects depending on the time of exposure [2]. Though the mechanisms whereby fetal or neonatal life changes pubertal timing have not been fully elucidated, EDCs can alter the genes involved in the modification of epigenetic marks [2,15]. Although researching the effect of EDCs on pubertal timing is difficult for the various aforementioned reasons, further investigation is warranted to determine which EDCs can affect pubertal timing, which periods of exposure are critical, and how different mechanisms are involved depending on the timing of exposure in humans [24].
Human epidemiologic data on EDCs in regards to pubertal timing in girls
The Endocrine Society's Scientific Statements present a review of the literature on human studies that assessed the associations between EDCs exposure and pubertal timing [10]. There have been extensive reviews about the contribution of EDCs on shifts in pubertal timing [2,10,24,25] as well as a recent review of publications from 2016 to 2017 that examined EDC associations with pubertal milestones [26]. The EDCs most extensively studied in regards to puberty include bisphenol A (BPA), phthalate esters, pesticides (dichlorodiphenyl trichloroethane [DDT], pyrethroids), dioxins and polychlorinated biphenyls (PCBs), and flame retardants (polybrominated biphenyls [PBB], polybrominated diphenyl ethers [PBDEs]) (Table 1). This section reviews the human epidemiologic studies regarding the relationship of individual EDCs with pubertal development or menarche in girls.
Bisphenol A
BPA is used in polycarbonate plastics, plastic bottles and toys, epoxy resins, dental sealants, and linings of food cans and has a half-life of 4 to 5 hours [27]. BPA has weak ER agonist activity at lower concentrations but can also compete with endogenous estrogens for binding, and they have antiandrogenic properties at higher concentrations [28]. Epidemiological studies on BPA and puberty have produced inconsistent results (Table 2) [29-51]. Serum or urinary BPA concentrations were significantly associated with premature thelarche [39,51], precocious puberty [32,37,44,50], and earlier pubertal development [48]. However, other studies have reported no significant relationship [29-31,33-36,38,40-43,47] or later onset of puberty or menarche [45,46,49]. Although most previous studies for BPA and pubertal milestones were limited by cross-sectional or case-control study designs, 6 longitudinal studies have been reported [33,41,45,47-49]. Early childhood exposure to BPA showed no relationship to pubertal timing [33,41,47] or late onset of puberty [45]. Prenatal exposure was associated with earlier thelarche [48], but rather later thelarche, pubarche, and menarche [49]. Recently in 2017, a critical review on the effect of BPA on puberty [52] concluded that the current available data cannot establish a clear role for BPA in pubertal development due to conflicting results among the clinical and epidemiological studies examined.
Phthalates
Phthalates are used as liquid plasticizers in plastics and flooring, personal care products, medical devices and tubing with half-lives of 12 hours. Although the mechanism remains to be further elucidated, phthalates might act as ER agonists or AR antagonists and may also interfere with androgen synthesis [53]. Phthalates may be classified into low-molecular-weight phthalates (ester side-chain lengths, 1 to 4 carbons) and high-molecular-weight-phthalates (ester side-chain lengths, 5 or more carbons). Di(2-ethylhexyl) phthalate (DEHP) metabolites (mono(2-ethyl-5-oxohexyl) phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate), which are classified into high-molecular-weight-metabolites, were the phthalates most commonly studied.
The results from studies regarding the relationship between phthalate and puberty in girls conflict depending on the timing of exposure and/or different phthalate metabolites (Table 2) [31,33,34,36,42,45,47-49,54-65]. Different studies have shown significant associations with premature thelarche [54,56] and precocious or early puberty [31,36,42,55,58,61,62,64,65], while no relationship with puberty [34,57,59] or an association with later onset of puberty [45,47-49,60] have also been reported. Among several studies on phthalate exposure, nine studies had a longitudinal cohort design [33,45,47-49,59-61,63]. Prenatal exposure to high-molecular-weight phthalate metabolites was associated with later onset of puberty [48]. Early childhood exposure to phthalate metabolites was not associated to puberty [59] or associated with earlier [61] or later [45,47,49,60] pubertal progression. Meanwhile, differences in pubertal development or age at menarche has been reported depending on the timing of exposure or classes of exposures (high or low-molecular-weight-phthalates) [33,63]. Whereas high-molecular-weight phthalate levels were associated with later pubic hair development, low-molecular-weight phthalate levels were related to advanced breast or pubic hair development [33]. While prepubertal exposure to DEHP was associated with later menarche, pubertal exposure to monomethyl phthalate (low-molecular-weight) was related to earlier menarche only among overweight or obese girls and not among those that were of normal weight [63].
Pesticides
Pesticides are substances used to kill or reduce the quantity of insects, weeds, rodents, or fungi. They are classified as insecticides, herbicides, fungicides, and rodenticides depending on their target. While over 100 pesticides are identified as EDCs, DDT and its metabolite dichlorodiphenyl dichloroethane (DDE) are the most extensively studied compounds [66]. DDT/DDE have estrogenic, antiandrogenic, and antiprogestin effects [67]. DDT is a persistent organic pollutant with a half-life of 6–10 years. Although many, but not all, countries have banned organochlorine pesticides, it is insoluble in water and very persistent in the environment [68,69]. The results of human studies on the relationship between DDT exposure and puberty are inconsistent (Table 3) [30,70-78]; results have ranged from no relation to puberty [30,72,73,75,78] to associations with precocious puberty [74], earlier age at menarche [70,71], and later onset of puberty [76,77]. Three longitudinal studies have revealed that higher exposure to DDE prenatally was associated with early onset of puberty [70] or no relation to puberty [78], whereas higher exposure in childhood was related to later onset of puberty [76].
