View source for Xenoestrogen

{{Short description|Environmental hormones that imitate estrogen}}
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'''Xenoestrogens''' are a type of [[xenohormone]] that imitates [[estrogen]]. They can be either synthetic or natural [[chemical compound]]s. Synthetic xenoestrogens include some widely used industrial compounds, such as [[Polychlorinated biphenyls|PCBs]], [[Bisphenol A|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 [[phytoestrogen]]s 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". [[Mycoestrogen]]s, estrogenic substances from [[fungus|fungi]], are another type of xenoestrogen that are also considered [[mycotoxin]]s.<ref>{{cite journal | vauthors = Paterni I, Granchi C, Minutolo F | title = Risks and benefits related to alimentary exposure to xenoestrogens | journal = Critical Reviews in Food Science and Nutrition | volume = 57 | issue = 16 | pages = 3384–3404 | date = November 2017 | pmid = 26744831 | pmc = 6104637 | doi = 10.1080/10408398.2015.1126547 }}</ref><ref>{{cite journal | vauthors = Wang X, Ha D, Yoshitake R, Chan YS, Sadava D, Chen S | title = Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts | journal = International Journal of Molecular Sciences | volume = 22 | issue = 16 | pages = 8798 | date = August 2021 | pmid = 34445499 | pmc = 8395949 | doi = 10.3390/ijms22168798 | doi-access = free }}</ref>

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.<ref name="Aksglaede_2006"/><ref name="Herman-Giddens_1997"/>

Xenoestrogens include pharmacological estrogens (in which estrogenic action is an intended effect, as in the drug [[ethinylestradiol]] used in [[Combined oral contraceptive pill|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.<ref name="pmid3203635">{{cite journal | vauthors = Hughes CL | title = Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens | journal = Environmental Health Perspectives | volume = 78 | pages = 171–174 | date = June 1988 | pmid = 3203635 | pmc = 1474615 | doi = 10.1289/ehp.8878171 }}</ref><ref>{{cite book | chapter = Wild-life studies | title = Infertility in the modern world: present and future prospects | vauthors = Bentley GR, Mascie-Taylor CG | publisher = Cambridge University Press | pages = 99–100 | date = November 2000 | isbn = 978-0-521-64387-0 }}</ref>

The potential ecological and human health impact of xenoestrogens is of growing concern.<ref name= "Repro">{{cite book | vauthors = Korach KS | title = Reproductive and Developmental Toxicology| publisher = Marcel Dekker Ltd.|year=1998| pages = 278–279, 294–295| isbn = 978-0-8247-9857-4}}</ref> 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, or [[Endocrine disruptor]] for short). Most scientists that study xenoestrogens, including [[The Endocrine Society]], regard them as serious environmental hazards that have [[Endocrine disruptor|hormone disruptive effects]] on both wildlife and humans.<ref name="isbn0-911131-35-3">{{cite book | vauthors = Bern HA, Blair P, Brasseur S, Colborn T, Cunha GR, Davis W, Dohler KD, Fox G, Fry M, Gray E, Green R, Hines M, Kubiak TJ, McLachlan J, Myers JP, Peterson RE, Reijnders PJ, Soto A, Van Der Kraak G, vom Saal F, Whitten P | veditors = Clement C, Colborn T | title = Chemically-induced alterations in sexual and functional development -- the wildlife/human connection | chapter = Statement from the Work Session on Chemically-Induced Alterations in Sexual Development: The Wildlife/Human Connection | publisher = Princeton Scientific Pub. Co | location = Princeton, N.J | year = 1992 | pages = 1–8 | isbn = 978-0-911131-35-2 | chapter-url = http://www.endocrinedisruption.org/files/wingspread_consensus_statement.pdf | access-date = 2010-11-16 | archive-date = 2013-05-24 | archive-url = https://web.archive.org/web/20130524193414/http://www.endocrinedisruption.org/files/wingspread_consensus_statement.pdf | url-status = dead }}</ref><ref name="pmid17539108">{{cite journal | title = Statement from the Work Session on Environmentally induced Alterations in Development: A Focus on Wildlife | journal = Environmental Health Perspectives | volume = 103 | issue = Suppl 4 | pages = 3–5 | date = May 1995 | pmid = 17539108 | pmc = 1519268 | doi = 10.2307/3432404 | jstor = 3432404 | vauthors = Colborn T }}</ref><ref name="isbn1-880611-19-8">{{cite book | vauthors = Benson WH, Bern HA, Bue B, Colborn T, Cook P, Davis WP, Denslow N, Donaldson EM, Edsall CC, Fournier M, Gilbertson M, Johnson R, Kocan R, Monosson E, Norrgren L, Peterson RE, Rolland R, Smolen M, Spies R, Sullivan C, Thomas P, Van Der Kraak G | veditors = Rolland RM, Gilbertson M, Peterson RE | title = Chemically Induced Alterations in Functional Development and Reproduction of Fishes | publisher = Society of Environmental Toxicology & Chemist | year = 1997 | chapter = Statement from the work session on chemically induced alterations in functional development and reproduction of fishes | pages = [https://archive.org/details/chemicallyinduce1997unse/page/3 3–8] | isbn = 978-1-880611-19-7 | chapter-url = https://archive.org/details/chemicallyinduce1997unse/page/3 }}</ref><ref name="pmid9460166">{{cite journal | vauthors = | title = Statement from the work session on environmental endocrine-disrupting chemicals: neural, endocrine, and behavioral effects | journal = Toxicology and Industrial Health | volume = 14 | issue = 1–2 | pages = 1–8 | year = 1998 | pmid = 9460166 | doi = 10.1177/074823379801400103 | bibcode = 1998ToxIH..14....1. | s2cid = 45902764 }}</ref><ref name="Brook_1999">{{cite journal |vauthors=Brock J, Colborn T, Cooper R, Craine DA, Dodson SF, Garry VF, Gilbertson M, Gray E, Hodgson E, Kelce W, Klotz D, Maciorowski AF, Olea N, Porter W, Rolland R, Scott GI, Smolen M, Snedaker SC, Sonnenschein C, Vyas NB, Welshons WV, Whitcomb CE | title = Statement from the Work Session on Health Effects of Contemporary-Use Pesticides: the Wildlife / Human Connection | journal = Toxicol Ind Health | volume = 15 | issue = 1–2 | pages = 1–5 | year = 1999 | doi = 10.1191/074823399678846547| bibcode = 1999ToxIH..15....1. }}</ref>

== Mechanism of action ==
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.<ref name="Speroff_1994"/><ref name="Roy_2009"/> Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.<ref name="Massart_2006"/>

