From Wikipedia, the free encyclopedia

Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.[1][2]

Xenoestrogens are clinically significant because they can mimic the effects of endogenous estrogen and thus have been implicated in precocious puberty and other disorders of the reproductive system.[3][4]

Xenoestrogens include pharmacological estrogens (in which estrogenic action is an intended effect, as in the drug ethinylestradiol used in contraceptive pills), but other chemicals may also have estrogenic effects. Xenoestrogens have been introduced into the environment by industrial, agricultural and chemical companies and consumers only in the last 70 years or so, but archiestrogens exist naturally. Some plants (like the cereals and the legumes) are using estrogenic substances possibly as part of their natural defence against herbivore animals by controlling their fertility.[5][6]

The potential ecological and human health impact of xenoestrogens is of growing concern.[7] The word xenoestrogen is derived from the Greek words ξένο (xeno, meaning foreign), οἶστρος (estrus, meaning sexual desire) and γόνο (gene, meaning "to generate") and literally means "foreign estrogen". Xenoestrogens are also called "environmental hormones" or "EDC" (Endocrine Disrupting Compounds). Most scientists that study xenoestrogens, including The Endocrine Society, regard them as serious environmental hazards that have hormone disruptive effects on both wildlife and humans.[8][9][10][11][12]

Mechanism of action[edit]

The onset of puberty is characterized by increased levels of hypothalamic gonadotropin releasing hormone (GnRH). GnRH triggers the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland, which in turn causes the ovaries to respond and secrete estradiol. Increases in gonadal estrogen promote breast development, female fat distribution and skeletal growth. Adrenal androgen and gonadal androgen result in pubic and axillary hair.[13][14] Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.[15]

Xenoestrogens in plastics, packaged food, drink trays and containers, (more so, when they've been heated in the Sun, or an oven), may interfere with pubertal development by actions at different levels – hypothalamic-pituitary axis, gonads, peripheral target organs such as the breast, hair follicles and genitals. Exogenous chemicals that mimic estrogen can alter the functions of the endocrine system and cause various health defects by interfering with synthesis, metabolism, binding or cellular responses of natural estrogens.[14][16][17][18]

Although the physiology of the reproductive system is complex, the action of environmental exogenous estrogens is hypothesized to occur by two possible mechanisms. Xenoestrogens may temporarily or permanently alter the feedback loops in the brain, pituitary, gonads, and thyroid by mimicking the effects of estrogen and triggering their specific receptors or they may bind to hormone receptors and block the action of natural hormones. Thus it is plausible that environmental estrogens can accelerate sexual development if present in a sufficient concentration or with chronic exposure.[16][18][19][20] The similarity in the structure of exogenous estrogens and the estrogens has changed the hormone balance within the body and resulted in various reproductive problems in females.[14] The overall mechanism of action is binding of the exogenous compounds that mimic estrogen to the estrogen binding receptors and cause the determined action in the target organs.[21]

Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action
Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol 16.39 (0.7–60) 6.5 (1.36–52) 0.445 (0.3–1.01) 1.75 (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen
Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2 120.9 (68.8–480) 44.4 (2.0–144) 0.02–0.05 0.29–0.81 Estrogen
Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen
Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen
Diethylstilbestrol DES; Stilbestrol 129.5 (89.1–468) 219.63 (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol 153.6 (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol 37 (20.4–223) 56–404 0.05 0.03 Estrogen
Benzestrol (B2) 114 ? ? ? Estrogen
Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen
Triphenylethylene TPE 0.074 ? ? ? Estrogen
Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen
Tamoxifen ICI-46,474 3 (0.1–47) 3.33 (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT 100.1 (1.7–257) 10 (0.98–339) 2.3 (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 25 (19.2–37.2) 12 0.9 1.2 SERM
Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM
Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM
Raloxifene 41.2 (7.8–69) 5.34 (0.54–16) 0.188–0.52 20.2 SERM
Arzoxifene LY-353,381 ? ? 0.179 ? SERM
Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM
Ormeloxifene Centchroman ? ? 0.313 ? SERM
Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM
Ospemifene Deaminohydroxytoremifene 0.82–2.63 0.59–1.22 ? ? SERM
Bazedoxifene ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384 63.5 (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 43.5 (9.4–325) 21.65 (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT 49 (10.0–89.1) 0.12 0.40 92.8 ERα agonist
16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist
Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist
Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist
Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist
ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist
SERBA-2 ? ? 14.5 1.54 ERβ agonist
Coumestrol 9.225 (0.0117–94) 64.125 (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein 0.445 (0.0012–16) 33.42 (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol 0.2–0.287 0.85 (0.10–2.85) ? ? Xenoestrogen
Daidzein 0.07 (0.0018–9.3) 0.7865 (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A 0.04 (0.022–0.15) 0.6225 (0.010–1.2) 174 8.9 Xenoestrogen
Kaempferol 0.07 (0.029–0.10) 2.2 (0.002–3.00) ? ? Xenoestrogen
Naringenin 0.0054 (<0.001–0.01) 0.15 (0.11–0.33) ? ? Xenoestrogen
8-Prenylnaringenin 8-PN 4.4 ? ? ? Xenoestrogen
Quercetin <0.001–0.01 0.002–0.040 ? ? Xenoestrogen
Ipriflavone <0.01 <0.01 ? ? Xenoestrogen
Miroestrol 0.39 ? ? ? Xenoestrogen
Deoxymiroestrol 2.0 ? ? ? Xenoestrogen
β-Sitosterol <0.001–0.0875 <0.001–0.016 ? ? Xenoestrogen
Resveratrol <0.001–0.0032 ? ? ? Xenoestrogen
α-Zearalenol 48 (13–52.5) ? ? ? Xenoestrogen
β-Zearalenol 0.6 (0.032–13) ? ? ? Xenoestrogen
Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol 16 (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN 7.68 (2.04–28) 9.45 (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA 0.0315 (0.008–1.0) 0.135 (0.002–4.23) 195 35 Xenoestrogen
Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen
Kepone Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen
o,p'-DDT 0.0073–0.4 ? ? ? Xenoestrogen
p,p'-DDT 0.03 ? ? ? Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT 0.01 (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen
Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen
Dihydrotestosterone DHT; 5α-Androstanolone 0.01 (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen
Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen
Dehydroepiandrosterone DHEA; Prasterone 0.038 (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen
5-Androstenediol A5; Androstenediol 6 17 3.6 0.9 Androgen
4-Androstenediol 0.5 0.6 23 19 Androgen
4-Androstenedione A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen
3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen
3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen
Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen
Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT 0.085 (0.0015–<0.1) 0.1 (0.01–0.3) 152 1084 Progestogen
Norethynodrel 5(10)-Norethisterone 0.5 (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel 0.5 (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<0.1 ? ? Progestogen
3α-Hydroxytibolone 2.5 (1.06–5.0) 0.6–0.8 ? ? Progestogen
3β-Hydroxytibolone 1.6 (0.75–1.9) 0.070–0.1 ? ? Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.