Pyrethroids are the most commonly used residential insecticides, having replaced some of the agricultural use of organophosphorus and carbamate insecticides. Pyrethroids are quickly metabolized and eliminated through the kidneys in humans, and their half-life is less than 10 hours [79]. The most frequently utilized pyrethroid biomarker is 3-phenoxyboenzoic acid, and it has been reported as weakly androgenic [80]. One cross-sectional study [81] reported an association between pyrethroids exposure and later onset of puberty in girls.
Dioxins and PCBs
Dioxins are byproducts of manufacturing processes, including smelting, bleaching of paper pulp, and the manufacturing of herbicides and pesticides. The chemical name for dioxin is 2,3,7,8-tetrachlorodibenzo para dioxin (TCDD). The name "Dioxins" is often used in chemically and structurally similar compounds, such as polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzo furans. Dioxins are known to have estrogenic and antiandrogenic activities, and their half-life is 7–11 years in the body [82]. In addition, PCBs also constitute a group of these polychlorinated aromatic hydrocarbons and have similar toxic properties with dioxin. PCBs have estrogenic and antiandrogenic effects [83], and the maximum elimination half-life for PCBs is approximately 10–15 years [84]. The few studies on the relevance of dioxins/PCBs to puberty (Table 3) [70,72,73,76,85-87] have shown inconsistent and limited data. They have shown a positive association with early onset of menarche [72] as well as with delayed pubertal development [73,85]. Two longitudinal cohort studies have reported different outcomes: one study reported no association between prenatal PCBs exposure and menarcheal age [70], while the other reported a significant correlation between prenatal PCDD/Fs exposure and delayed breast development [87]. Other prospective studies on childhood TCDD exposure have reported no associations with pubertal development [76] or the onset of menarche [86].
Polybrominated flame retardants
Flame retardants refer to a variety of substances that are added to materials to prevent the start and growth of fires. With approximate half-lives of 2–7 days, they are used in many products, such as furniture, mattresses, carpets, and flame-retardant textiles [88]. Polybrominated flame retardants include compounds such as PBDEs, PBB, and so on [88]. Estrogenic and anti androgenic activities have been reported with exposure to these compounds [89]. To date, there have been limited studies on pubertal timing, with inconsistent results that depend on the timing of exposure (Table 3) [76,87,90-93]. The limited studies have shown positive associations with premature thelarche [92], earlier pubertal development [90], and age at menarche [91], although associations with later onset of puberty [76,93] or no association [87] have also been reported. Three prospective studies have reported contrasting outcomes in which prenatal PBB/PBDE exposures showed no association [87] or associations with both earlier [90] and later [93] pubertal timing. Another prospective study reported an association between childhood PBDE exposure and later onset of puberty [76].
Revised paradigm of EDCs on pubertal timing and future directions
Parent et al. [2] suggested a revised paradigm of EDCs on pubertal timing. Since improvements in public health and nutrition have paralleled a downward trend in pubertal timing and menarche, environmental factors are the predominant determinants in pubertal timing. Classically, environmental factors, including EDCs, might advance pubertal timing via central mechanisms, particularly during the prepubertal period. According to the revised paradigm [2], environmental factors can influence puberty and reproduction through not only central but also peripheral mechanisms, depending on whether they take place early during fetal and neonatal life or late during the prepubertal period. Environmental factors can affect energy availability during the fetal and neonatal period or in infancy and early childhood. They can also act as obesogens and promote early adiposity rebound, leading to changes in metabolic or peripheral signals and increases in adrenal androgen levels, with subsequent early pubertal development. Environmental factors, including EDCs, might affect genetic or epigenetic pathways during critical windows of development. Further investigation is warranted in order to reveal the underlying mechanisms whereby early-life exposure to EDCs affects the HPG-peripheral tissue axis.
Conclusion
The onset of puberty in girls is occurring earlier, without changes in the timing of completion of puberty. Physiological variability and multiple other factors affect the initiation of puberty. Exposure to a broad mixture of EDCs is ubiquitous, and the shifts in pubertal timing may be mediated by exposures to EDCs at critical developmental windows. EDCs are hormonally active substances that can act via several mechanisms to perturb puberty either peripherally on target organs (adipose tissue or adrenal glands) or centrally via the HPG axis. EDCs can influence pubertal timing through different mechanisms depending on when the exposure occurs during early-life. Evidence for associations between exposures of EDCs and altered pubertal timing makes it reasonable to support the hypothesis that a relationship between EDCs and pubertal timing exists. However, the current data is insufficient and conflicting to provide sufficient evidence for a causal relationship between EDCs exposure and changes in pubertal timing in humans. Further human epidemiologic studies of prospective and longitudinal design are needed to determine the combined effect of EDC exposure on puberty and reproduction during critical periods. In addition, the underlying mechanisms whereby early-life exposures to EDCs influence puberty, including epigenetic marks, need to be explored in further studies.