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.<ref name="Roy_2009"/><ref name="Toppari_2010"/><ref name="Caserta_2008"/><ref name="Danzo_1998">{{cite journal | vauthors = Danzo BJ | title = The effects of environmental hormones on reproduction | journal = Cellular and Molecular Life Sciences | volume = 54 | issue = 11 | pages = 1249–1264 | date = November 1998 | pmid = 9849617 | doi = 10.1007/s000180050251 | s2cid = 11913134 | pmc = 11337879 }}</ref>

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.<ref name="Toppari_2010"/><ref name="Danzo_1998"/><ref name="Louis_2008"/><ref name="Raiser_2006"/> 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.<ref name="Roy_2009"/> 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.<ref name="Mueller_2004">{{cite journal | vauthors = Mueller SO | title = Xenoestrogens: mechanisms of action and detection methods | journal = Analytical and Bioanalytical Chemistry | volume = 378 | issue = 3 | pages = 582–587 | date = February 2004 | pmid = 14564443 | doi = 10.1007/s00216-003-2238-x | s2cid = 46507842 }}</ref>

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

== Effects ==

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.{{refn|<ref name="pmid14657511">{{cite journal | vauthors = Aravindakshan J, Paquet V, Gregory M, Dufresne J, Fournier M, Marcogliese DJ, Cyr DG | title = Consequences of xenoestrogen exposure on male reproductive function in spottail shiners (Notropis hudsonius) | journal = Toxicological Sciences | volume = 78 | issue = 1 | pages = 156–165 | date = March 2004 | pmid = 14657511 | doi = 10.1093/toxsci/kfh042 }}</ref><ref name="pmid9460178">{{cite journal | vauthors = vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV | title = 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 | journal = Toxicology and Industrial Health | volume = 14 | issue = 1–2 | pages = 239–260 | year = 1998 | pmid = 9460178 | doi = 10.1177/074823379801400115 | bibcode = 1998ToxIH..14..239V | s2cid = 27382573 }}</ref><ref name="pmid15159524">{{cite journal | vauthors = Aravindakshan J, Gregory M, Marcogliese DJ, Fournier M, Cyr DG | title = Consumption of xenoestrogen-contaminated fish during lactation alters adult male reproductive function | journal = Toxicological Sciences | volume = 81 | issue = 1 | pages = 179–189 | date = September 2004 | pmid = 15159524 | doi = 10.1093/toxsci/kfh174 | doi-access = free }}</ref><ref name="pmid11403892">{{cite journal | vauthors = Luconi M, Bonaccorsi L, Forti G, Baldi E | title = Effects of estrogenic compounds on human spermatozoa: evidence for interaction with a nongenomic receptor for estrogen on human sperm membrane | journal = Molecular and Cellular Endocrinology | volume = 178 | issue = 1–2 | pages = 39–45 | date = June 2001 | pmid = 11403892 | doi = 10.1016/S0303-7207(01)00416-6 | s2cid = 27021549 }}</ref><ref name="pmid12477510">{{cite journal | vauthors = Rozati R, Reddy PP, Reddanna P, Mujtaba R | title = Role of environmental estrogens in the deterioration of male factor fertility | journal = Fertility and Sterility | volume = 78 | issue = 6 | pages = 1187–1194 | date = December 2002 | pmid = 12477510 | doi = 10.1016/S0015-0282(02)04389-3 | doi-access = free }}</ref><ref name="pmid8747020">{{cite journal | vauthors = Sharpe RM, Fisher JS, Millar MM, Jobling S, Sumpter JP | title = Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production | journal = Environmental Health Perspectives | volume = 103 | issue = 12 | pages = 1136–1143 | date = December 1995 | pmid = 8747020 | pmc = 1519239 | doi = 10.1289/ehp.951031136 }}</ref><ref name="pmid12151423">{{cite journal | vauthors = Dallinga JW, Moonen EJ, Dumoulin JC, Evers JL, Geraedts JP, Kleinjans JC | title = Decreased human semen quality and organochlorine compounds in blood | journal = Human Reproduction | volume = 17 | issue = 8 | pages = 1973–1979 | date = August 2002 | pmid = 12151423 | doi = 10.1093/humrep/17.8.1973 | doi-access = free }}</ref><ref name="pmid8819018">{{cite journal | vauthors = Palmlund I | title = Exposure to a xenoestrogen before birth: the diethylstilbestrol experience | journal = Journal of Psychosomatic Obstetrics and Gynaecology | volume = 17 | issue = 2 | pages = 71–84 | date = June 1996 | pmid = 8819018 | doi = 10.3109/01674829609025667 }}</ref><ref name="pmid10188197">{{cite journal | vauthors = Olea N, Olea-Serrano F, Lardelli-Claret P, Rivas A, Barba-Navarro A | title = Inadvertent exposure to xenoestrogens in children | journal = Toxicology and Industrial Health | volume = 15 | issue = 1–2 | pages = 151–158 | year = 1999 | pmid = 10188197 | doi = 10.1177/074823379901500112 | bibcode = 1999ToxIH..15..152O | s2cid = 25327579 }}</ref><ref name="pmid21035116">{{cite journal | vauthors = Li DK, Zhou Z, Miao M, He Y, Wang J, Ferber J, Herrinton LJ, Gao E, Yuan W | title = Urine bisphenol-A (BPA) level in relation to semen quality | journal = Fertility and Sterility | volume = 95 | issue = 2 | pages = 625–30.e1–4 | date = February 2011 | pmid = 21035116 | doi = 10.1016/j.fertnstert.2010.09.026 }}</ref><ref name="pmid12837917">{{cite journal | vauthors = Rogan WJ, Ragan NB | title = Evidence of effects of environmental chemicals on the endocrine system in children | journal = Pediatrics | volume = 112 | issue = 1 Pt 2 | pages = 247–252 | date = July 2003 | pmid = 12837917 | doi = 10.1542/peds.112.S1.247 | s2cid = 13058233 }}</ref>}}

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 10<sup>5</sup> –10<sup>6</sup>, fish are extremely susceptible to pollutants.<ref name="Williams_1998">{{cite journal | vauthors = Williams DE, Lech JJ, Buhler DR | title = Xenobiotics and xenoestrogens in fish: modulation of cytochrome P450 and carcinogenesis | journal = Mutation Research | volume = 399 | issue = 2 | pages = 179–192 | date = March 1998 | pmid = 9672659 | doi = 10.1016/S0027-5107(97)00255-8 }}</ref> Streams in more arid conditions are thought to have more effects due to higher concentrations of the chemicals arising from lack of dilution.<ref name="Vajda_2008">{{cite journal | vauthors = Vajda AM, Barber LB, Gray JL, Lopez EM, Woodling JD, Norris DO | title = Reproductive disruption in fish downstream from an estrogenic wastewater effluent | journal = Environmental Science & Technology | volume = 42 | issue = 9 | pages = 3407–3414 | date = May 2008 | pmid = 18522126 | doi = 10.1021/es0720661 | bibcode = 2008EnST...42.3407V }}</ref>