Xenoestrogens have been implicated in a variety of medical problems, and during the last 10 years many scientific studies have found hard evidence of adverse effects on human and animal health.[33]

There is a concern that xenoestrogens may act as false messengers and disrupt the process of reproduction. Xenoestrogens, like all estrogens, can increase growth of the endometrium, so treatments for endometriosis include avoidance of products which contain them. Likewise, they are avoided in order to prevent the onset or aggravation of adenomyosis. Studies have implicated observations of disturbances in wildlife with estrogenic exposure. For example, discharge from human settlement including runoff and water flowing out of wastewater treatment plants release a large amount of xenoestrogens into streams, which lead to immense alterations in aquatic life. With a bioaccumulation factor of 105 –106, fish are extremely susceptible to pollutants.[34] Streams in more arid conditions are thought to have more effects due to higher concentrations of the chemicals arising from lack of dilution.[35]

When comparing fish from above a wastewater treatment plant and below a wastewater treatment plant, studies found disrupted ovarian and testicular histopathology, gonadal intersex, reduced gonad size, vitellogenin induction, and altered sex ratios.[35]

The sex ratios are female biased because xenoestrogens interrupt gonadal configuration causing complete or partial sex reversal. When comparing adjacent populations of white sucker fish, the exposed female fish can have up to five oocyte stages and asynchronously developing ovaries versus the unexposed female fish who usually have two oocyte stages and group-synchronously developing ovaries. Previously, this type of difference has only been found between tropical and temperate species.[35]

Sperm concentrations and motility perimeters are reduced in male fish exposed to xenoestrogens in addition to disrupt stages of spermatogenesis.[24][35] Moreover, xenoestrogens have been leading to vast amounts of intersex in fish. For example, one study indicates the numbers of intersex in white sucker fish to be equal to the number of males in the population downstream of a waste water treatment plant. No intersex members were found upstream from the plant. Also, they found differences in the proportion of testicular and ovarian tissue and its degree of organization between the intersex fish.[35] Furthermore, xenoestrogens expose fish to CYP1A inducers through inhibiting a putative labile protein and enhancing the Ah receptor, which has been linked to epizootics of cancer and the initiation of tumors.[34]

The induction of CYP1A has been established to be a good bioindicator for xenoestrogen exposure. In addition, xenoestrogens stimulate vitellogenin (Vtg), which acts as a nutrient reserve, and Zona readiata proteins (Zrp), which forms eggshells. Therefore, Vtg and Zrp are biomarkers to exposure for fish.[36]

Another potential effect of xenoestrogens is on oncogenes, specifically in relation to breast cancer. Some scientists doubt that xenoestrogens have any significant biological effect, in the concentrations found in the environment.[37] However, there is substantial evidence in a variety of recent studies to indicate that xenoestrogens can increase breast cancer growth in tissue culture.[38][39][40][41]

It has been suggested that very low levels of a xenoestrogen, Bisphenol A, could affect fetal neural signalling more than higher levels, indicating that classical models where dose equals response may not be applicable in susceptible tissue.[42] As this study involved intra-cerebellar injections, its relevance to environmental exposures is unclear, as is the role of an estrogenic effect compared to some other toxic effect of bisphenol A.

Other scientists argue that the observed effects are spurious and inconsistent, or that the quantities of the agents are too low to have any effect.[43] A 1997 survey of scientists in fields pertinent to evaluating estrogens found that 13 percent regarded the health threats from xenoestrogens as "major," 62 percent as "minor" or "none," and 25 percent were unsure.[44]

There has been speculation that falling sperm counts in males may be due to increased estrogen exposure in utero.[45] Sharpe in a 2005 review indicated that external estrogenic substances are too weak in their cumulative effects to alter male reproductive functioning, but indicates that the situation appears to be more complex as external chemicals may affect the internal testosterone-estrogen balance.[46]


The ubiquitous presence of such estrogenic substances is a significant health concern, both individually and for a population. Life relies on the transmission of biochemical information to the next generation, and the presence of xenoestrogens may interfere with this transgenerational information process through "chemical confusion" (Vidaeff and Sever),[47] who state: "The results do not support with certainty the view that environmental estrogens contribute to an increase in male reproductive disorders, neither do they provide sufficient grounds to reject such a hypothesis."

A 2008 report demonstrates further evidence of widespread effects of feminizing chemicals on male development in each class of vertebrate species as a worldwide phenomenon.[48] Ninety-nine percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.[48]

Agencies such as the United States Environmental Protection Agency and the World Health Organization International Programme on Chemical Safety are charged to address these issues.[citation needed]

Precocious puberty[edit]

Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function.[13][19][49][50] The first sign of female puberty is an acceleration of growth followed by the development of a palpable breast bud (thelarche). The median age of thelarche is 9.8 years. Although the sequence may be reversed, androgen dependent changes such as growth of axillary and pubic hair, body odor and acne (adrenarche) usually appears 2 years later. Onset of menstruation (menarche) is a late event (median 12.8 years), occurring after the peak of growth has passed.[13]

Puberty is considered precocious (precocious puberty) if secondary sex characteristics occur before the age of 8 in girls and 9 years in boys.[13][15] Increased growth is often the first change in precocious puberty, followed by breast development and growth of pubic hair. However, thelarche, adrenarche, and accelerated growth can occur simultaneously and although uncommon, menarche can be the first sign.[13] Precocious puberty can be classified into central (gonadotropin-dependent) precocious puberty or peripheral (gonadotropin-independent) puberty.[13][19][50][51] Both central and peripheral precocious puberty have been linked to exposure to exogenous estrogenic compounds.[50][51]

Central precocious puberty is due to early maturation of the hypothalamic–pituitary–gonadal (HPG) axis. Majority of central precocious puberty cases are spontaneous or arise from an unknown cause, but some of these cases arise from organic lesions, environmental factors, and endocrine disrupting chemicals.[51] Central precocious puberty is most commonly caused through idiopathic (unknown) reasons in girls, but there is an increased risk of these organic causes for central precocious puberty in boys.[51]