Conflict of interest No potential conflict of interest relevant to this article was reported.
This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2018R1D1A1B07049806).
ReferencesAbreuAPKaiserUBPubertal development and regulation2016425464ParentASFranssenDFudvoyeJGérardABourguignonJPDevelopmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents2015381236hnJHLimSWSongBSSeoJLeeJAKimDHAge at menarche in the Korean female: secular trends and relationship to adulthood body mass index201318604ChoGJParkHTShinJHHurJYKimYTKimSHAge at menarche in a Korean population: secular trends and influencing factors20101698994AksglaedeLSørensenKPetersenJHSkakkebaekNEJuulARecent decline in age at breast development: the Copenhagen Puberty Study2009123e9329ZhuJKusaTOChanYMGenetics of pubertal timing20183053240BiroFMKhouryPMorrisonJAInfluence of obesity on timing of puberty2006292727; discussion 286-90ChengGBuykenAEShiLKaraolis-DanckertNKrokeAWudySABeyond overweight: nutrition as an important lifestyle factor influencing timing of puberty20127013352DungerDBAhmedMLOngKKEarly and late weight gain and the timing of puberty2006254-2551405GoreACChappellVAFentonSEFlawsJANadalAPrinsGSEDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals201536E1E150FrischRERevelleRHeight and weight at menarche and a hypothesis of critical body weights and adolescent events19701693979ElksCEPerryJRSulemPChasmanDIFranceschiniNHeCThirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies201042107785PerryJRDayFElksCESulemPThompsonDJFerreiraTParent-of-origin-specific allelic associations among 106 genomic loci for age at menarche2014514927WillemsenRHDungerDBNormal variation in pubertal timing: genetic determinants in relation to growth and adiposity2016291735RothCLDiVallSConsequences of early life programing by genetic and environmental influences: a synthesis regarding pubertal Timing20162913452KaplowitzPBSloraEJWassermanRCPedlowSEHerman-GiddensMEEarlier onset of puberty in girls: relation to increased body mass index and race200110834753ShalitinSKiessWPutative Effects of Obesity on Linear Growth and Puberty20178810110LomnicziALocheACastellanoJMRonnekleivOKBoschMKaidarGEpigenetic control of female puberty2013162819VazquezMJToroCACastellanoJMRuiz-PinoFRoaJBeiroaDSIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression201894194ParentASFranssenDFudvoyeJPinsonABourguignonJPCurrent changes in pubertal timing: revised vision in relation with environmental factors including endocrine disruptors20162917484ParentASTeilmannGJuulASkakkebaekNEToppariJBourguignonJPThe timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration20032466893EulingSYSelevanSGPescovitzOHSkakkebaekNERole of environmental factors in the timing of puberty2008121 Suppl 3S16771pii: E5. https://doi.org/10.3390/toxics7010005CombarnousYNguyenTMDComparative overview of the mechanisms of action of hormones and endocrine disruptor compounds20197BourguignonJPJuulAFranssenDFudvoyeJPinsonAParentASContribution of the endocrine perspective in the evaluation of endocrine disrupting chemical effects: the case study of pubertal timing20168622132MouritsenAAksglaedeLSørensenKMogensenSSLeffersHMainKMHypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty20103334659GreenspanLCLeeMMEndocrine disrupters and pubertal timing20182514954VölkelWColnotTCsanádyGAFilserJGDekantWMetabolism and kinetics of bisphenol a in humans at low doses following oral administration20021512817WetherillYBAkingbemiBTKannoJMcLachlanJANadalASonnenscheinCIn vitro molecular mechanisms of bisphenol A action20072417898HanEJYimOKChungJBaekSYKimYThe study of relationship between the concentrations of Bisphenol A and DEHP in human plasma and precocious puberty20082137582WolffMSBrittonJABoguskiLHochmanSMaloneyNSerraNEnvironmental exposures and puberty in inner-city girls2008107393400LeeSWLeeWJChaeHWLeeEBKimJHKimDHDetermination of serum Di-(2-ethylhexyl) phthalate and bisphenol A level in children with idiopathic central precocious puberty20091415462QiaoLZhengLCaiDStudy on the levels of the bisphenol A, octylphenol, 4-nonylphenol in serum of precocious girls201039912WolffMSTeitelbaumSLPinneySMWindhamGLiaoLBiroFInvestigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls2010118103946ButtkeDESircarKMartinCExposures to endocrine-disrupting chemicals and age of menarche in adolescent girls in NHANES (2003-2008)201212016138FrederiksenHAksglaedeLSorensenKNielsenOMainKMSkakkebaekNEBisphenol A and other phenols in urine from Danish children and adolescents analyzed by isotope diluted TurboFlow-LC-MS/MS201321671020YumTLeeSKimYAssociation between precocious puberty and some endocrine disruptors in human