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.<ref name="Vajda_2008"/>

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.<ref name="Vajda_2008"/>

Sperm concentrations and motility perimeters are reduced in male fish exposed to xenoestrogens in addition to disrupt stages of spermatogenesis.<ref name="pmid15159524"/><ref name="Vajda_2008"/> 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 wastewater 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.<ref name="Vajda_2008"/> 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.<ref name="Williams_1998"/>

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.<ref name="pmid10856602">{{cite journal | vauthors = Arukwe A, Celius T, Walther BT, Goksøyr A | title = Effects of xenoestrogen treatment on zona radiata protein and vitellogenin expression in Atlantic salmon (Salmo salar) | journal = Aquatic Toxicology | volume = 49 | issue = 3 | pages = 159–170 | date = June 2000 | pmid = 10856602 | doi = 10.1016/S0166-445X(99)00083-1 | bibcode = 2000AqTox..49..159A }}</ref>

Another potential effect of xenoestrogens is on [[oncogene]]s, specifically in relation to [[breast cancer]]. Some scientists doubt that xenoestrogens have any significant biological effect, in the concentrations found in the environment.<ref name="pmid9557209">{{cite journal | vauthors = Golden RJ, Noller KL, Titus-Ernstoff L, Kaufman RH, Mittendorf R, Stillman R, Reese EA | title = Environmental endocrine modulators and human health: an assessment of the biological evidence | journal = Critical Reviews in Toxicology | volume = 28 | issue = 2 | pages = 109–227 | date = March 1998 | pmid = 9557209 | doi = 10.1080/10408449891344191 }}</ref> However, there is substantial evidence in a variety of recent studies to indicate that xenoestrogens can increase breast cancer growth in [[tissue culture]].<ref name="pmid17121429">{{cite journal | vauthors = Pugazhendhi D, Sadler AJ, Darbre PD | title = Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells | journal = Journal of Applied Toxicology | volume = 27 | issue = 1 | pages = 67–77 | year = 2007 | pmid = 17121429 | doi = 10.1002/jat.1200 | s2cid = 19942049 }}</ref><ref name="pmid16474171">{{cite journal | vauthors = Buterin T, Koch C, Naegeli H | title = Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells | journal = Carcinogenesis | volume = 27 | issue = 8 | pages = 1567–1578 | date = August 2006 | pmid = 16474171 | doi = 10.1093/carcin/bgi339 | doi-access = free }}</ref><ref name="pmid16522524">{{cite journal | vauthors = Darbre PD | title = Environmental oestrogens, cosmetics and breast cancer | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 20 | issue = 1 | pages = 121–143 | date = March 2006 | pmid = 16522524 | doi = 10.1016/j.beem.2005.09.007 }}</ref><ref name="pmid14745841">{{cite journal | vauthors = Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS | title = Concentrations of parabens in human breast tumours | journal = Journal of Applied Toxicology | volume = 24 | issue = 1 | pages = 5–13 | year = 2004 | pmid = 14745841 | doi = 10.1002/jat.958 | s2cid = 11999424 }}</ref>

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.<ref name="pmid16123166">{{cite journal | vauthors = Zsarnovszky A, Le HH, Wang HS, Belcher SM | title = 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 | journal = Endocrinology | volume = 146 | issue = 12 | pages = 5388–5396 | date = December 2005 | pmid = 16123166 | doi = 10.1210/en.2005-0565 | doi-access = free }}</ref> 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.<ref name="pmid15458784">{{cite journal | vauthors = Safe S | title = Endocrine disruptors and human health: is there a problem | journal = Toxicology | volume = 205 | issue = 1–2 | pages = 3–10 | date = December 2004 | pmid = 15458784 | doi = 10.1016/j.tox.2004.06.032 }}</ref> 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.<ref name="pmid9527611">{{cite journal | vauthors = Murray DW, Lichter SR | title = Organochlorine residues and breast cancer | journal = The New England Journal of Medicine | volume = 338 | issue = 14 | pages = 990–991 | date = April 1998 | pmid = 9527611 | doi = 10.1056/nejm199804023381411 }}</ref>

There has been speculation that falling sperm counts in males may be due to increased estrogen exposure in utero.<ref name="pmid8098802">{{cite journal | vauthors = Sharpe RM, Skakkebaek NE | title = Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? | journal = Lancet | volume = 341 | issue = 8857 | pages = 1392–1395 | date = May 1993 | pmid = 8098802 | doi = 10.1016/0140-6736(93)90953-E | s2cid = 33135527 }}</ref> 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.<ref name="pmid12534932">{{cite journal | vauthors = Sharpe RM | title = The 'oestrogen hypothesis'- where do we stand now? | journal = International Journal of Andrology | volume = 26 | issue = 1 | pages = 2–15 | date = February 2003 | pmid = 12534932 | doi = 10.1046/j.1365-2605.2003.00367.x | doi-access = free }}</ref>

=== Impact ===

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),<ref name="pmid15808781">{{cite journal | vauthors = Vidaeff AC, Sever LE | title = In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence | journal = Reproductive Toxicology | volume = 20 | issue = 1 | pages = 5–20 | year = 2005 | pmid = 15808781 | doi = 10.1016/j.reprotox.2004.12.015 }}</ref> 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.<ref name=indepen/> Ninety-nine percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.<ref name=indepen>[https://web.archive.org/web/20081208001730/http://www.independent.co.uk/news/science/its-official-men-really-are-the-weaker-sex-1055688.html It's official: Men are the weaker sex] 7 December 2008. [[The Independent]].</ref>

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|date=May 2022}}

=== Precocious puberty ===

Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function.<ref name="Speroff_1994">{{cite book |vauthors=Kase NG, Speroff L, Glass RL | title = Clinical gynecologic endocrinology and infertility |url=https://archive.org/details/clinicalgynecolo0005unse |url-access=registration | publisher = Williams & Wilkins | location = Baltimore | year = 1994 | pages = [https://archive.org/details/clinicalgynecolo0005unse/page/371 371–382]| isbn = 978-0-683-07899-2 | edition = 5 }}</ref><ref name="Louis_2008">{{cite journal | vauthors = Buck Louis GM, Gray LE, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, Sippell W, Abbott DH, Soto A, Tyl RW, Bourguignon JP, Skakkebaek NE, Swan SH, Golub MS, Wabitsch M, Toppari J, Euling SY | title = Environmental factors and puberty timing: expert panel research needs | journal = Pediatrics | volume = 121 | issue = Suppl 3 | pages = S192–S207 | date = February 2008 | pmid = 18245512 | doi = 10.1542/peds.1813E | s2cid = 9375302 }}</ref><ref name="Mouritsen_2010">{{cite journal | vauthors = Mouritsen A, Aksglaede L, Sørensen K, Mogensen SS, Leffers H, Main KM, Frederiksen H, Andersson AM, Skakkebaek NE, Juul A | title = Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty | journal = International Journal of Andrology | volume = 33 | issue = 2 | pages = 346–359 | date = April 2010 | pmid = 20487042 | doi = 10.1111/j.1365-2605.2010.01051.x }}</ref><ref name=":0">{{Cite journal |last1=Kota |first1=Archana S. |last2=Kumar |first2=Krishan |last3=Ejaz |first3=Sehar |date=2020-01-01 |title=Case 3: Poor Weight Gain and Severe Dehydration in a 3-month-old Infant |url=http://dx.doi.org/10.1542/neo.21-1-e52 |journal=NeoReviews |volume=21 |issue=1 |pages=e52–e54 |doi=10.1542/neo.21-1-e52 |pmid=31894084 |issn=1526-9906}}</ref> 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.<ref name="Speroff_1994"/>

