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SUPPLEMENT ARTICLE
Environmental Factors and Puberty Timing: Expert
Panel Research Needs
Germaine M. Buck Louis, PhDa, L. Earl Gray, Jr, PhDb, Michele Marcus, PhD, MPHc, Sergio R. Ojeda, DVMd, Ora H. Pescovitz, MDe,
Selma Feldman Witchel, MDf, Wolfgang Sippell, MD, PhDg, David H. Abbott, PhDh, Ana Soto, MDi, Rochelle W. Tyl, PhDj,
Jean-Pierre Bourguignon, MD, PhDk, Niels E. Skakkebaek, MD, DMScl, Shanna H. Swan, PhDm, Mari S. Golub, PhDn, Martin Wabitsch, MD, PhDo,
Jorma Toppari, MD, PhDp, Susan Y. Euling, PhDq
aEpidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; bEndocrinology Branch, National
Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North
Carolina; cDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; dDivision of Neuroscience, Oregon National Primate Research
Center-Oregon Health and Sciences University, Beaverton, Oregon; eDepartment of Pediatrics and Cellular and Integrative Physiology, Riley Hospital for Children, Indiana
University School of Medicine, Indianapolis, Indiana; fDivision of Endocrinology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania; gDivision of Endocrinology,
Department of Pediatrics, University of Kiel, Kiel, Germany; hDepartment of Obstetrics/Gynecology and Wisconsin National Primate Research Center, University of
Wisconsin, Madison, Wisconsin; iDepartment of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, Massachusetts; jCenter for Life Sciences and
Toxicology, RTI International, Research Triangle Park, North Carolina; kCHU Sart-Tilman, University of Liege, Belgium; lUniversity Department of Growth and Reproduction,
Rigshospitalet, Copenhagen, Denmark; mDepartment of Family & Community Medicine, University of Missouri, Columbia, Missouri; nOffice of Environmental Health
Hazard Assessment, California Environmental Protection Agency, Sacramento, California; oDepartment of Pediatric and Adolescent Medicine, University of Ulm, Ulm,
Germany; pDepartments of Physiology and Pediatrics, University of Turku, Turku, Finland; qNational Center for Environmental Assessment, Office of Research and
Development, US Environmental Protection Agency, Washington, DC
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
Serono Symposia International convened an expert panel to review the impact of
environmental influences on the regulation of pubertal onset and progression while
identifying critical data gaps and future research priorities. An expert panel reviewed www.pediatrics.org/cgi/doi/10.1542/
peds.2007-1813E
the literature on endocrine-disrupting chemicals, body size, and puberty. The panel
concluded that available experimental animal and human data support a possible doi:10.1542/peds.1813E
role of endocrine-disrupting chemicals and body size in relation to alterations in The views expressed in this article are
those of the authors and do not necessarily
pubertal onset and progression in boys and girls. Critical data gaps prioritized for reflect the views or policies of the US
future research initiatives include (1) etiologic research that focus on environmen- Environmental Protection Agency. Mention
tally relevant levels of endocrine-disrupting chemicals and body size in relation to of trade names of commercial products
normal puberty as well as its variants, (2) exposure assessment of relevant endo- does not constitute endorsement or
recommendation for use.
crine-disrupting chemicals during critical windows of human development, and (3) Drs Buck Louis, Gray, and Marcus
basic research to identify the primary signal(s) for the onset of gonadotropin- contributed equally to this work.
releasing hormone– dependent/central puberty and gonadotropin-releasing hor- Key Words
mone–independent/peripheral puberty. Prospective studies of couples who are plan- human puberty, puberty timing, breast
development, menarche, pubic hair
ning pregnancies or pregnant women are needed to capture the continuum of development, genital development,
exposures at critical windows while assessing a spectrum of pubertal markers as endocrine disruptors, body fat
outcomes. Coupled with comparative species studies, such research may provide Accepted for publication Sep 5, 2007
insight regarding the causal ordering of events that underlie pubertal onset and Address correspondence to Germaine M. Buck
progression and their role in the pathway of adult-onset disease. Louis, PhD, Epidemiology Branch, Division of
Epidemiology, Statistics and Prevention
Research, National Institute of Child Health
and Human Development, 6100 Executive
Blvd, Room 7B03, Rockville, MD 20852. E-mail:
I N LIGHT OF an increasing body of evidence supporting environmental influences on
pubertal onset and progression in contemporary birth cohorts, an expert panel met
during and after the Serono Symposia International’s “The Role of Environmental
louisg@mail.nih.gov
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2008 by the
American Academy of Pediatrics
Factors on the Onset and Progression of Puberty” to identify research priorities for
delineating the impact of environmental influences on children’s pubertal experi-
ences. An expert review of available animal, clinical, and epidemiologic data was undertaken and synthesized for
identifying critical data gaps that are relevant for prioritizing a multidisciplinary research agenda. For purposes of this
article, the environment is defined as the sum of all external conditions that affect life, development, and survival of
an organism (www.epa.gov/ocepaterms/eterms.html). By extension, an environmental factor is defined as a non-
S192 BUCK LOUIS et al
Downloaded from www.aappublications.org/news by guest on October 23, 2021FIGURE 1
Regulation of human puberty onset and progression via
the HPG and the HPA axes. The key regulatory changes
that occur for the initiation and progression of puberty in
boys and girls are shown. The HPG activation requires sig-
naling from the central nervous system (CNS) to the hy-
pothalamus. The hypothalamus releases GnRH, which in
turn stimulates the production of LH and FSH from the
pituitary. LH and FSH activate the gonad to produce sex
hormones, which in turn initiates pubertal changes in
many of the target organs. The HPA activation requires
signaling from the CNS to the hypothalamus. The hypo-
thalamus releases adrenocorticotropin releasing hor-
mone (CRH) that in turn stimulates the production of ad-
renocortical tropic hormone (ACTH) from the pituitary.
ACTH activates the adrenal cortex to produce andro-
stenedione and dehydroepiandrosterone (DHEA) that in
turn initiates armpit hair, pubic hair, and skin changes.