Peripheral precocious puberty is independent of gonadotropin and thus does not activate the HPG axis. [51] Peripheral precocious puberty in females most commonly shows through ovarian follicular cysts, which may cause vaginal bleeding.[51]  LH receptor activating mutations (familial testotoxicosis) are autosomal dominate diseases found in male children.[51][52] These diseases are usually characterized by enlarged testis and can be an indication of peripheral precocious puberty in boys.[51]

Age of onset of puberty is influenced by many factors such as genetics, nutritional status, ethnicity and environmental factors including socio-economic conditions and geographical location.[3][53] A decline of age at onset of puberty from 17 years of age to 13 years of age has occurred over a period of 200 years until the middle of the 20th century.[3][16][49] Trends toward earlier puberty have been attributed to improved public health and living conditions.[54] A leading hypothesis for this change toward early puberty is improved nutrition resulting in rapid body growth, increased weight and fat deposition.[55] However, recent studies have shown that chemical exposure to environmental estrogen disruptors the HPG axis and result in precocious puberty.[56][57] In 1999, US Food and Drug Administration has recommended to not take estrogen in food of more than 0.43 ng/day for boys and 3.24 ng/day for females.[58] Two recent epidemiologic studies in the United States (PROS and NMANES III)[59] highlighted a recent unexpected advance in sexual maturation in girls.[3][4][60] American, European and Asian studies suggest breast development in girls occurs at a much younger age than a few decades ago, irrespective of race and socioeconomic conditions.[16][49][55] Environmental chemical exposure is one of the factors implicated in the recent downward trend of earlier sexual maturation.[16][49][60]


The prevelance of precocious puberty is difficult to determine as it is highly variable depending on the population from which the data has been collected. The Danish national registry estimated that roughly 20-23 per 10,000 (0.2%) of girls and 5 per 10,000 (0.05%) of boys suffer from a form of precocious puberty.[61] An additional study conducted in Korea reported a where 55.9 per 100,000 girls and 1.7 per 100,000 boys indicated signs of central precocious puberty.[62]

Thelarche in Puerto Rico[edit]

Since 1979, pediatric endocrinologists in Puerto Rico recognized an increase in number of patients with premature thelarche.[63] The presence of phthalates were measured in the blood of 41 girls experiencing early onset breast development and matched set of controls. The average age of girls with premature thelarche was 31 months. They found high phthalate levels in the girls suffering from premature thelarche compared to the controls.[64] Not all cases of premature thelarche in the study sample contained elevated levels of phthalate esters and there was concern whether artificial contamination from vinyl lab equipment and tubing invalidated the results, hence weakening the link between exposure and causation.[63][65]

Tuscany precocious puberty cases[edit]

Dr. Massart and colleagues from the University of Pisa studied the increased prevalence of precocious puberty in a region of northwest Tuscany. This region of Italy is represented by a high density of navy yards and greenhouses where exposures to pesticides and mycoestrogens (estrogens produced by fungi) are common. Although unable to identify a definitive cause of the high rates of precocious puberty, the authors concluded environmental pesticides and herbicides may be implicated.[66]

Dairy contamination[edit]

Animal feed was contaminated with several thousand pounds of polybrominated biphenyl in Michigan in 1973 resulting in high exposures of PBB in the population via milk and other products from contaminated cows. Perinatal exposure of children was estimated by measuring PBB in serum of mothers some years after exposure. Girls that had been exposed to high PBB levels through lactation had an earlier age of menarche and pubic hair development than girls who had less perinatal exposure. The study noted there no differences found in the timing of breast development among the cases and controls.[16][20][65]

Fish contamination[edit]

The Great Lakes have been polluted with industrial wastes (mainly PCBs and DDT) since the beginning of the 20th century. These compounds have accumulated in birds and sports fish. A study was designed to assess the impact of consumption of contaminated fish on pregnant women and their children. Concentrations of maternal serum PCB and DDE and their daughters' age at menarche were reviewed. In multivariate analysis, DDE but not PCB was linked with a lowered age of menarche.[20][63][65] Limitations of the study included indirect measurement of the exposure and self reporting of menarche.[20]


Precocious puberty has numerous significant physical, psychological and social implications for young children. It has been associated with metabolic disorders (insulin resistance and diabetes), increased cardiometabolic risk (high blood pressure and cholesterol levels), obesity,[60][67] increased cancer risk (breast[60] and endometrial for girls and testicular for boys).[68] Precocious puberty is linked with other gynecologic disorders such as endometriosis, adenomyosis, polycystic ovarian syndrome and infertility.[17][69][70] Premature pubertal growth spurt and accelerated bone maturation will result in premature closure of distal epiphysis which causes reduced adult height and short stature.[67] Precocious puberty can lead to psychosocial distress, a poor self-image, and poor self-esteem.[71] Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse.[17][69][71] Studies indicate that girls who become sexually mature at earlier ages are also more likely to engage in risk-taking behaviors such as smoking, alcohol or drug use, and engage in unprotected sex.[67][71]

The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty.[60] Gaps in our knowledge are the result of limitations in the designs of studies, small sample sizes, challenges to conducting exposure assessment and the few number of chemicals studied.[60] Unfortunately exposure is inferred and not actually measured in available studies.[17] The ability to detect the possible role of chemicals in altering pubertal development is confounded by many nutritional, genetic and lifestyle factors capable of affecting puberty and the complex nature of the reproductive endocrine system.[55][72] Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds.[72] Overall the literature does not with certainty support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. However data does not refute such a hypothesis either. Accelerated sexual development is plausible in individuals exposed to high concentration of estrogenic substances. There is a concerning steady increase in exposure to a wide variety of xenoestrogens in the industrial world. Further research is needed to assess the impact of these compounds on pubertal development.

In other animals[edit]

Non-human animal studies have shown that exposure to environmental contaminants with estrogenic activity can accelerate the onset of puberty. A potential mechanism has been described in rats exposed to DDT or beta-estradiol in which GnRH pulsatile secretion was found to be increased.[20][73] Oral exposure of female rats to xenoestrogens has been shown to cause pseudo precocious puberty (early vaginal opening and early first estrus).[53][74][75][76] A study of dioxin in immature female rats induced early follicular development[77] and phthalates are known to decrease the anogenital distance in newborn rats.[65] Although this article focuses on the effects of xenoestrogens and reproductive function in females, numerous animal studies also implicate environmental estrogens' and androgens' adverse effects on the male reproduction system.[77] Administration of estrogens to developing male animals reduces testicular weight and decreases sperm production.[18] The small phallus size of male alligators has been linked to contamination of their natural Florida habitat with DDT.[67][77] Data from animal research is abundant demonstrating the adverse effects on reproduction of hormonally active compounds found in the environment.[18][77][78][79]