Puberty is considered precocious ([[precocious puberty]]) if [[secondary sex characteristic]]s occur before the age of 8 in girls and 9 years in boys.<ref name="Speroff_1994"/><ref name="Massart_2006">{{cite journal | vauthors = Massart F, Parrino R, Seppia P, Federico G, Saggese G | title = How do environmental estrogen disruptors induce precocious puberty? | journal = Minerva Pediatrica | volume = 58 | issue = 3 | pages = 247–254 | date = June 2006 | pmid = 16832329 }}</ref> 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.<ref name="Speroff_1994"/> Precocious puberty can be classified into central (gonadotropin-dependent) precocious puberty or peripheral (gonadotropin-independent) puberty.<ref name="Speroff_1994"/><ref name="Louis_2008"/><ref name=":0" /><ref name=":1">{{Cite journal |last=Berberoğlu |first=Merih |date=2009-06-05 |title=Precocious Puberty and Normal Variant Puberty: Definition, etiology, diagnosis and current management - Review |url=http://cms.galenos.com.tr/Uploads/Article_23/JCRPE-1-164-En.pdf |journal=Journal of Clinical Research in Pediatric Endocrinology |volume=1 |issue=4 |pages=164–174 |doi=10.4274/jcrpe.v1i4.3|pmid=21274291 }}</ref> Both central and peripheral precocious puberty have been linked to exposure to exogenous estrogenic compounds.<ref name=":0" /><ref name=":1" />

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.<ref name=":1" /> 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.<ref name=":1" />

Peripheral precocious puberty is independent of gonadotropin and thus does not activate the HPG axis. <ref name=":1" /> Peripheral precocious puberty in females most commonly shows through ovarian follicular cysts, which may cause vaginal bleeding.<ref name=":1" /> LH receptor activating mutations ([[Familial male-limited precocious puberty|familial testotoxicosis]]) are autosomal dominate diseases found in male children.<ref name=":1" /><ref>{{Cite journal |last1=Traggiai |first1=C. |last2=Stanhope |first2=R. |date=February 2003 |title=Disorders of pubertal development |url=https://linkinghub.elsevier.com/retrieve/pii/S1521693402001669 |journal=Best Practice & Research Clinical Obstetrics & Gynaecology |language=en |volume=17 |issue=1 |pages=41–56 |doi=10.1053/ybeog.2003.0360|pmid=12758225 }}</ref> These diseases are usually characterized by enlarged testis and can be an indication of peripheral precocious puberty in boys.<ref name=":1" />

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.<ref name="Aksglaede_2006">{{cite journal | vauthors = Aksglaede L, Juul A, Leffers H, Skakkebaek NE, Andersson AM | title = The sensitivity of the child to sex steroids: possible impact of exogenous estrogens | journal = Human Reproduction Update | volume = 12 | issue = 4 | pages = 341–349 | year = 2006 | pmid = 16672247 | doi = 10.1093/humupd/dml018 }}</ref><ref name="Parent_2004">{{cite journal | vauthors = Parent AS, Rasier G, Gerard A, Heger S, Roth C, Mastronardi C, Jung H, Ojeda SR, Bourguignon JP | title = Early onset of puberty: tracking genetic and environmental factors | journal = Hormone Research | volume = 64 | issue = Suppl 2 | pages = 41–47 | year = 2005 | pmid = 16286770 | doi = 10.1159/000087753 | s2cid = 22073984 | hdl = 2268/69899 | hdl-access = free }}</ref> 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.<ref name="Aksglaede_2006" /><ref name="Toppari_2010">{{cite journal | vauthors = Toppari J, Juul A | title = Trends in puberty timing in humans and environmental modifiers | journal = Molecular and Cellular Endocrinology | volume = 324 | issue = 1–2 | pages = 39–44 | date = August 2010 | pmid = 20298746 | doi = 10.1016/j.mce.2010.03.011 | s2cid = 19235168 }}</ref><ref name="Mouritsen_2010" /> Trends toward earlier puberty have been attributed to improved public health and living conditions.<ref name="Jacobson-Dickman_Lee_2009">{{cite journal | vauthors = Jacobson-Dickman E, Lee MM | title = The influence of endocrine disruptors on pubertal timing | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 16 | issue = 1 | pages = 25–30 | date = February 2009 | pmid = 19115521 | doi = 10.1097/MED.0b013e328320d560 | s2cid = 35633602 }}</ref> A leading hypothesis for this change toward early puberty is improved nutrition resulting in rapid body growth, increased weight and fat deposition.<ref name="Guillette_2006">{{cite journal | vauthors = Guillette EA, Conard C, Lares F, Aguilar MG, McLachlan J, Guillette LJ | title = Altered breast development in young girls from an agricultural environment | journal = Environmental Health Perspectives | volume = 114 | issue = 3 | pages = 471–475 | date = March 2006 | pmid = 16507474 | pmc = 1392245 | doi = 10.1289/ehp.8280 }}</ref> However, recent studies have shown that chemical exposure to environmental estrogen disruptors the HPG axis and result in precocious puberty.<ref>{{Cite journal |last1=Massart |first1=Francesco |last2=Seppia |first2=Patrizia |last3=Pardi |first3=Daniela |last4=Lucchesi |first4=Sonia |last5=Meossi |first5=Cristiano |last6=Gagliardi |first6=Luigi |last7=Liguori |first7=Roberto |last8=Fiore |first8=Lisa |last9=Federico |first9=Giovanni |last10=Saggese |first10=Giuseppe |date=February 2005 |title=High incidence of central precocious puberty in a bounded geographic area of northwest Tuscany: An estrogen disrupter epidemic? |url=http://dx.doi.org/10.1080/09513590400021060 |journal=Gynecological Endocrinology |volume=20 |issue=2 |pages=92–98 |doi=10.1080/09513590400021060 |pmid=15823828 |issn=0951-3590}}</ref><ref>{{Cite journal |last1=Parent |first1=Anne-Simone |last2=Rasier |first2=Gregory |last3=Gerard |first3=Arlette |last4=Heger |first4=Sabine |last5=Roth |first5=Christian |last6=Mastronardi |first6=Claudio |last7=Jung |first7=Heike |last8=Ojeda |first8=Sergio R. |last9=Bourguignon |first9=Jean-Pierre |date=2005 |title=Early onset of puberty: tracking genetic and environmental factors |url=https://pubmed.ncbi.nlm.nih.gov/16286770/ |journal=Hormone Research |volume=64 |issue=Suppl 2 |pages=41–47 |doi=10.1159/000087753 |issn=0301-0163 |pmid=16286770|hdl=2268/69899 |hdl-access=free }}</ref> 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&nbsp;ng/day for females.<ref name="Partsch_Sippell_2001">{{cite journal |vauthors=Partsch CJ, Sippell WG |year=2001 |title=Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens |journal=Human Reproduction Update |volume=7 |issue=3 |pages=292–302 |doi=10.1093/humupd/7.3.292 |pmid=11392376 |doi-access=free}}</ref> Two recent epidemiologic studies in the United States (PROS and NMANES III)<ref>The National Health and Nutrition Examination Survey III (NHANES III) and the Pediatric Research in Office Settings (PROS)</ref> highlighted a recent unexpected advance in sexual maturation in girls.<ref name="Aksglaede_2006" /><ref name="Herman-Giddens_1997">{{cite journal | vauthors = Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM | title = Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network | journal = Pediatrics | volume = 99 | issue = 4 | pages = 505–512 | date = April 1997 | pmid = 9093289 | doi = 10.1542/peds.99.4.505 }}</ref><ref name="Wang_2005">{{cite journal | vauthors = Wang RY, Needham LL, Barr DB | title = Effects of environmental agents on the attainment of puberty: considerations when assessing exposure to environmental chemicals in the National Children's Study | journal = Environmental Health Perspectives | volume = 113 | issue = 8 | pages = 1100–1107 | date = August 2005 | pmid = 16079085 | pmc = 1280355 | doi = 10.1289/ehp.7615 }}</ref> 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.<ref name="Toppari_2010" /><ref name="Mouritsen_2010" /><ref name="Guillette_2006" /> Environmental chemical exposure is one of the factors implicated in the recent downward trend of earlier sexual maturation.<ref name="Toppari_2010" /><ref name="Mouritsen_2010" /><ref name="Wang_2005" />