plasma2013489127DurmazEAşçıAErkekoğluPAkçurinSGümüşelBKBircanIUrinary bisphenol a levels in girls with idiopathic central precocious puberty201461621LeeSHKangSMChoiMHLeeJParkMJKimSHChanges in steroid metabolism among girls with precocious puberty may not be associated with urinary levels of bisphenol A20144416ChenLHShiJRFangYLLiangLChenWQChenXZSerum bisphenol A concentration and premature thelarche in female infants aged 4-month to 2-year2015822214McGuinnLAGhazarianAAJoseph SuLEllisonGLUrinary bisphenol A and age at menarche among adolescent girls: evidence from NHANES 2003-201020151363816WolffMSTeitelbaumSLMcGovernKPinneySMWindhamGCGalvezMEnvironmental phenols and pubertal development in girls20158417480BuluşADAşciAErkekogluPBalciAAndiranNKoçer-GümüşelBThe evaluation of possible role of endocrine disruptors in central and peripheral precocious puberty201626493500ÖzgenİTTorunEBayraktar-TanyeriBDurmazEKılıçECesurYThe relation of urinary bisphenol A with kisspeptin in girls diagnosed with central precocious puberty and premature thelarche20162933741SupornsilchaiVJantaratCNosoognoenWPornkunwilaiSWacharasindhuSSoderOIncreased levels of bisphenol A (BPA) in Thai girls with precocious puberty20162912339Kasper-SonnenbergMWittsiepeJWaldKKochHMWilhelmMPre-pubertal exposure with phthalates and bisphenol A and pubertal development201712e0187922MiaoMWangZLiuXLiangHZhouZTanHUrinary bisphenol A and pubertal development in Chinese school-aged girls: a cross-sectional study20171680WolffMSPajakAPinneySMWindhamGCGalvezMRybakMAssociations of urinary phthalate and phenol biomarkers with menarche in a multiethnic cohort of young girls2017675664WatkinsDJSánchezBNTéllez-RojoMMLeeJMMercado-GarcíaABlank-GoldenbergCPhthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls201715914351BergerKEskenaziBKogutKParraKLustigRHGreenspanLCAssociation of prenatal urinary concentrations of phthalates and bisphenol A and pubertal timing in boys and girls201812697004ChenYWangYDingGTianYZhouZWangXAssociation between bisphenol a exposure and idiopathic central precocious puberty (ICPP) among school-aged girls in Shanghai, China20181154106DurmazEAsciAErkekogluPBalcıABircanIKoçer-GumuselBUrinary bisphenol A levels in Turkish girls with premature thelarche201837100716LeonardiACofiniMRiganteDLucchettiLCipollaCPentaLThe effect of bisphenol A on puberty: a critical review of the medical literature201714BenjaminSMasaiEKamimuraNTakahashiKAndersonRCFaisalPAPhthalates impact human health: epidemiological evidences and plausible mechanism of action201734036083ColónICaroDBourdonyCJRosarioOIdentification of phthalate esters in the serum of young Puerto Rican girls with premature breast development2000108895900QiaoLZhengLCaiDStudy on the di-n-butyl phthalate and di-2-ethylhexyl phthalate level of girl serum related with precocious puberty in Shanghai200736935ChouYYHuangPCLeeCCWuMHLinSJPhthalate exposure in girls during early puberty2009226977FrederiksenHSørensenKMouritsenAAksglaedeLHagenCPPetersenJHHigh urinary phthalate concentration associated with delayed pubarche in girls20123521626ChenCYChouYYWuYMLinCCLinSJLeeCCPhthalates may promote female puberty by increasing kisspeptin activity201328276573MouritsenAFrederiksenHSørensenKAksglaedeLHagenCSkakkebaekNEUrinary phthalates from 168 girls and boys measured twice a year during a 5-year period: associations with adrenal androgen levels and puberty201398375564WolffMSTeitelbaumSLMcGovernKWindhamGCPinneySMGalvezMPhthalate exposure and pubertal development in a longitudinal study of US girls201429155866ZhangYCaoYShiHJiangXZhaoYFangXCould exposure to phthalates speed up or delay pubertal onset and development? A 1.5-year follow-up of a school-based population201583419SrilanchakonKThadsriTJantaratCThengyaiSNosoognoenWSupornsilchaiVHigher phthalate concentrations are associated with precocious puberty in normal weight Thai girls20173012938BinderAMCorvalanCCalafatAMYeXMericqVPereiraAChildhood and adolescent phenol and phthalate exposure and the age of menarche in Latina girls20181732DurmazEErkekogluPAsciAAkçurinSBircanİKocer-GumuselBUrinary phthalate metabolite concentrations in girls with premature thelarche20185917281HashemipourMKelishadiRAminMMEbrahimKIs there any association between phthalate exposure and precocious puberty in girls?2018251358996MnifWHassineAIBouazizABartegiAThomasORoigBEffect of endocrine disruptor pesticides: a review201182265303CrellinNKRodwayMRSwanCLGillio-MeinaCChedresePJDichlorodiphenyldichloroethylene potentiates the effect of protein kinase A pathway activators on progesterone synthesis in cultured porcine granulosa cells1999611099103TsaiWTCurrent status and