Common environmental estrogens[edit]


Atrazine is widely used as an herbicide to control broad-leaf weed species that grow in crops such as corn, sugarcane, hay and winter wheat. Atrazine is also applied to Christmas trees, residential lawns, golf courses, and other recreational areas. Atrazine is the second largest selling pesticide in the world and estimated to be the most heavily used herbicide in the United States.[14] Atrazine has been implicated in interfering with the neuroendocrine system, blocking the release of gonadotropin-releasing hormone (GnRH) which in turn reduces luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.[80]


BPA (Bisphenol A) is the monomer used to manufacture polycarbonate plastic and epoxy resins used as a lining in most food and beverage cans. BPA global capacity is in excess of 6.4 billion pounds (2.9×109 kg) per year and thus is one of the highest-volume chemicals produced worldwide.[81] The ester bonds in the BPA-based polycarbonates could be subject to hydrolysis and leaching of BPA. But in the case of epoxypolymers formed from bisphenol A, it is not possible to release bisphenol A by such a reaction. It is also noteworthy that, of the bisphenols, bisphenol A is a weak xenoestrogen. Other compounds, such as bisphenol Z, have been shown to have stronger estrogenic effects in rats.[82]

It has been suggested that biphenol A and other xenoestrogens might cause disease to humans[72] and animals.[78] BPA exposure is linked to dysfunctions in human systems including the immune, neuroendocrine, and excretory systems. The damage that results in these dysfunctions is via the mechanisms of enzyme interference, cellular oxidation, epigenetic changes, and the breaking of DNA strands.[83]

Bisphenol S (BPS), an analog of BPA, has also been shown to alter estrogenic activity.[84][85] One study demonstrated that when cultured rat pituitary cells were exposed to low levels of BPS, it altered the estrogen-estradiol signaling pathway and led to the inappropriate release of prolactin.[85]


DDT (Dichlorodiphenyltrichloroethane) was widely used in pesticides for agricultural purposes until it was banned in 1972 in the United States. DDT's hazardous effects on the environment include being linked to the production of fragile eggshells in birds and showed a 90% decline in the birth rates of alligators.[86] Though it is banned in the United States, DDT continues to be used in many parts of the world for agricultural use, insect control, and to fight the spread of malaria.[14][17][65][78]

DDT and its metabolites DDE and DDD are persistent in the environment and accumulate in fatty tissues. In vertebrates, DDT is unable to be broken down and remains within the organism. There is little risk of DDT causing an increase in health risk upon exposure in adulthood, but in key developmental periods prenatally and in adolescence, there has been evidence to suggest an increased risk of breast cancer.[86]


Dioxin, a group of highly toxic chemicals are released during combustion processes, pesticide manufacturing and chlorine bleaching of wood pulp. Dioxin is discharged into waterways from pulp and paper mills. Consumption of animals fats is thought to be the primary pathway for human exposure.[14][17][54] The connection between dioxin and dioxin-like compound (DLC) exposure and human disease is one not well established. Bioassays performed in animals does not show a strong connection between the two.[87]


Endosulfan is an insecticide used on numerous vegetables, fruits, cereal grains and trees. Endosulfan can be produced as a liquid concentrate, wettable powder or smoke tablet. Human exposure occurs through food consumption or ground and surface water contamination.[14][88] Endosulfan exposure is known to cause seizures that are the result of hyper-stimulation of the central nervous system (CNS). Upon significant exposure and accumulation in the system, toxicity of the major organs such as the heart, liver and kidneys has been reported and can lead to death within hours.[89]

Brominated Flame Retardants (BFRs)[edit]

Both PBBs and PBDEs belong to the same class of chemicals known as brominated flame retardants.[90] PBBs (Polybrominated biphenyls) are chemicals added to plastics used in computer monitors, televisions, textiles and plastics foams to make them more difficult to burn. Manufacturing of PBBs in the United States stopped in 1976, however because they do not degrade easily. PBBs continue to be found in soil, water and air. PBDEs (Polybrominated biphenyl ethers) behave similarly to PBBs in that they are also a flame retardant. PBDEs are not chemically bound to the items they are attached to, and thus can leech into the environment.[91][14][20][78]


PCBs (Polychlorinated biphenyls) are man made organic chemicals known as chlorinated hydrocarbons. PCBs were manufactured primarily for use as insulating fluids and coolants given their chemical stability, low flammability and electrical insulating properties. PCBs were banned in 1979 but, like DDT, continue to persist in the environment.[14][17][65] The effects of PCBs are not limited to the environment. There have been associations revealed between maternal PCB levels and conditions such as asthma, eczema, roseola, and upper respiratory infections.[92]


Phthalates are plasticizers providing durability and flexibility to plastics such as polyvinyl chloride. High molecular weight phthalates are used in flooring, wall coverings and medical device such as intravenous bags and tubing. Low molecular weight phthalates are found in perfumes, lotions, cosmetics, varnishes, lacquers and coatings including timed releases in pharmaceuticals.[14][78][93] Exposure to phthalates can have varying effects in humans depending on maturity. In adults, phthalate exposure has been linked to conditions like asthma, metabolic disorders like type II diabetes and insulin resistance, allergies, and asthma. In children, exposure to phthalates has a marked difference when compared to adults, having been associated with disrupted reproductive hormone levels and thyroid function.[94]


Zeranol is currently used as an anabolic growth promoter for livestock in the US[95] and Canada.[96] It has been banned in the EU since 1985,[97] but is still present as a contaminant in food through meat products that were exposed to it.[14]


See also[edit]