'''Epidemiology'''

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.<ref>{{Cite journal |last1=Teilmann |first1=Grete |last2=Pedersen |first2=Carsten B. |last3=Jensen |first3=Tina Kold |last4=Skakkebæk |first4=Niels E. |last5=Juul |first5=Anders |date=2005-12-01 |title=Prevalence and Incidence of Precocious Pubertal Development in Denmark: An Epidemiologic Study Based on National Registries |url=https://publications.aap.org/pediatrics/article/116/6/1323/62974/Prevalence-and-Incidence-of-Precocious-Pubertal |journal=Pediatrics |language=en |volume=116 |issue=6 |pages=1323–1328 |doi=10.1542/peds.2005-0012 |pmid=16322154 |issn=0031-4005}}</ref> 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.<ref>{{Cite journal |last1=Kim |first1=Shin Hye |last2=Huh |first2=Kyoung |last3=Won |first3=Sungho |last4=Lee |first4=Kuk-Wha |last5=Park |first5=Mi-Jung |date=2015-11-05 |editor-last=Gonzalez-Bulnes |editor-first=Antonio |title=A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010 |journal=PLOS ONE |language=en |volume=10 |issue=11 |pages=e0141844 |doi=10.1371/journal.pone.0141844 |doi-access=free |pmid=26539988 |bibcode=2015PLoSO..1041844K |issn=1932-6203}}</ref>

==== Thelarche in Puerto Rico ====
Since 1979, [[pediatric endocrinologist]]s in Puerto Rico recognized an increase in number of patients with premature [[thelarche]].<ref name="Den_Hond_Schoeters_2006">{{cite journal | vauthors = Den Hond E, Schoeters G | title = Endocrine disrupters and human puberty | journal = International Journal of Andrology | volume = 29 | issue = 1 | pages = 264–71; discussion 286–90 | date = February 2006 | pmid = 16466548 | doi = 10.1111/j.1365-2605.2005.00561.x | doi-access = free }}</ref> 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.<ref name="Colón_2000">{{cite journal | vauthors = Colón I, Caro D, Bourdony CJ, Rosario O | title = Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development | journal = Environmental Health Perspectives | volume = 108 | issue = 9 | pages = 895–900 | date = September 2000 | pmid = 11017896 | pmc = 2556932 | doi = 10.1289/ehp.00108895 }}</ref> 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.<ref name="Den_Hond_Schoeters_2006"/><ref name="Rogan_2007"/>

==== Tuscany precocious puberty cases ====
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.<ref name="Massart_2008">{{cite journal | vauthors = Massart F, Meucci V, Saggese G, Soldani G | title = High growth rate of girls with precocious puberty exposed to estrogenic mycotoxins | journal = The Journal of Pediatrics | volume = 152 | issue = 5 | pages = 690–5, 695.e1 | date = May 2008 | pmid = 18410776 | doi = 10.1016/j.jpeds.2007.10.020 | doi-access = free }}</ref>

==== Dairy contamination ====
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.<ref name="Toppari_2010"/><ref name="Raiser_2006"/><ref name="Rogan_2007"/>

==== Fish contamination ====
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.<ref name="Raiser_2006"/><ref name="Den_Hond_Schoeters_2006"/><ref name="Rogan_2007"/> Limitations of the study included indirect measurement of the exposure and self reporting of menarche.<ref name="Raiser_2006"/>