regulatory aspects of pesticides considered to be persistent organic pollutants (POPs) in Taiwan20107361527TurusovVRakitskyVTomatisLDichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks20021101258VasiliuOMuttineniJKarmausWIn utero exposure to organochlorines and age at menarche200419150612OuyangFPerryMJVennersSAChenCWangBYangFSerum DDT, age at menarche, and abnormal menstrual cycle length20056287884DenhamMSchellLMDeaneGGalloMVRavenscroftJDeCaprioAPRelationship of lead, mercury, mirex, di chlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyls to timing of menarche among Akwesasne Mohawk girls2005115e12734Den HondEDhoogeWBruckersLSchoetersGNelenVvan de MieroopEInternal exposure to pollutants and sexual maturation in Flemish adolescents20112122433DengFTaoFBLiuDYXuYYHaoJHSunYEffects of growth environments and two environmental endocrine disruptors on children with idiopathic precocious puberty20121668039OzenSDarcanSBayindirPKarasuluESimsekDGGurlerTEffects of pesticides used in agriculture on the development of precocious puberty2012184422332WindhamGCPinneySMVossRWSjödinABiroFMGreenspanLCBrominated flame retardants and other persistent organohalogenated compounds in relation to timing of puberty in a longitudinal study of girls2015123104652BapayevaGIssayevaRZhumadilovaANurkasimovaRKulbayevaSTleuzhanROrganochlorine pesticides and female puberty in South Kazakhstan2016656775NamulandaGMaisonetMTaylorEFlandersWDOlsonDSjodinAIn utero exposure to organochlorine pesticides and early menarche in the Avon Longitudinal Study of Parents and Children20169446772MorganMKMacMillanDKZehrDSobusJRPyrethroid insecticides and their environmental degradates in repeated duplicate-diet solid food samples of 50 adults201828405BurnsCJPastoorTPPyrethroid epidemiology: a quality-based review201848297311YeXPanWZhaoYZhaoSZhuYLiuWAssociation of pyrethroids exposure with onset of puberty in Chinese girls201722760612SchecterABirnbaumLRyanJJConstableJDDioxins: an overview200610141928CarpenterDOPolychlorinated biphenyls (PCBs): routes of exposure and effects on human health200621123RitterRScheringerMMacLeodMMoeckelCJonesKCHungerbühlerKIntrinsic human elimination half-lives of polychlorinated biphenyls derived from the temporal evolution of cross-sectional biomonitoring data from the United Kingdom201111922531Den HondERoelsHAHoppenbrouwersKNawrotTThijsLVandermeulenCSexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek's hypothesis revisited20021107716WarnerMSamuelsSMocarelliPGerthouxPMNeedhamLPattersonDGJrSerum dioxin concentrations and age at menarche2004112128992LeijsMMKoppeJGOlieKvan AalderenWMVoogtPdVulsmaTDelayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study2008739991004SjödinAPattersonDGJrBergmanAA review on human exposure to brominated flame retardants--particularly polybrominated diphenyl ethers20032982939YangWMuYGiesyJPZhangAYuHAnti-androgen activity of polybrominated diphenyl ethers determined by comparative molecular similarity indices and molecular docking200975115964BlanckHMMarcusMTolbertPERubinCHendersonAKHertzbergVSAge at menarche and tanner stage in girls exposed in utero and postnatally to polybrominated biphenyl2000116417ChenAChungEDeFrancoEAPinneySMDietrichKNSerum PBDEs and age at menarche in adolescent girls: analysis of the National Health and Nutrition Examination Survey 2003-200420111118317DeodatiASallemiAMaranghiFGermaniDPuglianielloABaldariFSerum levels of polybrominated diphenyl ethers in girls with premature thelarche2016862339HarleyKGRauchSAChevrierJKogutKParraKLTrujilloCAssociation of prenatal and childhood PBDE exposure with timing of puberty in boys and girls20171001328Tables
Chemical endocrine disruptors in regards to puberty in girls
BPA
Phthalates
DDT/DDE
Pyrethroids
Dioxin
PCBs
PBB/PBDE
Group
Bisphenols
Plasticizers
Organochloride
Insecticide
Polychlorinated dibenzo-p-dioxin
Organochloride
Organohalogen
Introduction date
1960s
1920s
1940s
1960s
1872
1927
1970s
Restricted/ Banned date
Restricted 2012
Restricted 2009
Banned 1972
Restricted
Banned 1979
Banned 1979
Restricted 2007
Route of exposure
Ingestion, dermal absorption, inhalation
Ingestion, dermal absorption, inhalation
Ingestion, dermal absorption, inhalation
Ingestion, dermal abruption, inhalation
Ingestion, inhalation
Ingestion, dermal absorption, inhalation
Ingestion, dermal abruption, inhalation
Half-life
4–5 hours
12 hours
6–10 years
10 hours
7–11 years
12 days–16 years
2 days–3 months
Sources
Polycarbonate plastics, epoxy resins, plastic toys and bottles, lining of food cans
Contaminated food, PVC plastics and flooring, personal care products, medical devices and tubing
Contaminated water, soil crops, fish