  1. ^ Paterni I, Granchi C, Minutolo F (November 2017). "Risks and benefits related to alimentary exposure to xenoestrogens". Critical Reviews in Food Science and Nutrition. 57 (16): 3384–3404. doi:10.1080/10408398.2015.1126547. PMC 6104637. PMID 26744831.
  2. ^ Wang X, Ha D, Yoshitake R, Chan YS, Sadava D, Chen S (August 2021). "Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts". International Journal of Molecular Sciences. 22 (16): 8798. doi:10.3390/ijms22168798. PMC 8395949. PMID 34445499.
  3. ^ a b c d Aksglaede L, Juul A, Leffers H, Skakkebaek NE, Andersson AM (2006). "The sensitivity of the child to sex steroids: possible impact of exogenous estrogens". Human Reproduction Update. 12 (4): 341–349. doi:10.1093/humupd/dml018. PMID 16672247.
  4. ^ a b Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, et al. (April 1997). "Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network". Pediatrics. 99 (4): 505–512. doi:10.1542/peds.99.4.505. PMID 9093289.
  5. ^ Hughes CL (June 1988). "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environmental Health Perspectives. 78: 171–174. doi:10.1289/ehp.8878171. PMC 1474615. PMID 3203635.
  6. ^ Bentley GR, Mascie-Taylor CG (November 2000). "Wild-life studies". Infertility in the modern world: present and future prospects. Cambridge University Press. pp. 99–100. ISBN 978-0-521-64387-0.
  7. ^ Korach KS (1998). Reproductive and Developmental Toxicology. Marcel Dekker Ltd. pp. 278–279, 294–295. ISBN 978-0-8247-9857-4.
  8. ^ Bern HA, Blair P, Brasseur S, Colborn T, Cunha GR, Davis W, et al. (1992). "Statement from the Work Session on Chemically-Induced Alterations in Sexual Development: The Wildlife/Human Connection" (PDF). In Clement C, Colborn T (eds.). Chemically-induced alterations in sexual and functional development -- the wildlife/human connection. Princeton, N.J: Princeton Scientific Pub. Co. pp. 1–8. ISBN 978-0-911131-35-2. Archived from the original (PDF) on 2013-05-24. Retrieved 2010-11-16.
  9. ^ Colborn T (May 1995). "Statement from the Work Session on Environmentally induced Alterations in Development: A Focus on Wildlife". Environmental Health Perspectives. 103 (Suppl 4): 3–5. doi:10.2307/3432404. JSTOR 3432404. PMC 1519268. PMID 17539108.
  10. ^ Benson WH, Bern HA, Bue B, Colborn T, Cook P, Davis WP, et al. (1997). "Statement from the work session on chemically induced alterations in functional development and reproduction of fishes". In Rolland RM, Gilbertson M, Peterson RE (eds.). Chemically Induced Alterations in Functional Development and Reproduction of Fishes. Society of Environmental Toxicology & Chemist. pp. 3–8. ISBN 978-1-880611-19-7.
  11. ^ "Statement from the work session on environmental endocrine-disrupting chemicals: neural, endocrine, and behavioral effects". Toxicology and Industrial Health. 14 (1–2): 1–8. 1998. Bibcode:1998ToxIH..14....1.. doi:10.1177/074823379801400103. PMID 9460166. S2CID 45902764.
  12. ^ Brock J, Colborn T, Cooper R, Craine DA, Dodson SF, Garry VF, et al. (1999). "Statement from the Work Session on Health Effects of Contemporary-Use Pesticides: the Wildlife / Human Connection". Toxicol Ind Health. 15 (1–2): 1–5. Bibcode:1999ToxIH..15....1.. doi:10.1191/074823399678846547.
  13. ^ a b c d e f Kase NG, Speroff L, Glass RL (1994). Clinical gynecologic endocrinology and infertility (5 ed.). Baltimore: Williams & Wilkins. pp. 371–382. ISBN 978-0-683-07899-2.
  14. ^ a b c d e f g h i j k Roy JR, Chakraborty S, Chakraborty TR (June 2009). "Estrogen-like endocrine disrupting chemicals affecting puberty in humans--a review". Medical Science Monitor. 15 (6): RA137–RA145. PMID 19478717.
  15. ^ a b Massart F, Parrino R, Seppia P, Federico G, Saggese G (June 2006). "How do environmental estrogen disruptors induce precocious puberty?". Minerva Pediatrica. 58 (3): 247–254. PMID 16832329.
  16. ^ a b c d e f Toppari J, Juul A (August 2010). "Trends in puberty timing in humans and environmental modifiers". Molecular and Cellular Endocrinology. 324 (1–2): 39–44. doi:10.1016/j.mce.2010.03.011. PMID 20298746. S2CID 19235168.
  17. ^ a b c d e f g Caserta D, Maranghi L, Mantovani A, Marci R, Maranghi F, Moscarini M (2008). "Impact of endocrine disruptor chemicals in gynaecology". Human Reproduction Update. 14 (1): 59–72. doi:10.1093/humupd/dmm025. PMID 18070835.
  18. ^ a b c d Danzo BJ (November 1998). "The effects of environmental hormones on reproduction". Cellular and Molecular Life Sciences. 54 (11): 1249–1264. doi:10.1007/s000180050251. PMID 9849617. S2CID 11913134.
  19. ^ a b c Buck Louis GM, Gray LE, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, et al. (February 2008). "Environmental factors and puberty timing: expert panel research needs". Pediatrics. 121 (Suppl 3): S192–S207. doi:10.1542/peds.1813E. PMID 18245512. S2CID 9375302.
  20. ^ a b c d e f Rasier G, Toppari J, Parent AS, Bourguignon JP (July 2006). "Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data". Molecular and Cellular Endocrinology. 254–255: 187–201. doi:10.1016/j.mce.2006.04.002. hdl:2268/69898. PMID 16720078. S2CID 26180396.
  21. ^ Mueller SO (February 2004). "Xenoestrogens: mechanisms of action and detection methods". Analytical and Bioanalytical Chemistry. 378 (3): 582–587. doi:10.1007/s00216-003-2238-x. PMID 14564443. S2CID 46507842.
  22. ^ Aravindakshan J, Paquet V, Gregory M, Dufresne J, Fournier M, Marcogliese DJ, et al. (March 2004). "Consequences of xenoestrogen exposure on male reproductive function in spottail shiners (Notropis hudsonius)". Toxicological Sciences. 78 (1): 156–165. doi:10.1093/toxsci/kfh042. PMID 14657511.
  23. ^ vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, et al. (1998). "A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior". Toxicology and Industrial Health. 14 (1–2): 239–260. Bibcode:1998ToxIH..14..239V. doi:10.1177/074823379801400115. PMID 9460178. S2CID 27382573.