Androgen action is also considered to be part of the initi-
ation of armpit and pubic hair development. Positive (⫹)
and negative (⫺) indicate stimulatory and inhibitory sig-
nals and “⫹/⫺” in the CNS indicates a combination of
excitatory and inhibitory neuronal signals.
genetic factor; however, for purposes of brevity and during childhood. Puberty is marked by the reactivation
consistent with the weight of evidence regarding envi- of the HPG axis manifested by an increase in frequency
ronmental influences on puberty, this review focuses on and amplitude of gonadotropin releasing hormone
endocrine-disrupting chemicals (EDCs) and body size in (GnRH) pulses in the hypothalamus, leading to a rise in
relation to puberty timing. An in-depth discussion of the pulsatile secretion of the gonadotropins LH and FSH
literature cited in this article is beyond the scope of this from the anterior pituitary. Gonadotropin release stim-
article, but key study aspects are summarized in accom- ulates the gonads. In girls, such maturation of reproduc-
panying tables. tive neuroendocrine function eventually leads to the
onset of ovulatory menstrual cycles. Appropriate gonad-
REGULATION OF NORMAL PUBERTY ONSET AND otropin regulation of ovarian function results in ovarian
PROGRESSION IN HUMANS AND ANIMALS follicle secretion of ovarian androgens from theca cells
Puberty is the period of transition from childhood to and estradiol from granulosa cells before ovulation and
adolescence and is marked by the development of sec- secretion of progesterone from the corpus luteum and
ondary sexual characteristics, accelerated growth, be- estradiol after ovulation. In boys, LH initiates the secre-
havioral changes, and eventual attainment of reproduc- tion of androgens (testosterone and androstenedione)
tive capacity. Available approaches for the assessment of from the testicular Leydig cells. Such onset of gonadal
pubertal onset and progression have recently been re- endocrine function is termed gonadarche. The initial
viewed,1 including the use of Tanner stages2,3 for female molecular triggers of puberty onset remain unknown,
breast and pubic hair development and male gonadal although genetic and environmental factors are sus-
and pubic hair development. Menarche is also an impor- pected.
tant marker used for assessing puberty in girls. Biochemical Puberty is also associated with an independent phys-
markers for female puberty onset and progression include iologic event, adrenarche, or adrenal activation, that
assaying elevations in reproductive hormones (eg, lutein- typically occurs between 6 and 8 years of age in both
izing hormone [LH], follicle-stimulating hormone [FSH], genders. Adrenarche leads to pubarche, the secondary
17-estradiol, inhibin A and B) before the onset of physical sexual changes including pubic hair development, acne,
signs (eg, Tanner breast development stage 2). Other mat- and body odor. Adrenarche is marked by increased 17␣-
urational markers, such as bone age determinations (radio- hydroxylase (17,20 lyase) activity of the P450c17 en-
graph of left wrist) and ultrasonographic assessment of zyme and increased cytochrome b activity resulting in
ovarian and uterine volume, can be used. increased dehydroepiandrosterone, dehydroepiandros-
Puberty changes occur as a consequence of the acti- terone sulfate, and androstenedione production. These
vation of the hypothalamic-pituitary-gonadal (HPG) axis initial hormonal increases rise over time, resulting in a
and hypothalamic-pituitary-adrenal (HPA) axis. The cumulative dosage of androgens. Adrenarche is a strictly
HPG axis is under the control of both inhibitory and primate phenomenon.4 Although little information is
stimulatory mechanisms, as illustrated in Fig 1. In the available, there is some evidence that adrenarche occurs
human, the HPG is active in the midfetal, neonatal, and before puberty in chimpanzees and during the neonatal
early infancy periods but becomes relatively quiescent period in rhesus macaques and baboons.5
PEDIATRICS Volume 121, Supplement 3, February 2008 S193
Downloaded from www.aappublications.org/news by guest on October 23, 2021Recently, much has been learned about the central been identified, gene(s) upstream that provide the initial
mechanisms underlying the initiation of mammalian pu- trigger of puberty timing remain largely unknown. The
berty. Rodents, nonhuman primates, and humans have integrated use of genomics and proteomics using trans-
been and remain the main species used to study the basic genic rodent models, nonhuman primates, and humans
components and regulatory hierarchies that control the with alterations in the onset of puberty is beginning to
process of puberty. Traditionally assessed pubertal onset uncover some of the common evolutionary conserved
end points in rodents include the age of male preputial molecular components that are used by the neuroendo-
separation (PPS), an androgen-mediated event, and, in crine brain to control GnRH secretion and, in turn, the
females, the age of female vaginal opening (VO), an initiation of puberty in both rodents and higher pri-
estrogen-mediated event. Age at first estrus is an end mates.20–23 An example is the homeodomain gene TTF1,
point used to assess completion of the pubertal process in a transcription factor that was recently shown to be
females because it occurs the day after the first preovu- involved in the neuroendocrine control of both primate
latory surge of gonadotropins.6 Some studies have as- and rodent puberty.24 In addition, recent findings sug-
sessed the age of breast cell differentiation events in the gest that structural remodeling of GnRH neurons may
mouse and rat.7,8 Estrogen-mediated pubertal events play a key role in the onset of puberty.25
that occur in nonhuman female primates include men- Although the initiating trigger(s) for pubertal onset is
arche, sex skin swelling and reddening, and nipple unknown for rodents, nonhuman primates and humans,
growth.9,10 Epiphyseal closure and cessation of long bone earlier molecular markers have been identified, such as
growth also have been assessed.11 In male monkeys, the newly described kisspeptin-GPR54 regulatory sys-
increases in testicular volume indicate onset of male tem. Humans who carry mutations of the GPR54 recep-
puberty and reflect both gonadotropin- and testoster- tor22,23 and mice that lack this receptor23,26 each fail to
one-mediated events.12 Measurement of changes in tes- reach puberty, indicative that activation of this signaling
ticular size seems to be a reliable, noninvasive procedure complex is essential for pubertal onset. Peptides that are
to detect the initiation of puberty in both human and produced by peripheral tissues, such as leptin and insu-
nonhuman primates.13 lin-like growth factor 1, seem to be more important in
In addition to differences in the time frame, progres- maintaining pubertal progression rather than in its ini-
sion, and phenotypic landmarks of puberty,14 there is a tiation despite that insulin-like growth factor 1 has been
fundamental difference in the neuroendocrine process reported to accelerate pubertal initiation in rodents and
that controls the initiation of puberty in rodents versus monkeys (reviewed by Ojeda and Terasawa18).
primates. In rodents and sheep,15 GnRH secretion is Understanding the mechanisms underlying the initi-
maintained at low levels during juvenile development ation, progression, and regulation of normal human pu-
by strong steroid inhibitory control, whereas a similar berty is essential for assessing the effect(s) of EDCs on
reduction in GnRH secretion is achieved in primates human development. With limited empirical popula-
(including humans) by central mechanisms that operate tion-based data, it is important to consider other sources
independent of gonadal regulatory inputs.16,17 Thus, data of data, such as those that arise from clinical populations.
indicate that the peripubertal regulation of the GnRH- Although external validity may be limited from these
releasing system is a more centrally controlled process in data sources, useful information about potential cause is
primates than in rodents that exhibit “gonadal” control possible.