Contaminated water, soil, food
By-product of chlorinated herbicide production, smelting, chlorine bleaching of paper
Contaminated air and food, skin contact with old electrical equipment
Modified from Gore AC, et al. Endocr Rev 2015;36:E1-E150, with permission of Oxford University Press.[10]
Human studies investigating the relationship of BPAs and phthalate metabolites with pubertal development in girls
Chemical exposure (biospecimen)
Study population (sample size)
Subjects age
Study design
Correlation with puberty
Findings
Reference
Phthalate (serum)
Puerto Rico (41 with PT+35 controls)
6 months-10 years old
CC
YES (early)
Higher DBP DEHP, and MEHP levels in girls with PT
Colon, 2000 [54]
Phthalate (serum)
China (110 with PP+100 controls)
6-8 years old
CC
YES (early)
Higher DBP and DEHP levels in girls with PP
Qiao, 2007 [55]
BPA (serum)
Korea (50 with PP+50 controls)
8-11 years old
CC
NO
No significant differences between PP and control group regarding BPA levels
Han, 2008 [29]
BPA (urine)
US (192)
9 years old
CS; assessed pubertal status by questionnaire and examination
NO
No effects of BPA on pubertal status
Wolff, 2008 [30]
Phthalate (urine)
Taiwan (30 with PT+ 26 with CPP+ 33 controls)
6-9 years old
CC
YES (early)
Higher MMP levels in girls with PT
Chou, 2009 [56]
BPA/Phthalate (serum)
Korea (29 with CPP+ 29 controls)
CC
NO (BPA)/YES (phthalate, early)
No significant differences between CPP and control groups regarding BPA levels/higher DEHP levels in girls with CPP
Lee, 2009 [31]
BPA (serum)
China (110 with PP+100 controls)
6-8 years old
CC
YES (early)
Higher BPA levels in girls with CPP
Qiao, 2010 [32]
BPA/Phthalate (urine at enrollment)
US, BCERP cohort (1,151)
6-8 years old
C (1-year followup); assessed Tanner stages by inspection and palpation
NO (BPA)/YES (high-molecular-weight-phthalates, late vs. low-molecular- weight-phthalates, early)
No effects of BPA on breast or public hair development/High-molecular-weight-phthalates levels were associated with late pubic hair development, while low-molecular-weight-phthalates levels with advanced breast/pubic hair development
Wolff, 2010 [33]
BPA/Phthalate (urine)
US, NHANES 2003-2008 (461)
12-16 years old
CS; assessed age at menarche
NO (both)
No effects of BPA levels or total phthalate metabolite levels on the age of menarche
Buttke, 2012 [34]
Phthalate (urine)
Denmark (Total 725 girls, 24 with PP+184 controls)
5-19 years old
CS or CC; assessed pubertal stages by clinical examination
NO
MBzP and MBP levels were associated with late pubarche, not associated with thelarche No significant differences between PP and control group regarding phthalate metabolite levels
Frederiksen, 2012 [57]
Phthalate (urine)
Taiwan (73 with CPP +31 controls)
2-11 years old
CC
YES (early)
Higher phthalate metabolite (MEP, MBzP MEHHP, and MEOHP) levels in girls with CPP
Chen, 2013 [58]
BPA (urine)
Denmark (129)
6-21 years old
CS; assessed pubertal status by clinical examination or questionnaire
NO
No effects of BPA on pubertal developmental stage
Frederiksen, 2013 [35]
Phthalate (urine at enrollment and at follow-up)
Denmark (84)
5-12 years old
C (follow-up every 6 months for 5 years); assessed Tanner stages to determine age at puberty
NO
No effects of phthalate on the age of pubertal development
Mouritsen, 2013 [59]
BPA/Phthalate (serum)
Korea (150 with PP +90 controls)
6-12 years old
CC
NO (BPA)/YES (phthalate, early)
No significant differences between PP group and control group regarding BPA levels/Higher MBP levels in girls with PP
Yum, 2013 [36]
BPA (urine)
Turkey (28 with CPP + 25 controls)
4-8 years old
CC
YES (early)
Higher BPA levels in girls with CPP
Durmaz, 2014 [37]
BPA (urine)
Korea (42 with CPP +40 with PPP+ 37 controls)
7-9 years old
CC
NO
No significant differences between PP group and control group regarding BPA levels
Lee, 2014 [38]
Phthalate (urine at enrollment)
US, BCERP cohort (1,239)
6-8 years old
C (follow-up until breast and pubic hair development); pubertal status examination 1-2 times/year
YES (late)
Higher exposure to high-molecular-weight-phthalates (DEHP) was associated with later pubarche
Wolff, 2014 [60]
BPA (serum)
China (251 with PT +33 controls)
4 months-2 years old
CC; PT in female infants
YES (early)
Higher BPA levels in girl with PT
Chen, 2015 [39]
BPA (urine)
US, NHANES 2003-2010 (987)
12-19 years old
CS; assessed age at menarche by questionnaire
NO
BPA level was associated with delayed menarche (not statistically significant)
McGuinn, 2015 [40]
BPA (urine at enrollment)
US, BCERP cohort (1,239 girls)
6-8 years old
C (follow-up for 7-year); annual pubertal assessment
NO