==== Implications ====
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,<ref name="Wang_2005" /><ref name="Cesario_Hughes_2007">{{cite journal |vauthors=Cesario SK, Hughes LA |year=2007 |title=Precocious puberty: a comprehensive review of literature |journal=Journal of Obstetric, Gynecologic, and Neonatal Nursing |volume=36 |issue=3 |pages=263–274 |doi=10.1111/j.1552-6909.2007.00145.x |pmid=17489932}}</ref> increased cancer risk ([[Breast cancer|breast]]<ref name="Wang_2005" /> and [[Endometrial cancer|endometrial]] for girls and [[Testicular cancer|testicular]] for boys).<ref>{{Cite web |date=2023-02-09 |title=Precocious Puberty and Why it Matters |url=https://www.cuimc.columbia.edu/news/precocious-puberty-and-why-it-matters |access-date=2024-04-14 |website=Columbia University Irving Medical Center |language=en}}</ref> Precocious puberty is linked with other gynecologic disorders such as endometriosis, adenomyosis, polycystic ovarian syndrome and infertility.<ref name="Caserta_2008" /><ref name="Grün_Blumberg_2009">{{cite journal |vauthors=Grün F, Blumberg B |date=May 2009 |title=Endocrine disrupters as obesogens |journal=Molecular and Cellular Endocrinology |volume=304 |issue=1–2 |pages=19–29 |doi=10.1016/j.mce.2009.02.018 |pmc=2713042 |pmid=19433244}}</ref><ref name="Genuis_2006">{{cite journal |vauthors=Genuis SJ |date=September 2006 |title=Health issues and the environment--an emerging paradigm for providers of obstetrical and gynaecological health care |journal=Human Reproduction |volume=21 |issue=9 |pages=2201–2208 |doi=10.1093/humrep/del181 |pmid=16775159}}</ref> Premature pubertal growth spurt and accelerated bone maturation will result in premature closure of [[distal]] [[epiphysis]] which causes reduced adult height and short stature.<ref name="Cesario_Hughes_2007" /> Precocious puberty can lead to [[psychosocial distress]], a poor self-image, and poor self-esteem.<ref name=":2">{{Cite journal |last1=Copeland |first1=William |last2=Shanahan |first2=Lilly |last3=Miller |first3=Shari |last4=Costello |first4=E. Jane |last5=Angold |first5=Adrian |last6=Maughan |first6=Barbara |date=October 2010 |title=Outcomes of Early Pubertal Timing in Young Women: A Prospective Population-Based Study |journal=American Journal of Psychiatry |language=en |volume=167 |issue=10 |pages=1218–1225 |doi=10.1176/appi.ajp.2010.09081190 |pmid=20478880 |pmc=2992443 |issn=0002-953X}}</ref> Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse.<ref name="Caserta_2008" /><ref name="Grün_Blumberg_2009" /><ref name=":2" /> 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.<ref name="Cesario_Hughes_2007" /><ref name=":2" />

The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty.<ref name="Wang_2005"/> 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.<ref name="Wang_2005"/> Unfortunately exposure is inferred and not actually measured in available studies.<ref name="Caserta_2008"/> 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.<ref name="Guillette_2006"/><ref name="Meeker_2009"/> Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds.<ref name="Meeker_2009"/> 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 ===

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.<ref name="Raiser_2006"/><ref name="Nikaido_2004">{{cite journal | vauthors = Nikaido Y, Yoshizawa K, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, Tsubura A | title = Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring | journal = Reproductive Toxicology | volume = 18 | issue = 6 | pages = 803–811 | year = 2004 | pmid = 15279878 | doi = 10.1016/j.reprotox.2004.05.002 }}</ref> Oral exposure of female rats to xenoestrogens has been shown to cause pseudo precocious puberty (early vaginal opening and early first estrus).<ref name="Parent_2004" /><ref name="Hotchkiss_2008">{{cite journal | vauthors = Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, Foster PM, Gray CL, Gray LE | title = Fifteen years after "Wingspread"--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go | journal = Toxicological Sciences | volume = 105 | issue = 2 | pages = 235–259 | date = October 2008 | pmid = 18281716 | pmc = 2721670 | doi = 10.1093/toxsci/kfn030 }}</ref><ref name="Della_Seta_2008">{{cite journal | vauthors = Della Seta D, Farabollini F, Dessì-Fulgheri F, Fusani L | title = Environmental-like exposure to low levels of estrogen affects sexual behavior and physiology of female rats | journal = Endocrinology | volume = 149 | issue = 11 | pages = 5592–5598 | date = November 2008 | pmid = 18635664 | doi = 10.1210/en.2008-0113 | s2cid = 28304236 | doi-access = free }}</ref><ref name="Vandenberg_2007">{{cite journal | vauthors = Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM | title = Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland | journal = Endocrinology | volume = 148 | issue = 1 | pages = 116–127 | date = January 2007 | pmid = 17023525 | pmc = 2819269 | doi = 10.1210/en.2006-0561 }}</ref> A study of dioxin in immature female rats induced early follicular development<ref name="Acerini_Hughes_2006">{{cite journal | vauthors = Acerini CL, Hughes IA | title = Endocrine disrupting chemicals: a new and emerging public health problem? | journal = Archives of Disease in Childhood | volume = 91 | issue = 8 | pages = 633–641 | date = August 2006 | pmid = 16861481 | pmc = 2083052 | doi = 10.1136/adc.2005.088500 }}</ref> and phthalates are known to decrease the [[anogenital distance]] in newborn rats.<ref name="Rogan_2007"/> 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.<ref name="Acerini_Hughes_2006"/> Administration of estrogens to developing male animals reduces testicular weight and decreases sperm production.<ref name="Danzo_1998"/> The small phallus size of male alligators has been linked to contamination of their natural Florida habitat with DDT.<ref name="Cesario_Hughes_2007"/><ref name="Acerini_Hughes_2006"/> Data from animal research is abundant demonstrating the adverse effects on reproduction of hormonally active compounds found in the environment.<ref name="Danzo_1998"/><ref name="Acerini_Hughes_2006"/><ref name="Patisaul_2009" /><ref name="Degen_Bolt_2000">{{cite journal | vauthors = Degen GH, Bolt HM | title = Endocrine disruptors: update on xenoestrogens | journal = International Archives of Occupational and Environmental Health | volume = 73 | issue = 7 | pages = 433–441 | date = September 2000 | pmid = 11057411 | doi = 10.1007/s004200000163 | bibcode = 2000IAOEH..73..433D | s2cid = 24198566 }}</ref>

== Common environmental estrogens ==

=== Atrazine ===
[[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.<ref name="Roy_2009"/> Atrazine has been implicated in interfering with the neuroendocrine system, blocking the release of [[gonadotropin-releasing hormone]] (GnRH) which in turn reduces [[Luteinizing hormone-releasing hormone|luteinizing hormone]] (LH) and [[Follicle-stimulating hormone|follicle stimulating hormone]] (FSH) levels.<ref>{{cite journal | vauthors = Stradtman SC, Freeman JL | title = Mechanisms of Neurotoxicity Associated with Exposure to the Herbicide Atrazine | journal = Toxics | volume = 9 | issue = 9 | pages = 207 | date = August 2021 | pmid = 34564358 | pmc = 8473009 | doi = 10.3390/toxics9090207 | doi-access = free }}</ref>