of GnRH secretion. Despite this operational difference,
the pubertal activation of GnRH release in rodents and
CLUES FROM CLINICAL RESEARCH THAT SUPPORT
primates is initiated and regulated by similar excitatory
ENVIRONMENTAL INFLUENCES
and inhibitory pathways, providing input to GnRH neu-
A number of clinical conditions offer clues regarding the
rons (reviewed by Ojeda and Terasawa18 and Ojeda and
influence on environmental factors, such as nutrition
Skinner6). These inputs include both trans-synaptic and
and body size, on puberty. In fact, a recent clinical report
glia-to-neuron communication pathways. As neuronal
attributed topical application of lavender and tea tree oils
networks that use excitatory amino acids and the newly
to gynecomastia in prepubescent boys on the basis of in
discovered kisspeptin peptide for neurotransmission or
vitro evidence supporting their weak estrogenic and
neuromodulation become activated, there is a concom-
anti-androgenic activities.27 A brief overview of environ-
itant reduction in the activity of those neurons using the
mental influences follows in relation to precocious pu-
inhibitory neurotransmitters ␥ amino butyric acid and
berty, delayed puberty, and polycystic ovary syndrome
opioid peptides for transsynaptic communication. In ad-
(PCOS).
dition to this neuron-to-neuron flow of information,
several trophic molecules have been identified as com-
ponents of the cell– cell signaling process used by glial Precocious Puberty
cells to regulate GnRH secretion. Prominent among Precocious and delayed puberty in humans can have a
these regulatory systems is a signaling complex that uses genetic and/or environmental cause. Precocious puberty
epidermal growth factor–like ligands and members of is defined herein as the development of secondary sex-
the epidermal growth factor receptor family for glia-to- ual characteristics before 8 years of age in girls and boys.
neuron communication (reviewed by Ojeda et al19). Al- Precocious puberty can be classified into “central,” or go-
though some gene products that are involved in glia and nadotropin-dependent, precocious puberty; “peripheral,”
neuronal communication to regulate puberty onset have or gonadotropin-independent, precocious puberty; or
S194 BUCK LOUIS et al
Downloaded from www.aappublications.org/news by guest on October 23, 2021combined. Examples of genetic forms of peripheral pre- the National Institutes of Health definition to include 2
cocious puberty are McCune Albright syndrome in girls of 3 of the following: (1) clinical or biochemical evidence
and testotoxicosis (or familial male precocious puberty) of hyperandrogenism; (2) intermittent or absent men-
in boys. strual cycles; and (3) polycystic ovary morphology as
Premature thelarche and premature adrenarche may visualized by ultrasound.
be regarded as partial forms of precocious puberty, in Puberty timing is altered in some girls with PCOS,
which the full spectrum of pubertal changes is absent dependent, in part, on androgen secretion/exposure and
and only specific changes occur.28 Premature thelarche is nutritional status. Premature pubarche has been re-
usually slowly progressing or even self-limiting but can ported among some but not all girls with PCOS and is
occasionally transform into overt central precocious pu- believed to arise from increased adrenal androgen secre-
berty. Although not precocious puberty, per se, prema- tion secondary to premature adrenal pubertal matura-
ture breast development and gynecomastia after expo- tion in the absence of other known causes (eg, CAH,
sure to estrogen-containing products have been reported androgen-secreting tumors, Cushing syndrome). Andro-
in girls and boys, respectively, with reversal on cessation gen concentrations are elevated for chronologic age but
of the exposure.29–33 appropriate for the stage of pubic hair development.
Skeletal maturation may be normal or slightly advanced.
The presence of insulin resistance/hyperinsulinemia,
Pubertal Delay
dyslipidemia, exaggerated GnRH-stimulated ovarian
Delayed puberty, defined as the absence of breast devel-
thecal cell androgen secretion in the early stages of pu-
opment by 13 years of age in girls or testicular volume
berty, and subsequent development of hyperandrogenic
⬍4 mL by 14 years of age in boys, can occur as a result
chronic anovulation during the later stages of puberty
of primary hypothalamic-pituitary dysfunction or pri-
suggest that premature pubarche is related to the devel-
mary gonadal failure. The most common cause of pu-
opment of PCOS.36 In addition, the age at menarche is
bertal delay is constitutional, representing a transient
typically ⬃6 months earlier in girls with PCOS than in
delay in sexual development that is a variant of normal.
unaffected girls.37
Permanent hypogonadotropic hypogonadism may occur
The relation between PCOS and adult-onset diseases
as an isolated hypothalamic-pituitary deficiency (eg,
is now recognized. For example, girls and women with
Kallman’s with or without cleft lip and/or palate) and
PCOS are at increased risk for developing impaired glu-
may be associated with a variety of molecular genetic
cose tolerance (IGT) and type 2 diabetes in comparison
defects. All are congenital anomalies that are associated
with unaffected women; however, the clinical manifes-
with multiple pituitary hormone deficiencies, not just
tations of hyperandrogenemia (anovulation, hirsutism,
those that affect puberty onset. Not all cases of delayed
acne, and androgenic alopecia) differentiate PCOS from
puberty have a known genetic cause, such as those that
type 2 diabetes and obesity. Obese adolescent girls with
arise from head trauma or infection. Primary gonadal
PCOS have greater insulin resistance than obese girls
failure is associated with hypergonadotropism and is
without PCOS.38 In PCOS, IGT, and type 2 diabetes,
caused by numerous congenital or acquired disorders
impaired metabolic activity leads to suppression of insu-
with a genetic (eg, gonadal dysgenesis, Klinefelter syn-
lin-mediated glucose uptake and lipolysis, leading to
drome, molecular genetic defects of the steroidogenic
compensatory hyperinsulinemia.
pathway, galactosemia) or environmental cause (eg, go-
Potential mechanisms underlying PCOS include (1)
nadotoxic chemotherapy [alkylating chemotherapy im-
early origins or in utero programming stemming from
pairs spermatogenesis but rarely affects Leydig cell func-
exposures during critical windows of development,39
tion], radiotherapy, surgery). Autoimmune disorders
(2) LH hypersecretion, (3) primary ovarian abnormal-
can cause delayed puberty through 2 different mecha-
ity, (4) dysregulation of fat metabolism and adipogen-
nisms: hypogonadotropic hypogonadism as a result of
esis, and/or (5) dysregulation of the inflammatory
hypophysitis or primary gonadal failure as a result of
axis. Data arising from girls who present clinically
autoimmune gonadal destruction.