No association between pubertal development and BPA levels
Wolff, 2015 [41]
Phthalate (urine at enrollment and at follow-up)
China (208)
6-13 years old
CS or C; assessed pubertal development state at 18 months of follow-up
YES (early)
Phthalate levels (MBP, MMP MEP and MEHP) were associated with higher breast development stage, earlier menarche, and speedup in breast progression
Zhang, 2015 [61]
BPA (urine)/Phthalate (plasma)
Turkey (42 with CPP +42 with PPP+ 50 controls)
6-8 years old
CC
NO (BPA)/YES (phthalate, early)
No differences between CPP, PPP and control groups regarding BPA levels/ Higher DEHP and MEHP levels in girls with CPP than those with PPP or controls
Bulus, 2016 [42]
BPA (urine)
Turkey (28 with CPP +28 with PT+ 22 controls)
5-8 years old
CC
NO
No differences between CPP, PT and control groups regarding BPA levels
Ozgen, 2016 [43]
BPA (urine)
Thailand (41 with PP +47 controls)
6-8 years old
CC
Yes (early)
Higher BPA levels in girl with PP especially in overweight or obese group
Supornsilchai, 2016 [44]
BPA/Phthalate (urine at enrollment)
Germany (222)
8-10 years old
C (3-year follow-up); annually follow up for pubertal development scale questionnaires
YES (both, late)
BPA or phthalate metabolites (DEHP metabolites, MBP, and MEP) levels were associated with delayed pubertal development
Kasper-Sonnenberg, 2017 [45]
BPA (urine)
China (655)
9-18 years old
CS; assessed pubertal development by Tanner staging and self-reported age at menarche
YES (early pubarche, late menarche)
BPA exposures were associated with delayed menarche while with earlier onset of pubarche
Miao, 2017 [46]
Phthalate (urine)
Thailand (42 with PP+17 with early puberty+ 77 controls)
6-11 years old
CC
YES (early)
Higher MEP levels in girls with PP than those of controls
Srilanchakon, 2017 [62]
BPA/Phthalate (urine at enrollment)
US, BCERP cohort (1,051)
6-8 years old
C (11-year follow-up); annual pubertal assessment, selfreported age at menarche
NO (BPA)/YES (phthalate, late)
No association between pubertal development or menarche and BPA/ Higher MCPP levels were associated with later age of thelarche and menarche
Wolff, 2017 [47]
BPA/Phthalate (maternal urine, 1st, 2nd, and 3rd trimester)
Mexico (120)
8-13 years
C; assessed Tanner staging by examination
YES (BPA of 2nd trimester, early)/YES (phthalate, whole pregnancy, late)
Prenatal BPA of the 2nd trimester was positively associated with thelarche / Prenatal MEHP across pregnancy was negatively associated with thelarche, while MEHP of 3rd trimester was positively associated with pubarche
Watkins, 2017 [48]
BPA/Phthalate (maternal urine, at 14.0 and 26.9 weeks' gestation)
US, CHAMACOS cohort (179)
9-13 years old
C (follow-up every 9 months between 9-13 years of age); assessed Tanner staging by examination
YES (BPA / phthalate, late)
Prenatal BPA levels and phthalate (DEHP metabolites and MBzP) were associated with later onset of puberty (thelarche, menarche, or pubarche) in normal weight girls
Berger, 2018 [49]
Phthalate (urine at enrollment and last follow-up)
Chile (200)
6-9 years old
C (follow-up every 6 months from Tanner 1 to 4 breast development); assessed age at menarche
YES (pre-pubertal DEHP late/pubertal MMP early)
Prepubertal DEHP metabolite levels were associated with later menarche, while pubertal MMP levels were associated with earlier menarche
Binder, 2018 [63]
BPA (urine)
China (136 with CPP +136 controls)
6-9 years old
CC
YES (early)
Higher BPA levels in girls with CPP
Chen, 2018 [50]
BPA (urine)
Turkey (25 with PT +25 controls)
4-8 years old
CC
YES (early)
Higher BPA levels in girl with PT
Durmaz, 201 8 [51]
Phthalate (urine)
Turkey (29 with PT +25 controls)
4-8 years old
CC
YES (early)
Higher MEHP levels in girls with PT
Durmaz, 2018 [64]
Phthalate (serum)
Iran (87 with PP +63 controls)
7-9 years old
CC
YES (early)
Higher DEHP levels in girls with PP
Hashemipour, 2018 [65]
BCERP, the Breast Cancer and the Enviroment Reaserch Program; BPA, bisphenol A; BMI, body mass index; C, cohort study; CC, case-control study; CHAMACOS, the Center for the Health Assessment of Mothers and Children of Salinas; CPP, central precocious puberty; CS, crosssectional study; DBP, dibutyl phthalate; DEHP, di-2-ethylhexyl phthalate; MBP, mono-n-butyl phthalate; MBzP, mono-benzyl phthalate; MCPP, mono-3-carboxypropyl phthalate; MEHP, mono-2-ethylhexyl phthalate; MEHHP, mono-(2-ethyl-5-hydroxyhexyl) phthalate; MEOHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEP, mono-ethyl phthalate; MMP, monomethyl phthalate; NHANES, The National Health and Nutrition Examination Survey; PP, precocious puberty; PPP, peripheral precocious puberty; PT, premature thelarche; US, United States.