=== BPA ===
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 {{convert|6.4|e9lb|kg}} per year and thus is one of the highest-volume chemicals produced worldwide.<ref name="vom_Saal_Hughes_2005">{{cite journal | vauthors = vom Saal FS, Hughes C | title = An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment | journal = Environmental Health Perspectives | volume = 113 | issue = 8 | pages = 926–933 | date = August 2005 | pmid = 16079060 | pmc = 1280330 | doi = 10.1289/ehp.7713 }}</ref> 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.<ref name="Reid_1944">{{cite journal | vauthors = Reid EE, Wilson E | title = The Relation of Estrogenic Activity to Structure in Some 4,4'-Dihydroxydiphenylmethanes | journal = J. Am. Chem. Soc. | volume = 66 | issue = 6 | pages = 967–969 |date=1944 | doi =10.1021/ja01234a038 }}</ref>

It has been suggested that biphenol A and other xenoestrogens might cause disease to humans<ref name="Meeker_2009">{{cite journal | vauthors = Meeker JD, Sathyanarayana S, Swan SH | title = Phthalates and other additives in plastics: human exposure and associated health outcomes | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 364 | issue = 1526 | pages = 2097–2113 | date = July 2009 | pmid = 19528058 | pmc = 2873014 | doi = 10.1098/rstb.2008.0268 }}</ref> and animals.<ref name="Patisaul_2009"/> 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.<ref>{{cite journal | vauthors = Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X, Wang R, Marwa PW, Petlulu P, Chen X, Zhang H | title = The adverse health effects of bisphenol A and related toxicity mechanisms | journal = Environmental Research | volume = 176 | pages = 108575 | date = September 2019 | pmid = 31299621 | doi = 10.1016/j.envres.2019.108575 | s2cid = 196349678 | bibcode = 2019ER....176j8575M }}</ref>

[[Bisphenol S]] (BPS), an analog of BPA, has also been shown to alter estrogenic activity.<ref name=ETP>{{cite journal | vauthors = Kuruto-Niwa R, Nozawa R, Miyakoshi T, Shiozawa T, Terao Y | title = Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system | journal = Environmental Toxicology and Pharmacology | volume = 19 | issue = 1 | pages = 121–130 | date = January 2005 | pmid = 21783468 | doi = 10.1016/j.etap.2004.05.009 | bibcode = 2005EnvTP..19..121K }}</ref><ref name="ReferenceA">{{cite journal | vauthors = Viñas R, Watson CS | title = Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: effects on cell functions | journal = Environmental Health Perspectives | volume = 121 | issue = 3 | pages = 352–358 | date = March 2013 | pmid = 23458715 | pmc = 3621186 | doi = 10.1289/ehp.1205826 }}</ref> 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.<ref name="ReferenceA"/>

=== DDT ===
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.<ref name=":03">{{Cite book | vauthors = Gilbert S |title=Ecological Developmental Biology |publisher=Oxford University Press Academic US |year=2015 |isbn=9781605355429 |edition=2nd |pages=225–228}}</ref> 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.<ref name="Roy_2009">{{cite journal | vauthors = Roy JR, Chakraborty S, Chakraborty TR | title = Estrogen-like endocrine disrupting chemicals affecting puberty in humans--a review | journal = Medical Science Monitor | volume = 15 | issue = 6 | pages = RA137–RA145 | date = June 2009 | pmid = 19478717 }}</ref><ref name="Caserta_2008">{{cite journal | vauthors = Caserta D, Maranghi L, Mantovani A, Marci R, Maranghi F, Moscarini M | title = Impact of endocrine disruptor chemicals in gynaecology | journal = Human Reproduction Update | volume = 14 | issue = 1 | pages = 59–72 | year = 2008 | pmid = 18070835 | doi = 10.1093/humupd/dmm025 | doi-access = free }}</ref><ref name="Rogan_2007">{{cite journal | vauthors = Rogan WJ, Ragan NB | title = Some evidence of effects of environmental chemicals on the endocrine system in children | journal = International Journal of Hygiene and Environmental Health | volume = 210 | issue = 5 | pages = 659–667 | date = October 2007 | pmid = 17870664 | pmc = 2245801 | doi = 10.1016/j.ijheh.2007.07.005 }}</ref><ref name="Patisaul_2009">{{cite journal | vauthors = Patisaul HB, Adewale HB | title = Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior | journal = Frontiers in Behavioral Neuroscience | volume = 3 | pages = 10 | year = 2009 | pmid = 19587848 | pmc = 2706654 | doi = 10.3389/neuro.08.010.2009 | doi-access = free }}</ref>

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.<ref name=":03"/>

=== Dioxin ===
[[Dioxins and dioxin-like compounds|Dioxin]], a group of highly toxic chemicals are released during combustion processes, pesticide manufacturing and [[Bleaching of wood pulp#Chlorine and hypochlorite|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.<ref name="Roy_2009"/><ref name="Caserta_2008"/><ref name="Jacobson-Dickman_Lee_2009"/> 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.<ref>{{cite journal | vauthors = Tavakoly Sany SB, Hashim R, Salleh A, Rezayi M, Karlen DJ, Razavizadeh BB, Abouzari-Lotf E | title = Dioxin risk assessment: mechanisms of action and possible toxicity in human health | journal = Environmental Science and Pollution Research International | volume = 22 | issue = 24 | pages = 19434–19450 | date = December 2015 | pmid = 26514567 | doi = 10.1007/s11356-015-5597-x | bibcode = 2015ESPR...2219434T | s2cid = 9584022 }}</ref>

=== Endosulfan ===
[[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.<ref name="Roy_2009"/><ref name="Watson_2011">{{cite journal | vauthors = Watson CS, Jeng YJ, Guptarak J | title = Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 127 | issue = 1–2 | pages = 44–50 | date = October 2011 | pmid = 21300151 | pmc = 3106143 | doi = 10.1016/j.jsbmb.2011.01.015 }}</ref> Endosulfan exposure is known to cause seizures that are the result of hyper-stimulation of the central nervous system ([[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.<ref>{{cite journal | vauthors = Menezes RG, Qadir TF, Moin A, Fatima H, Hussain SA, Madadin M, Pasha SB, Al Rubaish FA, Senthilkumaran S | title = Endosulfan poisoning: An overview | journal = Journal of Forensic and Legal Medicine | volume = 51 | pages = 27–33 | date = October 2017 | pmid = 28734199 | doi = 10.1016/j.jflm.2017.07.008 | s2cid = 12535174 }}</ref>