with CAH40 and nonhuman female primates that are
exposed in utero to androgens39,41,42 are suggestive of
Polycystic Ovary Syndrome prenatal programming of gonadotropin secretory dy-
PCOS is a common heterogeneous disorder that affects namics and PCOS. Women with CAH and PCOS have
5% to 10% of reproductive-aged women. Insulin resis- accelerated episodic release of LH and increased hy-
tance/hyperinsulinemia occurs in 50% to 60% of PCOS- pothalamic release of GnRH.40
affected women compared with a prevalence of 10% to The persistence of the hyperandrogenic phenotype in
25% in the general population. Criteria for diagnosing cultured theca cells derived from women with PCOS
PCOS vary and were defined by the 1990 National In- suggests the possibility of a primary ovarian abnormality
stitutes of Health–National Institute of Child Health and in PCOS43 possibly with an in utero origin.44 Investiga-
Human Development conference as including chronic tion into the mechanism(s) responsible for insulin resis-
anovulation and hyperandrogenism (including acne, tance in type 2 diabetes has suggested that abnormalities
hirsutism, and male pattern baldness) after exclusion of in fatty acid uptake and use lead to increased plasma free
other disorders, such as congenital adrenal hyperplasia fatty acid concentrations followed by ectopic fat storage
(CAH), hypercortisolism, and hyperprolactinemia.34 The in skeletal muscle and liver; this aberrant fat storage
more recent “Rotterdam criteria” for PCOS35 expanded (lipotoxicity) alters insulin signaling, insulin metabo-
PEDIATRICS Volume 121, Supplement 3, February 2008 S195
Downloaded from www.aappublications.org/news by guest on October 23, 2021lism, and pancreatic -cell insulin secretion, leading to some natural products such as isoflavonoids, flavonoids,
the development of insulin resistance with compensa- stilbenes, lignans, equol, and phytoestrogens (eg,
tory hyperinsulinemia. Oxidative stress may also con- genistein, daidzein, coumestrol, 8-prenylnaringenin,
tribute to the development of insulin resistance. Activa- resveratrol). Gestational and lactational maternal oral
tion of the NF-B/IB-␣/IKK- pathway, a major exposure to dosages as low as 25 mg/kg per day me-
pathway for inflammatory processes, by free fatty acid thoxychlor resulted in an earlier age of VO and first
provides a potential link among coronary artery disease, estrus in the female rat.51 This was found to be pseudo-
type 2 diabetes, insulin resistance, and PCOS.45 Familial precocious rather than true precocious puberty because
clustering of IGT, type 2 diabetes, and PCOS suggests a VO was accelerated but the onset of estrous cyclicity was
role for genetic determinants of this metabolic pheno- not affected. Similarly, prenatal subcutaneous injections
type or in utero events such as decrements in fetal of BPA,52,53 genistein,53 resveratrol,53 zearalenone,53 or
growth as measured by reduced birth size.46 The hetero- DES53 accelerated VO in mice. Although prenatal oral
geneity of PCOS may account for the lack of candidate exposure to BPA did not significantly accelerate the age
genes identified to date.47 at VO or first estrus in either the rat or mouse, prenatal
oral treatment of mice with BPA significantly reduced
the number of days between VO and first vaginal es-
ENVIRONMENTAL INFLUENCES ON PUBERTY
trus.54 When female rats were exposed after weaning
Consistent with our definition, environmental factors
throughout puberty to xenoestrogens like methoxy-
are defined to include both EDCs and body shape and
chlor51 or 17 beta estradiol,56 early puberty onset was
adiposity. Consistent with the focus of the workshop,
induced as measured by age at VO in the female rat.55 In
this review focuses on single chemicals by mode of ac-
addition, prenatal BPA exposure resulted in altered mat-
tion. A more comprehensive review describing the tox-
uration of the mammary gland at puberty and increased
icology of puberty in rodents is found elsewhere.48,49
sensitivity to endogenous estrogens.7
Last, this review urges caution in assessing an individual
Androgen receptor (AR) antagonists (also called an-
pubertal marker given the highly interrelated and time-
drogen antagonists) compete with natural hormones
dependent nature of pubertal onset and progression as
testosterone and dihydrotestosterone for binding to the
orchestrated by gonadal hormones under the control of
AR. Thus, a decrease in binding between the natural
gonadotropins. In the presence of exogenous endocrine-
ligand and receptor occurs, which in turn inhibits AR-
active agents, pubertal markers can be independently
dependent gene expression in vivo. AR antagonist ex-
induced or blocked so that they are not necessarily in
posure in vivo can induce malformations in male repro-
synchrony with centrally regulated pubertal maturation.
ductive tract and delay puberty in the male rat. AR
For example, peripubertal exposure to the gonadotropin
antagonists include insecticides, herbicides, fungicides,
agonist Lupron and the estrogenic agent diethylstilbestrol
toxic chemicals, and combustion byproducts. HPTE has
both delayed menarche in monkeys, but other markers of
also been shown to act as an AR antagonist.57 Peripuber-
puberty were delayed or accelerated depending on the
tal exposure to the AR antagonists methoxychlor or
agent.9,50 Therefore, the relative timing of all puberty-onset
vinclozolin led to a delayed puberty in males as mea-
markers is the most informative, which argues for a com-
sured by the age of PPS in the rat.51,58
plete pubertal assessment and related deviations in lieu of
Conversely, AR agonists (also called androgen ago-
extreme categorization such as precocious puberty.
nists) compete with the endogenous hormones testos-
terone and dihydrotestosterone for AR, leading to an
Animal Studies increase in AR-DNA binding in vitro and AR-dependent
A summary of selected examples of single environmen- gene expression in vivo. Such environmental androgen
tal chemicals whose exposure at specific dosages may contaminants induce malformations in the female repro-
lead to puberty-timing alterations is presented in Table ductive tract59,60; accelerate male puberty in the rat61; and
1. This table is organized by mode of action (MOA). have been associated with the masculinization of female
Estrogen receptor (ER) agonists (also called estrogen fish in the United States, Sweden, and New Zealand.62
agonists or estrogens) and ER antagonists compete with Other receptors, including orphan receptors, are the
the endogenous estrogen hormones estradiol and es- targets of certain environmental agents. The environ-
trone for binding to the classical ER. Such agonists and mental chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin
antagonists bind to the ER and activate or repress, re- (TCDD) has 1 of the best-characterized MOAs, binding
spectively, transcription of ER-dependent genes and to the aryl hydrocarbon (Ah) receptor that in turn ini-
thereby enhance or diminish estrogenic activity in vivo tiates Ah-dependent gene expression changes. Even low
(eg, induce uterine weight increase/decrease, accelerate/ dosages of TCDD in utero can lead to gene expression
delay puberty). After in utero exposure to a potent es- changes and malformations in the reproductive tract in
trogen agonist, gross reproductive malformations may rodents.63–67 Ah receptor ligands other than TCDD include
result in female rats, presumably by altering the devel- other polychlorinated dibenzodioxins and some polychlo-
opment of reproductive organs that are responsive to rinated biphenyls (PCBs), polybrominated diphenyl ethers,
estrogen action. Examples of estrogen agonists that are and pesticide contaminants as well as the pesticide metho-
present as environmental contaminants include 2,2- prene, a juvenile hormone agonist. Exposure to TCDD in
bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), a utero caused delayed puberty in male and female rats as
metabolite of the pesticide chemical methoxychlor, and measured by an older age at acquisition of PPS and VO,
S196 BUCK LOUIS et al