Human studies regarding the relationship of pyrethroids, DDT/DDE, dioxins, PCBs, and flame retardants with pubertal development in girls
Chemical exposure (biospecimen)
Study population (sample size)
Subject age
Study design
Correlation with puberty
Finding
References
PBB (maternal serum, breast milk)
US (327)
5-24 years old
C; assessed Tanner stage and age at menarche by questionnaire
YES (early)
Perinatal PBB exposure was associated with earlier pubic hair stage and earlier age at menarche in breastfed girl
Blanck, 2000 [90]
TCDD/PCBs (serum)
Belgium (120)
16-18 years old
CS; assessed Tanner stage
YES (TCDD, late)
Higher serum dioxin levels were associated with delayed breast development
Den Hond, 2002 [85]
DDE/PCBs (maternal serum)
US (151)
20-50 years old
C; assessed age at menarche by questionnaire
YES (DDE, early)/NO (PCBs)
Higher prenatal DDE levels were associated with younger age at menarche/Prenatal PCB levels were not associated with age at menarche
Vasiliu, 2004 [70]
TCDD (serum soon after exposure)
Italy (282)
1 month to 40 years (premenarcheal at exposure)
C; assessed age at menarche by interview
NO
TCDD exposure was not related to age at menarche
Warner, 2004 [86]
DDT (serum)
China (446)
20-34 years old
CS; assessed age at menarche by interview
YES (early)
The mean age at menarche was younger in the highest DDT concentration quartile
Ouyang, 2005 [71]
DDE/PCBs (serum)
Akwesasne Mohawk Nation (138)
10-16 years old
CS; assessed menarche status by interview
NO (DDE)/YES (PCBs, early)
No association between DDE level and menarche status/PCB levels were significant predictors of reaching menarche
Denham, 2005 [72]
DDE (plasma)
US (192)
9 years old
CS; assessed pubertal status by questionnaire and examination
NO
No effects of plasma DDE levels on breast stage
Wolff, 2008 [30]
PCDD/F PCBs, PBDE (breast milk, child serum)
Netherland (19)
14-19 years old
C; assessed age at thelarche, pubarche, and menarche by questionnaire
YES (PCDD/F, late)/NO (PCBs, PBDE)
Prenatal PCDD/F exposure was associated with delayed breast development/No association between PCBs or PBDE and pubertal development
Leijs, 2008 [87]
PCDD/F PCBs, PBDE (breast milk, child serum)
Netherland (19)
14-19 years old
C; assessed age at thelarche, pubarche, and menarche by questionnaire
YES (PCDD/F, late)/ NO (PCBs, PBDE)
Prenatal PCDD/F exposure was associated with delayed breast development/No association between PCBs or PBDE and pubertal development
Leijs, 2008 [87]
PBDE (serum)
US, NHANES 2003-2004 (271)
12-19 years old
CS; assessed age at menarche by questionnaire
YES (early)
Higher PBDE levels were associated with earlier ages at menarche
Chen, 2011 [91]
DDE/PCBs (serum)
Belgium (792)
14-15 years old
CS; assessed pubertal status by Tanner stage and age at menarche
NO (DDE)/ YES (PCBs, late)
No effects of DDE levels on pubertal staging/Higher PCBs exposure was associated with late menarche
Den Hond, 2011 [73]
DDE (serum)
China (76 with PP+ 99 controls)
3-9 years old
CC
YES (early)
Higher positive rate of DDE in PP group
Deng, 2012 [74]
DDE (serum, adipose tissue)
Turkey (45 with PT+16 with PP+33 controls)
4-8 years old
CC
NO
Presence and levels of DDT/DDE were not associated with PP
Ozen, 2012 [75]
DDE/PCBs/PBDE (serum at enrollment, peri-pubertal)
US, BCERP cohort (645)
6-8 years old
CS or C (7-year follow-up); annual pubertal assessment
YES (DDE and PBDE of peri-pubertal, late)/NO (PCBs)
Higher peri-pubertal DDE and PBDE exposure was associated with later onset of puberty (attenuated effects of PCBs after BMI adjustment)
Windham, 2015 [76]
DDT (serum)
Kazakhstan (524)
10-17 years old
CS; assessed Tanner stage
YES (late)
Higher levels of DDT were associated with delayed pubertal development
Bapayeva, 2016 [77]
PBDE (serum)
Italy (37 with PP+56 with PT+31 controls)
5-8 years old
CC
YES (early)
Higher PBDE levels in girls with PT than those of controls
Deodati, 2016 [92]
DDT/DDE (maternal serum)
UK (218 with menarche <11.5 yrs +230 controls)
8-13 years old
C or CC (nested); assessed age at menarche by questionnaire (annually from ages 8-17)
NO
Prenatal DDT exposure was not associated with timing of menarche
Namulanda, 2016 [78]
PBDE (maternal serum, child serum at age 9 years)
US, CHAMACOS cohort (314)
9-13 years old
C (followed every 9 months between 9-13 years of age); assessed Tanner stage by examination
YES (prenatal, late)/NO (childhood)
Prenatal PBDE exposure was associated with later menarche, while childhood PBDE levels were not associated with pubertal timing
Harley, 2017 [93]
3-PBA (urine)
China (305)
9-15 years old
CS; Self-reported pubertal staging and menarche status
YES (late)
Negative association between urinary 3-PBA with pubertal development (breast/pubic hair stage, and menarche)
Ye, 2017 [81]
BCERP, the Breast Cancer and the Environment Research Program; BMI, body mass index; C, cohort study; CC, case-control study; CHAMACOS, the Center for the Health Assessment of Mothers and Children of Salinas; CS, cross-sectional study; DDE, dichlorodiphenyl dichloroethane; DDT, dichlorodiphenyl trichloroethane; NHANES, The National Health and Nutrition Examination Survey; PBB, polybrominated biphenyl; PBDE, polybrominated diphenyl ether; PCBs, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxins; PCDF, polychlorinated dibenzofurans; PP, precocious puberty; PT, premature thelarche; TCDD, tetrachlorodibenzo-p-dioxin; UK, United Kingdom; US, United States; 3-PBA, 3-phenoxybenzoic acid.