=== Brominated Flame Retardants (BFRs) ===
Both PBBs and PBDEs belong to the same class of chemicals known as brominated flame retardants.<ref>{{cite journal | vauthors = Jagić K, Dvoršćak M, Klinčić D | title = Analysis of brominated flame retardants in the aquatic environment: a review | journal = Arhiv Za Higijenu Rada I Toksikologiju | volume = 72 | issue = 4 | pages = 254–267 | date = December 2021 | pmid = 34985845 | pmc = 8785114 | doi = 10.2478/aiht-2021-72-3576 }}</ref> 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 diphenyl ethers|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.<ref>{{Cite web |title=Polybrominated Diphenyl Ethers (PBDEs) {{!}} Toxic Substances {{!}} Toxic Substance Portal {{!}} ATSDR |url=https://wwwn.cdc.gov/TSP/substances/ToxSubstance.aspx?toxid=183 |access-date=2023-03-29 |website=wwwn.cdc.gov}}</ref><ref name="Roy_2009"/><ref name="Raiser_2006">{{cite journal | vauthors = Rasier G, Toppari J, Parent AS, Bourguignon JP | title = Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data | journal = Molecular and Cellular Endocrinology | volume = 254-255 | pages = 187–201 | date = July 2006 | pmid = 16720078 | doi = 10.1016/j.mce.2006.04.002 | s2cid = 26180396 | hdl = 2268/69898 | hdl-access = free }}</ref><ref name="Patisaul_2009"/>

===PCBs===
PCBs ([[Polychlorinated biphenyls]]) are man made organic chemicals known as [[Organochloride|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.<ref name="Roy_2009"/><ref name="Caserta_2008"/><ref name="Rogan_2007"/> 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.<ref name="pmid34476758">{{cite journal | vauthors = Zhang MZ, Chu SS, Xia YK, Wang DD, Wang X | title = Environmental exposure during pregnancy and the risk of childhood allergic diseases | journal = World Journal of Pediatrics | volume = 17 | issue = 5 | pages = 467–475 | date = October 2021 | pmid = 34476758 | doi = 10.1007/s12519-021-00448-7 | s2cid = 237395252 }}</ref>

===Phthalates===
[[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.<ref name="Roy_2009"/><ref name="Patisaul_2009"/><ref name="Nilsson_2000">{{cite journal | vauthors = Nilsson R | title = Endocrine modulators in the food chain and environment | journal = Toxicologic Pathology | volume = 28 | issue = 3 | pages = 420–431 | year = 2000 | pmid = 10862560 | doi = 10.1177/019262330002800311 | s2cid = 34979477 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Wang Y, Qian H | title = Phthalates and Their Impacts on Human Health | journal = Healthcare | volume = 9 | issue = 5 | pages = 603 | date = May 2021 | pmid = 34069956 | doi = 10.3390/healthcare9050603 | pmc = 8157593 | doi-access = free }}</ref>

===Zeranol===
[[Zeranol]] is currently used as an anabolic growth promoter for [[livestock]] in the US<ref>{{cite web|last1=US Food and Drug Administration|title=21CFR522.2680|url=http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=522.2680|access-date=14 June 2014|ref=21CFR522.2680}}</ref> and Canada.<ref>{{cite web|last1=Health Canada|title=Questions and Answers - Hormonal Growth Promoters|url=http://www.hc-sc.gc.ca/dhp-mps/vet/faq/growth_hormones_promoters_croissance_hormonaux_stimulateurs-eng.php|access-date=14 June 2014|quote=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).|date=2012-09-05}}</ref> It has been banned in the [[EU]] since 1985,<ref>{{cite web|author=((Agriculture and Fisheries (including Agro-industry, Food technologies, Forestry, Aquaculture and Rural Development) )) |title=Development, validation and harmonisation of screening and confirmatory tests to distinguish zeranol abuse from fusarium toxin contamination in food animals |url=http://ec.europa.eu/research/agro/fair/en/uk3443.html |publisher=European Commission |access-date=14 June 2014 |quote=The use of zeranol for growth promotion in food animals was banned in the EU in 1985. |url-status=dead |archive-url=https://web.archive.org/web/20160305071349/http://ec.europa.eu/research/agro/fair/en/uk3443.html |archive-date=March 5, 2016 }}</ref> but is still present as a contaminant in food through meat products that were exposed to it.<ref name="Roy_2009"/>

=== Miscellaneous ===
{{columns-list|colwidth=35em|
* [[alkylphenol]]s (intermediate chemicals used in the manufacture of other chemicals)
* [[4-Methylbenzylidene camphor]] (4-MBC) (sunscreen lotions)
* [[bisphenol S]], BPS (an analog of BPA)
* [[butylated hydroxyanisole]], BHA (food preservative)
* [[dichlorodiphenyldichloroethylene]] (one of the breakdown products of DDT)
* [[dieldrin]] (banned insecticide)
* [[DDT]] (banned insecticide)
* [[endosulfan]] (widely banned insecticide)
* [[erythrosine]], FD&C Red No. 3 (E127)
* [[ethinylestradiol]] ([[combined oral contraceptive pill]]) (released into the environment as a xenoestrogen)<ref>[http://phys.org/news/2012-05-pair-discourse-wastewater-contaminated-birth.html Pair call for public discourse on treating wastewater contaminated with birth control pill chemicals, Phys.org]</ref>
* [[heptachlor]] (restricted insecticide)
* [[lindane]], hexachlorocyclohexane (restricted insecticide)
* [[metalloestrogen]]s (a class of inorganic xenoestrogens)
* [[methoxychlor]] (banned insecticide)
* [[nonylphenol]] and derivatives (industrial surfactants; emulsifiers for emulsion polymerization; laboratory detergents; pesticides)
* [[pentachlorophenol]] (restricted general [[biocide]] and wood preservative)
* [[polychlorinated biphenyl]]s, PCBs (banned; formerly used in electrical oils, lubricants, adhesives, paints)
* [[paraben]]s (lotions)
* [[phthalates]] ([[plasticizer]]s)
** [[DEHP]] (plasticizer for PVC)
* [[Propyl gallate]] (used to protect oils and fats in products from [[carbonization]])
}}

== See also ==
{{Columns-list|colwidth=30em|
* [[Diethylstilbestrol]] (obsolete pharmacological estrogen)
* [[Endocrine disruptor]]
* [[Environmental exogenous hormones]]
* [[Environmental impact of pharmaceuticals and personal care products]]
* [[Environmental xenobiotic]]
* [[Epidemiology and etiology of breast cancer]]
* [[List of breast carcinogenic substances]]
* [[Phytoestrogens]]
* [[SULT2B1]]
* [[Xenobiotic]]
* [[Xenoandrogen]]}}

== References ==
{{Reflist|colwidth=30em}}

== External links ==
* [https://web.archive.org/web/20050923102755/http://www.ourstolenfuture.org/basics/about.htm "Our Stolen Future" book about endocrine disruption]
* [http://www.nobreastcyst.com/xeno.html How to avoid xenoestrogens]
* [https://web.archive.org/web/20071217094102/http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4CY0H60-2&_coverDate=12%2F01%2F2004&_alid=323911814&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=5175&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8479e7f7db76ee593b73a6a5dabe66ba#cor1 S. Safe on lack of evidence for any effect]

{{Xenoestrogens}}
{{Estrogenics}}

[[Category:Xenoestrogens]]
[[Category:Endocrinology]]
[[Category:Water pollution]]
[[Category:Pollutants]]