Downloaded from www.aappublications.org/news by guest on October 23, 2021TABLE 1 Examples of Published Studies of Chemical Exposures With Puberty-Timing Effects in Animals
MOA Chemical Species, Treatment Interval Effects (at Dosages) Reference(s)
Gender
ER agonist E2 Rat, female Peripubertal Early VO (2 and 4 mg/kg per d) Marty et al56 (1999)
ER agonist DES Rhesus monkey, Peripubertal Early sex skin swelling and reddening; Golub et al50 (2003)
female delayed nipple growth; completely
suppressed menarche; increased serum
estrogen activity (0.5 mg/kg per d)
ER agonist BPA Mice, female In utero Increased lateral branching at 3 mo (25 Munoz de Toro124 (2005)
and 250 ng/kg per d)
ER agonist BPA Mice, female In utero Pregnancy stage–like mammary gland Markey et al7 (2001)
differentiation (25 and 250 ng/kg) at
PND 10, 1 mo, 6 mo
ER agonist BPA Mice, female In utero Reduced interval between VO and first Howdeshell et al54
vaginal estrus (dose) (1999)
ER agonist and AR Methoxychlor Rat, female and Peripubertal Female: early VO and first estrus (25, 50, Gray et al51 (1989)
antagonist male 100, 200 mg/kg per d); VO was
accelerated, but first estrus was not; F1
exposed in utero and lactation but not
directly; VO acceleration noted
Male: delayed PPS (100 and 200 mg/kg
per d)
ER agonist and AR Methoxychlor Rhesus monkey, Peripubertal Early sex skin swelling and reddening; Golub et al50 (2003)
antagonist female delayed nipple growth and menarche;
increased serum estrogen activity (25 or
50 mg/kg per d)
AR antagonist Vinclozolin Rat, male Peripubertal Delayed PPS (30 and 100 mg/kg per d) Monosson et al58 (1999)
AR antagonist p,p⬘-DDE Rat, male Peripubertal (PND 22–55) Delayed PPS at 100 mg/kg per d Ashby and Lefevre118
(2000)
AR antagonist p,p⬘-DDE Rat, male Peripubertal (PND 22–55) Delayed PPS at 30 and 100 mg/kg per d Kelce et al116 (1995)
Ah agonist TCDD Rat, female in utero Delayed VO and decreased/incomplete Gray and Ostby66 (1995);
mammary epithelial differentiation Gray et al64 (1997);
(0.8–1.0 g/kg per d) Fenton et al8 (2002)
Aromatase inhibitor Fadrozole Rat, female Peripubertal Delayed VO (0.6, 1.2, and 6.0 mg/kg per d) Marty et al56 (1999)
Steroidogenesis inhibitor Ketoconazole Rat, female Peripubertal Delayed VO (100 mg/kg per d) Marty et al56 (1999)
Steroidogenesis inhibitor Prochloraz Rat, male Peripubertal Delayed PPS (125 mg/kg per d) Blystone et al73 (2007)
CNS-HPG; reduces LH Atrazine Rat, male Peripubertal Delayed PPS (12.5, 50, 100, 150, 200 mg/ Stoker et al48,68 (2000)
and prolactin kg per d)
CNS-HPG; reduces LH Atrazine Rat, female Peripubertal Delayed VO (50, 100 and 200 mg/kg per d) Laws et al69 (2000)
and prolactin
GnRH agonist Leuprolide acetate Rhesus monkey, Prepubertal Blocked menarche; delayed body growth Golub et al9 (1997)
female (weight and height); decreased muscle
mass; increased serum IGF-1 (0.75 mg/
kg per month)
E2 indicates 17 -estradiol; DES, diethylstilbestrol; CNS, central nervous system; PND, postnatal day; IGF-1, insulin-like growth factor 1.
respectively,64–67 and a delayed or incomplete differentia- tricular preoptic area at 22 to 24 days of age (prepuber-
tion of mammary epithelium.8 tal), an important brain region that regulates estrous
Some environmental chemicals affect puberty via cyclicity and estrogen-positive feedback.71
MOAs that are involved in the central nervous system/ Chemicals that inhibit the synthesis of endogenous
HPG axis, altering brain, hypothalamic, and/or pituitary hormones (eg, testosterone, 17-estradiol, adrenal ste-
function via direct interactions with the central nervous roids) typically do so by competitively inhibiting the
system neuroendocrine function. These include the pes- activity of ⱖ1 P450 steroidogenic enzymes. The predom-
ticides thiram, molinate, metam sodium, chlordime- inant effects are mediated through the steroidogenic
form, amitraz, triazoles, dichloroacetic acid, atrazine, enzymes cholesterol side chain cleavage enzyme, steroid
propazine, simazine, methanol, and linuron. Prepubertal 17,20 lyase, and aromatase (which converts androgens
exposure to atrazine causes delayed puberty in the male to estrogens). Some affect estrogen synthesis preferen-
and the female, as evidenced by an older age at acqui- tially over testosterone or adrenal hormones, and others
sition of PPS68 and VO,69 respectively. The modes of affect adrenal and liver function. Examples of environ-
action for atrazine’s reproductive effects include puberty mental and pharmaceutical aromatase inhibitors include
timing and a reduction in circulating LH and prolactin.70 conazole and imadazole fungicides (eg, prochloraz, fe-
Perinatal exposure of mice to BPA results in a decrease of narimol, ketoconazole, fadrozole). Peripubertal expo-
tyrosine hydroxylase neurons in the rostral periven- sure to the aromatase inhibitor fadrozole at dosages as
PEDIATRICS Volume 121, Supplement 3, February 2008 S197
Downloaded from www.aappublications.org/news by guest on October 23, 2021low as 0.6 mg/kg per day led to a delayed VO in female pubic hair development compared with unexposed girls or
rats.56 Peripubertal exposure to 100 mg/kg per day of the girls who were not breastfed. There was no association
steroidogenesis inhibitor ketoconazole also led to a de- found with Tanner stage of breast development.
layed VO.56 The MOA of prochloraz is the inhibition of Various studies have evaluated pubertal development
aromatase72 and 17,20 lyase73,74 apparently directly in- among children who were exposed to DDT and its pri-
hibiting steroidogenesis of estrogens and androgens. Pro- mary metabolite DDE. Two studies specifically assessed
chloraz also delays puberty in male rats.73 The MOA of developmental exposure (in utero and/or postnatal via
the fungicide chemical ketoconazole is inhibition of side- lactation) within a cohort. Gladen et al97 conducted a
chain cleavage enzyme (SCC), progesterone, and adre- prospective cohort study of boys and girls who resided in
nal steroid synthesis. The MOA of many phthalate es- North Carolina in relation to DDE concentrations that
ters, including diethylhexyl phthalate, dibutyl phthalate, were previously measured in the mothers’ serum, cord
and benzyl butyl phthalate, is to inhibit fetal testis Leydig serum, and the placenta (averaged for in utero expo-
cell steroidogenesis and insl3 synthesis, leading to male sure). Concentrations in breast milk also were deter-
developmental and reproductive system malformations mined (lactational exposure). Puberty-timing measures,
(eg, retained nipples, reduced or absent reproductive or- Tanner stages (boys and girls), and menarche were as-
gans, undescended testes, hypospadias, delayed PPS) with sessed by annual questionnaires. For boys, no associa-
in utero exposure and delays in puberty with peripubertal tion was observed for either in utero or lactational DDE
exposure.75 Administration of phthalates during puberty to exposure. Among girls, there was no association with
marmosets induced ovarian and uterine alterations in fe- age at menarche; however, there was a suggestion of an
males and reduced peripubertal testosterone levels in association of higher in utero or lactational exposure and
males76; however, the effect on androgen levels was not earlier breast and pubic hair development that was not
significant because of the extreme variability in this mea- statistically significant. Vasiliu et al98 also evaluated in
sure in this species. utero exposure to DDT/DDE that was estimated using a
decay model based on maternal measurements among
Human Studies daughters of a Michigan angler cohort. The authors ob-
Many human studies have shown a positive relation
served a significantly earlier menarche among girls with
between body fat, primarily measured by BMI or skin-
an increased in utero exposure. Specifically, menarche
fold thickness, and onset of puberty, as determined by
was 1 year earlier for every 15-g/L increase in in utero
the onset of the growth spurt, breast development, or
exposure. No association was seen with breastfeeding
menarche.77–84 Similar findings are observed in boys as
and age at menarche.