  24. ^ a b Aravindakshan J, Gregory M, Marcogliese DJ, Fournier M, Cyr DG (September 2004). "Consumption of xenoestrogen-contaminated fish during lactation alters adult male reproductive function". Toxicological Sciences. 81 (1): 179–189. doi:10.1093/toxsci/kfh174. PMID 15159524.
  25. ^ Luconi M, Bonaccorsi L, Forti G, Baldi E (June 2001). "Effects of estrogenic compounds on human spermatozoa: evidence for interaction with a nongenomic receptor for estrogen on human sperm membrane". Molecular and Cellular Endocrinology. 178 (1–2): 39–45. doi:10.1016/S0303-7207(01)00416-6. PMID 11403892. S2CID 27021549.
  26. ^ Rozati R, Reddy PP, Reddanna P, Mujtaba R (December 2002). "Role of environmental estrogens in the deterioration of male factor fertility". Fertility and Sterility. 78 (6): 1187–1194. doi:10.1016/S0015-0282(02)04389-3. PMID 12477510.
  27. ^ Sharpe RM, Fisher JS, Millar MM, Jobling S, Sumpter JP (December 1995). "Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production". Environmental Health Perspectives. 103 (12): 1136–1143. doi:10.1289/ehp.951031136. PMC 1519239. PMID 8747020.
  28. ^ Dallinga JW, Moonen EJ, Dumoulin JC, Evers JL, Geraedts JP, Kleinjans JC (August 2002). "Decreased human semen quality and organochlorine compounds in blood". Human Reproduction. 17 (8): 1973–1979. doi:10.1093/humrep/17.8.1973. PMID 12151423.
  29. ^ Palmlund I (June 1996). "Exposure to a xenoestrogen before birth: the diethylstilbestrol experience". Journal of Psychosomatic Obstetrics and Gynaecology. 17 (2): 71–84. doi:10.3109/01674829609025667. PMID 8819018.
  30. ^ Olea N, Olea-Serrano F, Lardelli-Claret P, Rivas A, Barba-Navarro A (1999). "Inadvertent exposure to xenoestrogens in children". Toxicology and Industrial Health. 15 (1–2): 151–158. Bibcode:1999ToxIH..15..152O. doi:10.1177/074823379901500112. PMID 10188197. S2CID 25327579.
  31. ^ Li DK, Zhou Z, Miao M, He Y, Wang J, Ferber J, et al. (February 2011). "Urine bisphenol-A (BPA) level in relation to semen quality". Fertility and Sterility. 95 (2): 625–30.e1–4. doi:10.1016/j.fertnstert.2010.09.026. PMID 21035116.
  32. ^ Rogan WJ, Ragan NB (July 2003). "Evidence of effects of environmental chemicals on the endocrine system in children". Pediatrics. 112 (1 Pt 2): 247–252. doi:10.1542/peds.112.S1.247. PMID 12837917. S2CID 13058233.
  33. ^ [22][23][24][25][26][27][28][29][30][31][32]
  34. ^ a b Williams DE, Lech JJ, Buhler DR (March 1998). "Xenobiotics and xenoestrogens in fish: modulation of cytochrome P450 and carcinogenesis". Mutation Research. 399 (2): 179–192. doi:10.1016/S0027-5107(97)00255-8. PMID 9672659.
  35. ^ a b c d e Vajda AM, Barber LB, Gray JL, Lopez EM, Woodling JD, Norris DO (May 2008). "Reproductive disruption in fish downstream from an estrogenic wastewater effluent". Environmental Science & Technology. 42 (9): 3407–3414. Bibcode:2008EnST...42.3407V. doi:10.1021/es0720661. PMID 18522126.
  36. ^ Arukwe A, Celius T, Walther BT, Goksøyr A (June 2000). "Effects of xenoestrogen treatment on zona radiata protein and vitellogenin expression in Atlantic salmon (Salmo salar)". Aquatic Toxicology. 49 (3): 159–170. Bibcode:2000AqTox..49..159A. doi:10.1016/S0166-445X(99)00083-1. PMID 10856602.
  37. ^ Golden RJ, Noller KL, Titus-Ernstoff L, Kaufman RH, Mittendorf R, Stillman R, et al. (March 1998). "Environmental endocrine modulators and human health: an assessment of the biological evidence". Critical Reviews in Toxicology. 28 (2): 109–227. doi:10.1080/10408449891344191. PMID 9557209.
  38. ^ Pugazhendhi D, Sadler AJ, Darbre PD (2007). "Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells". Journal of Applied Toxicology. 27 (1): 67–77. doi:10.1002/jat.1200. PMID 17121429. S2CID 19942049.
  39. ^ Buterin T, Koch C, Naegeli H (August 2006). "Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells". Carcinogenesis. 27 (8): 1567–1578. doi:10.1093/carcin/bgi339. PMID 16474171.
  40. ^ Darbre PD (March 2006). "Environmental oestrogens, cosmetics and breast cancer". Best Practice & Research. Clinical Endocrinology & Metabolism. 20 (1): 121–143. doi:10.1016/j.beem.2005.09.007. PMID 16522524.
  41. ^ Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS (2004). "Concentrations of parabens in human breast tumours". Journal of Applied Toxicology. 24 (1): 5–13. doi:10.1002/jat.958. PMID 14745841. S2CID 11999424.
  42. ^ Zsarnovszky A, Le HH, Wang HS, Belcher SM (December 2005). "Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A". Endocrinology. 146 (12): 5388–5396. doi:10.1210/en.2005-0565. PMID 16123166.
  43. ^ Safe S (December 2004). "Endocrine disruptors and human health: is there a problem". Toxicology. 205 (1–2): 3–10. doi:10.1016/j.tox.2004.06.032. PMID 15458784.
  44. ^ Murray DW, Lichter SR (April 1998). "Organochlorine residues and breast cancer". The New England Journal of Medicine. 338 (14): 990–991. doi:10.1056/nejm199804023381411. PMID 9527611.
  45. ^ Sharpe RM, Skakkebaek NE (May 1993). "Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?". Lancet. 341 (8857): 1392–1395. doi:10.1016/0140-6736(93)90953-E. PMID 8098802. S2CID 33135527.
  46. ^ Sharpe RM (February 2003). "The 'oestrogen hypothesis'- where do we stand now?". International Journal of Andrology. 26 (1): 2–15. doi:10.1046/j.1365-2605.2003.00367.x. PMID 12534932.
  47. ^ Vidaeff AC, Sever LE (2005). "In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence". Reproductive Toxicology. 20 (1): 5–20. doi:10.1016/j.reprotox.2004.12.015. PMID 15808781.
  48. ^ a b It's official: Men are the weaker sex 7 December 2008. The Independent.
  49. ^ a b c d Mouritsen A, Aksglaede L, Sørensen K, Mogensen SS, Leffers H, Main KM, et al. (April 2010). "Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty". International Journal of Andrology. 33 (2): 346–359. doi:10.1111/j.1365-2605.2010.01051.x. PMID 20487042.