measured by growth spurt or genital and pubic hair mat-
Several additional studies evaluated DDT/DDE expo-
uration.81,85–87 Body size measures also have been associ-
sure in childhood using various designs. Krstevska-Kon-
ated with early puberty,82,86,88 as have dietary and physical
stantinova et al99 measured DDE concentration among
activity exposures and pubertal timing.79,89–94 Environmen-
tal exposure to persistent halogenated organic chemicals girls who were born in Belgium compared with those
such as PCBs, dichlorodiphenyltrichloroethane/dichlorodi- who were foreign-born. The foreign-born girls had sig-
phenyldichloroethylene (DDT/DDE), and brominated nificantly higher levels of DDE that were correlated with
flame retardants have been associated with pubertal alter- age at immigration and time since immigration than
ations, as have dioxin, hexachlorobenzene (HCB), en- native-born girls. Other migratory effects have been seen
dosulfan, and heavy metals, but to a lesser extent (Table 2). in other populations.100 They also estimated the inci-
The first study to report that timing of puberty was dence of precocious puberty among native Belgium girls
associated with developmental exposure to persistent and foreign adopted girls from vital records and adoption
organic pollutants was conducted among a cohort of registries and found the rate of precocious puberty to be
individuals who were exposed to brominated flame re- 80 times higher than that for native-born Belgium girls.
tardants.95 An industrial accident resulted in the contam- Although suggestive, this preliminary study was limited
ination of cattle feed with polybrominated biphenyls and in size and scope, especially with regard to other differ-
widespread human exposure through consumption of ences unaccounted for between the 2 groups of children.
meat and dairy products. Daughters of women who Ouyang et al101 studied newly married female textile
consumed contaminated farm products were inter- workers in China by measuring serum DDT/DDE con-
viewed or completed a self-administered mailed ques- centration. Women were asked to recall age at men-
tionnaire. Age at menarche and Tanner stages (for those arche. A significant dose-response relation was found
who were younger than 18 years) were assessed. Ma- between serum DDT/DDE concentrations and earlier
ternal serum levels of polybrominated biphenyl at the menarche. A 10 ng/g increase in exposure was associ-
time of conception were estimated from a decay model ated with 0.2 years earlier onset of menarche. Because
using serum concentrations that were measured before exposure occurred after pubertal development was com-
and/or after the pregnancy.96 Girls who were exposed in plete, the causal order of exposure-puberty cannot be
utero to high concentrations (ⱖ7 ppb) and who were established because pubertal development may have af-
breastfed reported menarche 1 full year earlier than unex- fected the metabolism/distribution of DDT or other be-
posed girls (⬍1 ppb, the limit of detection) or girls who haviors that influenced DDT exposure. Denham et al102
were exposed in utero but not breastfed. Breastfed girls conducted a cross-sectional study among girls who were
with high in utero exposure also reported more advanced aged 10 to 17 years and resided in the Mohawk Nation
S198 BUCK LOUIS et al
Downloaded from www.aappublications.org/news by guest on October 23, 2021TABLE 2 Human Studies That Assessed Associations Between Environmental Chemical Exposures and Puberty Timing
Chemical Exposure Population (Sample Size) Study Design Findings Reference
(Biospecimen)
Brominated flame US, Michigan girls aged 5–24, CS/C; assessment of Tanner stages Earlier menarche and pubic hair Blanck et al95 (2000)
retardant (estimated accidental in utero and/or in female offspring; recalled age development among girls
maternal serum PBB at lactational exposure (327) at menarche in postmenarchal highly exposed in utero and
conception) offspring breastfed; no association
with breast development
DDE (maternal blood, cord US, North Carolina boys and C; assessed menarche, Tanner Boys: no association; girls: Gladen et al97 (2000)
blood, and placenta girls (594) stages by annual questionnaire suggestion of earlier breast
averaged; breast milk) and pubic hair development
with high transplacental and
with high lactational
exposure
DDE (serum) Girls with precocious puberty: CS; serum DDE compared Foreign-born girls with Krstevska-Konstantinova
foreign-born girls (26); between foreign-born and precocious puberty had et al99 (2001)
Belgium girls (15) Belgium girls; all had significantly higher DDE
precocious puberty concentration than native
Belgium girls with
precocious puberty.
DDE (estimated maternal US, Michigan daughters of C; recalled age at menarche Higher DDE associated with Vasiliu et al98 (2004)
serum DDE at women who consumed earlier menarche.
conception) Great Lakes fish (151)
DDT/DDE (serum in Chinese female textile CS; recalled age at menarche Higher DDT/DDE associated Ouyang et al101 (2005)
adulthood) workers, newly married with earlier menarche
(466)
DDE (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) No association Denham et al102 (2005)
girls 10–17 (138)
Dioxin-like activity 17-y-old Belgium boys (78) CS; assessment of Tanner stage by Boys: no association; girls: girls Den Hond et al106 (2002)
(serum; CALUX) and girls (120) from examination (boys and girls), with high exposure were less
polluted and nonpolluted testicular volume (boys), likely to have reached the
areas recalled age at menarche (girls). highest stage of breast
development; no association
with pubic hair development
or age at menarche.
Dioxin (serum) Seveso, Italy, women C; recalled age at menarche No association; suggestion of Warner et al108 (2004)
exposed postnatally and earlier menarche among girls
prepuberty to dioxin exposed before the age of 5
industrial accident (282)
Endosulfan India, boys aged 10–17 in C/CS; Tanner stage by physical Exposed boys were less mature Saiyed et al111 (2003)
exposed (117) and examination; serum hormones and had lower testosterone
unexposed (90) areas and endosulfan levels for 70 and higher LH than
exposed, 45 unexposed. unexposed boys
HCB (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) No association Denham et al102 (2005)
girls 10–17 (138)
Lead (serum) US 8- to 16-y-old girls CS, assessed age at menarche and Later pubic hair and breast Selevan et al112 (2003)
NHANES III (2186) Tanner stages; analyses development associated
stratified by ethnic groups with higher lead among
blacks and Mexican
Americans, suggested
association among non-
Hispanic whites; later
menarche associated with
higher lead among blacks,
suggested association
among Mexican Americans
and non-Hispanic whites
Lead (serum) US 8- to 16-y-old girls CS, assessed age at menarche and Later menarche and pubic hair Wu et al113 (2003)
NHANES III (1706) Tanner stages development with higher
lead exposure; no association
with breast development
Lead (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) Exposure to lead associated Denham et al102 (2005)
girls 10–17 (138) with lower likelihood of
menarche
PEDIATRICS Volume 121, Supplement 3, February 2008 S199
Downloaded from www.aappublications.org/news by guest on October 23, 2021TABLE 2 Continued
Chemical Exposure Population (Sample Size) Study Design Findings Reference
(Biospecimen)
Mercury (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) Suggestion of earlier menarche Denham et al102 (2005)
girls 10–17 (138) with mercury exposure
Mirex (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) No association Denham et al102 (2005)
girls 10–17 (138)
PCBs (serum) US/Canada Mohawk Nation, CS; menarche (yes/no) 4 potentially estrogenic PCB Denham et al102 (2005)
girls 10–17 (138) congeners (52, 70, 101⫹90,
and 187) significantly
associated with a greater
probability of having
reached menarche
PCBs (maternal blood, US, North Carolina boys and C; assessed menarche, Tanner Boys: no association; girls: Gladen et al97 (2000)
cord blood, and girls (594) stages by annual questionnaire suggestion of earlier breast
placenta averaged; and pubic hair development
breast milk) with high transplacental,
suggestion of earlier pubic
hair development with
lactational exposure
PCBs (maternal serum) US, Michigan girls aged 5–24 CS; assessment of Tanner stages; No association Blanck et al95 (2000)
(256) recall of age at menarche in
postmenarchal girls
PCBs (cord blood) Faroe Islands boys (175) C/CS; genital anomalies at birth, No significant associations; Mol et al103 (2002)
examination at age 14 for suggestion of higher
Tanner stage, testicular size, testosterone with higher PCB
spermaturia, and serum exposure
hormones
PCBs (serum; congeners 17-y-old Belgium boys (78) CS; assessment of Tanner stage by Boys: high exposure to PCB 138 Den Hond et al106 (2002)
138, 153, and 180) and girls (120) from examination and testicular less likely to have reached
polluted and nonpolluted volume highest stage of genital
areas development, high PCB 153
less likely to have reached
highest stage of pubic hair;
girls: no associations
PCBs/PCDFs Taiwan, girls aged 13–19 C; recalled age at menarche, No association with age at Yang et al104 (2005)
exposed to contaminated menstrual cycle characteristics, menarche; exposed girls
oil (Yucheng) in utero (27) serum hormones reported shorter cycle length
and controls (21) and more irregular cycles,
exposed girls had higher
levels of estradiol and FSH
PCBs/PCDFs Taiwan, boys (mean age: C/CS; Tanner stages by exam, No association with Tanner Hsu et al105 (2005)
12.3) exposed to testicular size, serum hormones stage or testicular size; some
contaminated oil differences in hormone
(Yucheng) in utero (61) levels in boys ⱖ13 years
and controls (60)
PCBs (estimated maternal US, Michigan daughters of C; recalled age at menarche No association Vasiliu et al98 (2004)
serum PCBs at women who consumed
conception) Great Lakes fish (151)
PCBs (serum congeners) US/Canada Mohawk Nation, CS; menarche (yes/no) Exposure to estrogenic Denham et al102 (2005)
girls 10–17 (138) congeners (52, 70, 90, 101,
187, geometric mean)
associated with greater
likelihood of menarche; no
association with other
congener groups
Phthalates (serum) Puerto Rico (41 PT cases, 35 Case control Serum phthalate (primarily Colon et al109 (2000)
controls) DEHP) significantly higher in
cases than controls
CS, cross-sectional study; C, cohort study; CS/C cross-sectional assessment within a cohort; CALUX, chemically activated luciferase gene expression; PBB, polybrominated biphenyl; NHANES III, Third
National Health and Nutrition Examination Survey; PCDFs, polychlorinated dibenzo-furans; PT, premature thelarche.
along the United States/Canadian border to assess serum sure and menarche despite the authors’ assumption that
concentrations and self-reported menarchal status (yes/ current serum concentrations were indicative of in utero
no). No association was observed between DDT expo- and lactational exposures, given the long-standing con-
S200 BUCK LOUIS et al
Downloaded from www.aappublications.org/news by guest on October 23, 2021cern regarding consumption of contaminated fish were compared with 35 control girls with regard to
among this population. serum pesticides and phthalate esters. Significantly
Five studies evaluated developmental PCB exposures higher phthalate levels were found among the girls with
in relation to pubertal development. Gladen et al97 re- thelarche than comparison girls. The authors concluded
ported no relation between in utero or lactational PCB that the findings were suggestive of a possible associa-
exposure and age at menarche among girls. Higher lac- tion between exposures and premature breast develop-
tational exposure was associated with earlier Tanner ment in girls. Interpretation of these findings may be
staging in boys and girls, although the results did not limited by residual confounding and concerns about the
achieve statistical significance. Mol et al103 established a analytical method of measuring the phthalate parent
prospective cohort study of boys in the Faroe Islands, compound instead of the metabolites.110 Saiyed et al111
where PCB levels are known to be relatively high. PCB found that boys who were exposed to endosulfan in
levels were measured in cord serum and tissue. Boys India were less mature and had lower testosterone and
were examined at 14 years of age for Tanner staging, higher LH than unexposed boys.
testicular size, spermaturia (sperm in urine), and serum Three cross-sectional published articles assessed the
hormones. No statistically significant associations were relation between lead exposure and pubertal measures
found between PCB concentrations and measures of using either the Third National Health and Nutrition
pubertal development. A suggestion of a positive associ- Examination Survey112,113 or the Mohawk Nation
ation between testosterone and PCB exposure was re- Study.102 In the Third National Health and Nutrition
ported. Two cohort studies previously described95,98 also Examination Survey analyses, blood lead levels were
evaluated in utero exposure to PCBs among daughters of analyzed in relation to age at onset for Tanner stage 2 for
women who were exposed. Neither study found an as- breast and pubic hair and menarche among US girls aged
sociation between PCB exposure and age at menarche. 8 to 18 years.113 Selevan et al112 estimated odds ratios for
Last, Yang et al104 and Hsu et al105 described no pubertal lead levels in relation to progression of puberty (stages
developmental differences among boys or girls with and 2–5) among girls. Combined, these studies suggested an
without exposure to PCB- and polychlorinated dibenzo- inverse relation between blood lead levels and the onset
furan– contaminated cooking oil. and progression of puberty in girls, especially for sub-
Two cross-sectional studies of PCB exposure have groups within the population. An association also was
been conducted. Den Hond et al106 measured PCB con- found between higher blood lead level and delayed
geners in a sample of boys and girls who were aged 17 menarche, but this association was statistically signifi-
years and recruited from 1 of 2 exposed areas in Belgium: cant only for black girls. The cross-sectional analysis
residence near a lead smelter or waste incinerator or a among Mohawk nation girls also found later puberty
referent rural area. Puberty timing was measured using the among girls with higher lead exposures than girls with
Tanner staging as a part of a physical examination. Odds lower exposure.