  50. ^ a b c Kota AS, Kumar K, Ejaz S (2020-01-01). "Case 3: Poor Weight Gain and Severe Dehydration in a 3-month-old Infant". NeoReviews. 21 (1): e52–e54. doi:10.1542/neo.21-1-e52. ISSN 1526-9906. PMID 31894084.
  51. ^ a b c d e f g h Berberoğlu M (2009-06-05). "Precocious Puberty and Normal Variant Puberty: Definition, etiology, diagnosis and current management - Review" (PDF). Journal of Clinical Research in Pediatric Endocrinology. 1 (4): 164–174. doi:10.4274/jcrpe.v1i4.3. PMID 21274291.
  52. ^ Traggiai C, Stanhope R (February 2003). "Disorders of pubertal development". Best Practice & Research Clinical Obstetrics & Gynaecology. 17 (1): 41–56. doi:10.1053/ybeog.2003.0360. PMID 12758225.
  53. ^ a b Parent AS, Rasier G, Gerard A, Heger S, Roth C, Mastronardi C, et al. (2005). "Early onset of puberty: tracking genetic and environmental factors". Hormone Research. 64 (Suppl 2): 41–47. doi:10.1159/000087753. hdl:2268/69899. PMID 16286770. S2CID 22073984.
  54. ^ a b Jacobson-Dickman E, Lee MM (February 2009). "The influence of endocrine disruptors on pubertal timing". Current Opinion in Endocrinology, Diabetes, and Obesity. 16 (1): 25–30. doi:10.1097/MED.0b013e328320d560. PMID 19115521. S2CID 35633602.
  55. ^ a b c Guillette EA, Conard C, Lares F, Aguilar MG, McLachlan J, Guillette LJ (March 2006). "Altered breast development in young girls from an agricultural environment". Environmental Health Perspectives. 114 (3): 471–475. doi:10.1289/ehp.8280. PMC 1392245. PMID 16507474.
  56. ^ Massart F, Seppia P, Pardi D, Lucchesi S, Meossi C, Gagliardi L, et al. (February 2005). "High incidence of central precocious puberty in a bounded geographic area of northwest Tuscany: An estrogen disrupter epidemic?". Gynecological Endocrinology. 20 (2): 92–98. doi:10.1080/09513590400021060. ISSN 0951-3590. PMID 15823828.
  57. ^ Parent AS, Rasier G, Gerard A, Heger S, Roth C, Mastronardi C, et al. (2005). "Early onset of puberty: tracking genetic and environmental factors". Hormone Research. 64 (Suppl 2): 41–47. doi:10.1159/000087753. hdl:2268/69899. ISSN 0301-0163. PMID 16286770.
  58. ^ Partsch CJ, Sippell WG (2001). "Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens". Human Reproduction Update. 7 (3): 292–302. doi:10.1093/humupd/7.3.292. PMID 11392376.
  59. ^ The National Health and Nutrition Examination Survey III (NHANES III) and the Pediatric Research in Office Settings (PROS)
  60. ^ a b c d e f Wang RY, Needham LL, Barr DB (August 2005). "Effects of environmental agents on the attainment of puberty: considerations when assessing exposure to environmental chemicals in the National Children's Study". Environmental Health Perspectives. 113 (8): 1100–1107. doi:10.1289/ehp.7615. PMC 1280355. PMID 16079085.
  61. ^ Teilmann G, Pedersen CB, Jensen TK, Skakkebæk NE, Juul A (2005-12-01). "Prevalence and Incidence of Precocious Pubertal Development in Denmark: An Epidemiologic Study Based on National Registries". Pediatrics. 116 (6): 1323–1328. doi:10.1542/peds.2005-0012. ISSN 0031-4005. PMID 16322154.
  62. ^ Kim SH, Huh K, Won S, Lee KW, Park MJ (2015-11-05). Gonzalez-Bulnes A (ed.). "A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010". PLOS ONE. 10 (11): e0141844. Bibcode:2015PLoSO..1041844K. doi:10.1371/journal.pone.0141844. ISSN 1932-6203. PMID 26539988.
  63. ^ a b c Den Hond E, Schoeters G (February 2006). "Endocrine disrupters and human puberty". International Journal of Andrology. 29 (1): 264–71, discussion 286–90. doi:10.1111/j.1365-2605.2005.00561.x. PMID 16466548.
  64. ^ Colón I, Caro D, Bourdony CJ, Rosario O (September 2000). "Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development". Environmental Health Perspectives. 108 (9): 895–900. doi:10.1289/ehp.00108895. PMC 2556932. PMID 11017896.
  65. ^ a b c d e f Rogan WJ, Ragan NB (October 2007). "Some evidence of effects of environmental chemicals on the endocrine system in children". International Journal of Hygiene and Environmental Health. 210 (5): 659–667. doi:10.1016/j.ijheh.2007.07.005. PMC 2245801. PMID 17870664.
  66. ^ Massart F, Meucci V, Saggese G, Soldani G (May 2008). "High growth rate of girls with precocious puberty exposed to estrogenic mycotoxins". The Journal of Pediatrics. 152 (5): 690–5, 695.e1. doi:10.1016/j.jpeds.2007.10.020. PMID 18410776.
  67. ^ a b c d Cesario SK, Hughes LA (2007). "Precocious puberty: a comprehensive review of literature". Journal of Obstetric, Gynecologic, and Neonatal Nursing. 36 (3): 263–274. doi:10.1111/j.1552-6909.2007.00145.x. PMID 17489932.
  68. ^ "Precocious Puberty and Why it Matters". Columbia University Irving Medical Center. 2023-02-09. Retrieved 2024-04-14.
  69. ^ a b Grün F, Blumberg B (May 2009). "Endocrine disrupters as obesogens". Molecular and Cellular Endocrinology. 304 (1–2): 19–29. doi:10.1016/j.mce.2009.02.018. PMC 2713042. PMID 19433244.
  70. ^ Genuis SJ (September 2006). "Health issues and the environment--an emerging paradigm for providers of obstetrical and gynaecological health care". Human Reproduction. 21 (9): 2201–2208. doi:10.1093/humrep/del181. PMID 16775159.
  71. ^ a b c Copeland W, Shanahan L, Miller S, Costello EJ, Angold A, Maughan B (October 2010). "Outcomes of Early Pubertal Timing in Young Women: A Prospective Population-Based Study". American Journal of Psychiatry. 167 (10): 1218–1225. doi:10.1176/appi.ajp.2010.09081190. ISSN 0002-953X. PMC 2992443. PMID 20478880.
  72. ^ a b c Meeker JD, Sathyanarayana S, Swan SH (July 2009). "Phthalates and other additives in plastics: human exposure and associated health outcomes". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 364 (1526): 2097–2113. doi:10.1098/rstb.2008.0268. PMC 2873014. PMID 19528058.
  73. ^ Nikaido Y, Yoshizawa K, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, et al. (2004). "Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring". Reproductive Toxicology. 18 (6): 803–811. doi:10.1016/j.reprotox.2004.05.002. PMID 15279878.
  74. ^ Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, et al. (October 2008). "Fifteen years after "Wingspread"--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go". Toxicological Sciences. 105 (2): 235–259. doi:10.1093/toxsci/kfn030. PMC 2721670. PMID 18281716.
  75. ^ Della Seta D, Farabollini F, Dessì-Fulgheri F, Fusani L (November 2008). "Environmental-like exposure to low levels of estrogen affects sexual behavior and physiology of female rats". Endocrinology. 149 (11): 5592–5598. doi:10.1210/en.2008-0113. PMID 18635664. S2CID 28304236.
  76. ^ Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM (January 2007). "Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland". Endocrinology. 148 (1): 116–127. doi:10.1210/en.2006-0561. PMC 2819269. PMID 17023525.
  77. ^ a b c d Acerini CL, Hughes IA (August 2006). "Endocrine disrupting chemicals: a new and emerging public health problem?". Archives of Disease in Childhood. 91 (8): 633–641. doi:10.1136/adc.2005.088500. PMC 2083052. PMID 16861481.
  78. ^ a b c d e Patisaul HB, Adewale HB (2009). "Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior". Frontiers in Behavioral Neuroscience. 3: 10. doi:10.3389/neuro.08.010.2009. PMC 2706654. PMID 19587848.
  79. ^ Degen GH, Bolt HM (September 2000). "Endocrine disruptors: update on xenoestrogens". International Archives of Occupational and Environmental Health. 73 (7): 433–441. Bibcode:2000IAOEH..73..433D. doi:10.1007/s004200000163. PMID 11057411. S2CID 24198566.
  80. ^ Stradtman SC, Freeman JL (August 2021). "Mechanisms of Neurotoxicity Associated with Exposure to the Herbicide Atrazine". Toxics. 9 (9): 207. doi:10.3390/toxics9090207. PMC 8473009. PMID 34564358.
  81. ^ vom Saal FS, Hughes C (August 2005). "An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment". Environmental Health Perspectives. 113 (8): 926–933. doi:10.1289/ehp.7713. PMC 1280330. PMID 16079060.
  82. ^ Reid EE, Wilson E (1944). "The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenylmethanes". J. Am. Chem. Soc. 66 (6): 967–969. doi:10.1021/ja01234a038.
  83. ^ Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X, et al. (September 2019). "The adverse health effects of bisphenol A and related toxicity mechanisms". Environmental Research. 176: 108575. Bibcode:2019ER....176j8575M. doi:10.1016/j.envres.2019.108575. PMID 31299621. S2CID 196349678.
  84. ^ Kuruto-Niwa R, Nozawa R, Miyakoshi T, Shiozawa T, Terao Y (January 2005). "Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system". Environmental Toxicology and Pharmacology. 19 (1): 121–130. Bibcode:2005EnvTP..19..121K. doi:10.1016/j.etap.2004.05.009. PMID 21783468.
  85. ^ a b Viñas R, Watson CS (March 2013). "Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: effects on cell functions". Environmental Health Perspectives. 121 (3): 352–358. doi:10.1289/ehp.1205826. PMC 3621186. PMID 23458715.
  86. ^ a b Gilbert S (2015). Ecological Developmental Biology (2nd ed.). Oxford University Press Academic US. pp. 225–228. ISBN 9781605355429.
  87. ^ Tavakoly Sany SB, Hashim R, Salleh A, Rezayi M, Karlen DJ, Razavizadeh BB, et al. (December 2015). "Dioxin risk assessment: mechanisms of action and possible toxicity in human health". Environmental Science and Pollution Research International. 22 (24): 19434–19450. Bibcode:2015ESPR...2219434T. doi:10.1007/s11356-015-5597-x. PMID 26514567. S2CID 9584022.
  88. ^ Watson CS, Jeng YJ, Guptarak J (October 2011). "Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways". The Journal of Steroid Biochemistry and Molecular Biology. 127 (1–2): 44–50. doi:10.1016/j.jsbmb.2011.01.015. PMC 3106143. PMID 21300151.
  89. ^ Menezes RG, Qadir TF, Moin A, Fatima H, Hussain SA, Madadin M, et al. (October 2017). "Endosulfan poisoning: An overview". Journal of Forensic and Legal Medicine. 51: 27–33. doi:10.1016/j.jflm.2017.07.008. PMID 28734199. S2CID 12535174.
  90. ^ Jagić K, Dvoršćak M, Klinčić D (December 2021). "Analysis of brominated flame retardants in the aquatic environment: a review". Arhiv Za Higijenu Rada I Toksikologiju. 72 (4): 254–267. doi:10.2478/aiht-2021-72-3576. PMC 8785114. PMID 34985845.
  91. ^ "Polybrominated Diphenyl Ethers (PBDEs) | Toxic Substances | Toxic Substance Portal | ATSDR". wwwn.cdc.gov. Retrieved 2023-03-29.
  92. ^ Zhang MZ, Chu SS, Xia YK, Wang DD, Wang X (October 2021). "Environmental exposure during pregnancy and the risk of childhood allergic diseases". World Journal of Pediatrics. 17 (5): 467–475. doi:10.1007/s12519-021-00448-7. PMID 34476758. S2CID 237395252.
  93. ^ Nilsson R (2000). "Endocrine modulators in the food chain and environment". Toxicologic Pathology. 28 (3): 420–431. doi:10.1177/019262330002800311. PMID 10862560. S2CID 34979477.
  94. ^ Wang Y, Qian H (May 2021). "Phthalates and Their Impacts on Human Health". Healthcare. 9 (5): 603. doi:10.3390/healthcare9050603. PMC 8157593. PMID 34069956.
  95. ^ US Food and Drug Administration. "21CFR522.2680". Retrieved 14 June 2014.
  96. ^ Health Canada (2012-09-05). "Questions and Answers - Hormonal Growth Promoters". Retrieved 14 June 2014. There are six hormonal growth promoters approved in Canada for use in beef cattle: three natural - progesterone, testosterone and estradiol-17ß; and three synthetic - trenbolone acetate (TBA), zeranol and melengestrol acetate (MGA).
  97. ^ Agriculture and Fisheries (including Agro-industry, Food technologies, Forestry, Aquaculture and Rural Development) . "Development, validation and harmonisation of screening and confirmatory tests to distinguish zeranol abuse from fusarium toxin contamination in food animals". European Commission. Archived from the original on March 5, 2016. Retrieved 14 June 2014. The use of zeranol for growth promotion in food animals was banned in the EU in 1985.
  98. ^ Pair call for public discourse on treating wastewater contaminated with birth control pill chemicals, Phys.org

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