ratios were estimated for PCB concentration and odds for
being in a puberty stage that indicated that puberty was not Cross-species Concordance of Pubertal Timing Effects
yet complete (ie, lower than stage 5). Exposed boys had Most chemicals have not been consistently studied in
completed pubertal development later, because odds ratios both animals and humans, with a few notable excep-
for higher PCB exposures (for both specific congeners and tions. Even when such research is available for a partic-
total PCBs) were associated with stage ⬍5 for genital and ular chemical, interpretation is exceedingly challenging
pubic hair development. Because this study evaluated 17- given issues pertaining to dosage and timing of exposure
year-olds, it is not clear whether puberty began later or the and limited measurement of other relevant covariates.
peripubertal duration was longer. No pubertal delays were When such data are available (eg, TCDD, lead, DDE,
seen in girls with PCB exposure. Among Akwesasne Mo- PCBs, estrogens), similar findings tend to be observed
hawk Nation Girls, exposure to a group of 4 potentially across species. For example, pharmaceutical estrogens
estrogenic PCB congeners (52, 70, 101 ⫹ 90, and 187) was (eg, diethylstilbestrol, ethinyl estradiol) are the best ex-
associated with a significantly greater likelihood of having amples of accelerated female breast development in hu-
reached menarche.102 mans, but the effect tends to be reversible and isolated
Two studies assessed childhood exposure to dioxins from other pubertal effects.29,30–33 This is similar to the
and puberty. Den Hond et al106 measured dioxin-like effects of estrogen exposure in the female rat56 and the
activity with the chemically activated luciferase gene monkey, which cause pseudoprecocious or dysregulated
expression assay107 and reported an association with puberty markers.50 In male humans, pharmaceutical
Tanner stage ⬍5 breast development; however, pubic agents that are used to halt early puberty also cause
hair stage in boys and girls and genital stage in boys was similar effects in male rats. In the rat, in utero TCDD
not significantly associated with dioxin-like activity. exposure resulted in delayed puberty as measured by a
Warner et al108 examined pubertal development among late age of VO and a delayed or incomplete differentia-
girls who were exposed postnatally or during childhood tion of mammary epithelium.8 Similarly, Den Hond et
to dioxin in Seveso, Italy. TCDD was not associated with al106 reported an association between high dioxin blood
age of menarche (self-reported at interview). None of levels and later completion of breast development. This
the women was exposed prenatally. cross-species concordance may indicate that the Ah recep-
Colon et al109 studied phthalate esters exposure and tor agonism is active across species. For developmental lead
premature thelarche. Forty-one girls with thelarche exposure, animal and human studies both show a delay in
PEDIATRICS Volume 121, Supplement 3, February 2008 S201
Downloaded from www.aappublications.org/news by guest on October 23, 2021TABLE 3 Research Recommendations for Focusing on Environmental Influences on Puberty
Priority Research Questions Recommended Studies Recommended Species
Etiologic Research
1. Are environmental levels of EDCs Prospective epidemiologic research inclusive of Humans
affecting onset and progression existing cohort currently being followed (eg,
of puberty and aberrant Seveso, Yucheng, Yusho, PBB, DES
pubertal development such as grandchildren) or newly designed
delayed or precocious puberty epidemiologic research capturing
in children? environmentally relevant exposures (single
chemical and mixtures)
Cross-sectional studies for monitoring
population changes particularly across
geographic areas and inclusive of high-risk
subgroups of the population
2. Do body shape and adiposity Prospective epidemiologic research inclusive of Humans
affect onset and progression of existing cohort currently being followed
puberty and aberrant pubertal (eg, Seveso, Yucheng, Yusho, PBB, DES
development such as delayed or grandchildren) or newly designed
precocious puberty in children? epidemiologic research capturing
environmentally relevant exposures (single
chemical and mixtures)
Cross-sectional studies for monitoring
population changes particularly across
geographic areas and inclusive of high-risk
subgroups of the population
Critical windows of exposure
3. What are the critical windows, Prospective research comprising couples Humans and nonhuman
ranging from periconception attempting pregnancy to capture parentally primates
through adolescence, for human mediated exposures from periconception
pubertal development in window to prospective pregnancy cohorts
relation to environmental Research focusing on the early origins of
exposures? human health and disease
Mechanistic
4. What is the primary signal(s) for Genomics and proteomic studies using Nonhuman primates and
the onset of GnRH-dependent nonhuman primates and humans with humans
(central) puberty? alterations in the onset of puberty
5. What is the primary signal(s) for Genomic and proteomic studies using Rodents
the onset of GnRH-independent transgenic rodent model.
(peripheral) puberty?
6. What is the molecular basis for Identifying the similarities and differences in Rodents, nonhuman primates
sexual dimorphism in puberty molecules involved from puberty initiation
onset and progression? to final outcome (described in 4 and 5) in
males and females
7. How is the tempo of puberty Environmental exposure and puberty-timing Rodents, nonhuman primates,
progression including the studies that measure ⬎1 puberty-timing humans
temporal relationship among end point/outcome.
the different markers regulated?
pubertal development,112–115 suggesting a similar mecha- ture of compounds to which humans are exposed. Much
nism for rodents and humans. P,p⬘-DDE exposure in “for- of the data are derived from cross-sectional studies,
eign-born” girls was associated with earlier puberty relative which are unable to establish the causal ordering of
to native-born Belgians99 and, possibly, increasing DDE in environment in relation to puberty. To this end, timing
utero exposure with earlier puberty in girls97,98; however, and dose at critical windows of human development
no animal studies of DDE exposure and female puberty have not been purposefully assessed. Other relevant co-
timing were identified, limiting additional interpretation of variates such as lifestyle, genetic determinants, and
the human data. In male rats, peripubertal DDE exposure other xenobiotics in the chemical mixture have not been
delays PPS,116–118 although no relation to lower exposures well studied, if at all, in the context of EDCs.
was found in boys after in utero DDE exposure.97
The weight of animal and human data, although sug- RESEARCH RECOMMENDATIONS
gestive, remains inconclusive for establishing a causal The panel was asked to make research recommendations
relation between EDCs and human pubertal distur- that are responsive to critical data gaps regarding pur-
bances. As reviewed, much of the available literature ported environmental factors that may adversely affect
focuses on a single chemical or class, ignoring the mix- puberty, to prioritize research initiatives including meth-
S202 BUCK LOUIS et al
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