Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens are 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.
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.
Xenoestrogens include pharmacological estrogens (estrogenic action is an intended effect, as in the drug ethinyl estradiol used in contraceptive pill), 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 have been a ubiquitous part of the environment even before the existence of the human race given that 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 male fertility.
The potential ecological and human health impact of xenoestrogens is of growing concern. 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.
- 1 Mechanism of action
- 2 Effects
- 3 Common environmental estrogens
- 4 See also
- 5 References
- 6 External links
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. Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.
Hormones or substances with hormone disrupting capability 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 man made 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.
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. 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. 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.
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.
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 10^5 –10^6, fish are extremely susceptible to pollutants. Streams in more arid conditions are thought to have more effects due to higher concentrations of the chemicals arising from lack of dilution.
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.
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.
Sperm concentrations and motility perimeters are reduced in male fish exposed to xenoestrogens in addition to disrupt stages of spermatogenesis. 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. 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.
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.
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. However, there is substantial evidence in a variety of recent studies to indicate that xenoestrogens can increase breast cancer growth in tissue culture.
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. 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. 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.
There has been speculation that falling sperm counts in males may be due to increased estrogen exposure in utero. 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.
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), 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. 99% percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.
Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function. The first sign of 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.
Puberty is considered precocious (precocious puberty) if secondary sex characteristics occur before the age of 8 in girls and 9 years in boys. Increased growth is often the first change in precocious puberty, followed by breast development and growth of pubic hair. However, thelarche, adrenarche, and linear growth can occur simultaneously and although uncommon, menarche can be the first sign. Precocious puberty can be classified into central (gonadotropin-dependent) precocious puberty or peripheral (gonadotropin-independent) puberty. Peripheral precocious puberty has been linked to exposure to exogenous estrogenic compounds.
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. 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. Trends toward earlier puberty have been attributed to improved public health and living conditions. A leading hypothesis for this change toward early puberty is improved nutrition resulting in rapid body growth, increased weight and fat deposition.
Two recent epidemiologic studies in the United States (PROS and NMANES III) highlighted a recent unexpected advance in sexual maturation in girls. 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. Environmental chemical exposure is one of the factors implicated in the recent downward trend of earlier sexual maturation.
Thelarche in Puerto Rico
Since 1979, pediatric endocrinologists in Puerto Rico recognized an increase in number of patients with premature thelarche. 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. 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.
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.
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.
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. Limitations of the study included indirect measurement of the exposure and self reporting of menarche.
Precocious puberty has numerous significant physical, psychological and social implications for a young girl. Unfortunately, premature pubertal growth spurt and accelerated bone maturation will result in premature closure of distal epiphysis which causes reduced adult height and short stature. In 1999, US Food and Drug Administration has recommended to not take estrogen in food of more than 3.24 ng per day for females. Precocious puberty has also been implicated in pediatric and adult obesity. Some studies have suggested precocious puberty places girls at a higher risk of breast cancer later in life. Precocious puberty is linked with other gynecologic disorders such endometriosis, adenomyosis, polycystic ovarian syndrome and infertility. Precocious puberty can lead to psychosocial distress, a poor self-image, and poor self-esteem. Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse. 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.
The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty. 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. Unfortunately exposure is inferred and not actually measured in available studies. 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. Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds. 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. Oral exposure of female rats to xenoestrogens has been shown to cause pseudo precocious puberty (early vaginal opening and early first estrus). A study of dioxin in immature female rats induced early follicular development and phthalates are known to decrease the anogenital distance in newborn rats. 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. Administration of estrogens to developing male animals reduces testicular weight and decreases sperm production. The small phallus size of male alligators has been linked to contamination of their natural Florida habitat with DDT. Data from animal research is abundant demonstrating the adverse effects on reproduction of hormonally active compounds found in the environment.
Common environmental estrogens
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.
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 lbs per year and thus is one of the highest-volume chemicals produced worldwide. The ester bonds in these BPA-based polymers are subject to hydrolysis and leaching of BPA has led to widespread human exposure.
DDT (Dichlorodiphenyltrichloroethane) was widely used in pesticides for agriculture until it was banned in 1972 in the United States due to its hazardous effects on the environment. DDT continues to be used in many parts of the world for agricultural use, insect control and to fight the spread of malaria. DDT and its metabolites DDE and DDD are persistent in the environment and accumulate in fatty tissues.
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.
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.
PBB (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.
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.
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.
Zeranol is currently used as an anabolic growth promoter for livestock in the US and Canada. It has since been banned in the EU since 1985, but is still present as a contaminant in food through meat products that were exposed to it.
- alkylphenols (intermediate chemicals used in the manufacture of other chemicals)
- 4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)
- 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)
- heptachlor (restricted insecticide)
- lindane, hexachlorocyclohexane (restricted insecticide)
- metalloestrogens (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 biphenyls, PCBs (banned; formerly used in electrical oils, lubricants, adhesives, paints)
- parabens (lotions)
- phthalates (plasticizers)
- DEHP (plasticizer for PVC)
- Propyl gallate (used to protect oils and fats in products from oxidation)
- Diethylstilbestrol (obsolete pharmacological estrogen)
- Endocrine disruptor
- Environmental exogenous hormones
- Environmental xenobiotic
- Epidemiology and etiology of breast cancer
- List of breast carcinogenic substances
- Aksglaede L, Juul A, Leffers H, Skakkebaek NE, Andersson AM (2006). "The sensitivity of the child to sex steroids: possible impact of exogenous estrogens". Hum. Reprod. Update 12 (4): 341–9. doi:10.1093/humupd/dml018. PMID 16672247.
- Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM (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): 505–12. doi:10.1542/peds.99.4.505. PMID 9093289.
- Hughes CL (June 1988). "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environ. Health Perspect. 78: 171–4. doi:10.1289/ehp.8878171. PMC 1474615. PMID 3203635.
- Infertility in the modern world: present and future prospects, Gillian R. Bentley,C. G. N. Mascie-Taylor, Cambridge University Press, p.99-100
- Korach, Kenneth S. (1998). Reproductive and Developmental Toxicology. Marcel Dekker Ltd. pp. 278–279, 294–295. ISBN 978-0-8247-9857-4.
- 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 P.J.H., Soto A, Van Der Kraak G, vom Saal F, Whitten P (1992). "Statement from the Work Session on Chemically-Induced Alterations in Sexual Development: The Wildlife/Human Connection". In Clement C, Colborn T. Chemically-induced alterations in sexual and functional development -- the wildlife/human connection. Princeton, N.J: Princeton Scientific Pub. Co. pp. 1–8. ISBN 0-911131-35-3.
- Bantle J, Bowerman WW IV, Carey C, Colborn T, Deguise S, Dodson S, Facemire CF, Fox G, Fry M, Gilbertson M, Grasman K, Gross T, Guilvlette L Jr., Henny C, Henshel DS, Hose JE, Klein PA, Kubiak TJ, Lahvis G, Palmer B, Peterson C, Ramsay M, White D (May 1995). "Statement from the Work Session on Environmentally induced Alterations in Development: A Focus on Wildlife". Environ. Health Perspect. 103 (Suppl 4): 3–5. doi:10.2307/3432404. JSTOR 3432404. PMC 1519268. PMID 17539108.
- 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 (1997). "Statement from the work session on chemically induced alterations in functional development and reproduction of fishes". In Rolland RM, Gilbertson M, Peterson RE. Chemically Induced Alterations in Functional Development and Reproduction of Fishes. Society of Environmental Toxicology & Chemist. pp. 3–8. ISBN 1-880611-19-8.
- Alleva E, Brock J, Brouwer A, Colborn T, Fossi MC, Gray E, Guillette L, Hauser P, Leatherland J, MacLusky N, Mutti A, Palanza P, Parmigiani S, Porterfield, Santi R, Stein SA, vom Saal F (1998). "Statement from the work session on environmental endocrine-disrupting chemicals: neural, endocrine, and behavioral effects". Toxicol Ind Health 14 (1–2): 1–8. doi:10.1177/074823379801400103. PMID 9460166.
- Brock J, Colborn T, Cooper R, Craine DA, Dodson SFM, 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 (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. doi:10.1191/074823399678846547.
- Kase NG, Speroff L, Glass RL (1994). Clinical gynecologic endocrinology and infertility (5 ed.). Baltimore: Williams & Wilkins. pp. 371–382. ISBN 0-683-07899-2.
- Roy JR, Chakraborty S, Chakraborty TR (June 2009). "Estrogen-like endocrine disrupting chemicals affecting puberty in humans--a review". Med. Sci. Monit. 15 (6): RA137–45. PMID 19478717.
- Massart F, Parrino R, Seppia P, Federico G, Saggese G (June 2006). "How do environmental estrogen disruptors induce precocious puberty?". Minerva Pediatr. 58 (3): 247–54. PMID 16832329.
- Toppari J, Juul A (August 2010). "Trends in puberty timing in humans and environmental modifiers". Mol. Cell. Endocrinol. 324 (1–2): 39–44. doi:10.1016/j.mce.2010.03.011. PMID 20298746.
- Caserta D, Maranghi L, Mantovani A, Marci R, Maranghi F, Moscarini M (2008). "Impact of endocrine disruptor chemicals in gynaecology". Hum. Reprod. Update 14 (1): 59–72. doi:10.1093/humupd/dmm025. PMID 18070835.
- Danzo BJ (November 1998). "The effects of environmental hormones on reproduction". Cell. Mol. Life Sci. 54 (11): 1249–64. doi:10.1007/s000180050251. PMID 9849617.
- 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 (February 2008). "Environmental factors and puberty timing: expert panel research needs". Pediatrics. 121 Suppl 3: S192–207. doi:10.1542/peds.1813E. PMID 18245512.
- 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". Mol. Cell. Endocrinol. 254-255: 187–201. doi:10.1016/j.mce.2006.04.002. PMID 16720078.
- Mueller SO (February 2004). "Xenoestrogens: mechanisms of action and detection methods". Anal Bioanal Chem 378 (3): 582–7. doi:10.1007/s00216-003-2238-x. PMID 14564443.
- Aravindakshan J, Paquet V, Gregory M, Dufresne J, Fournier M, Marcogliese DJ, Cyr DG (March 2004). "Consequences of xenoestrogen exposure on male reproductive function in spottail shiners (Notropis hudsonius)". Toxicol. Sci. 78 (1): 156–65. doi:10.1093/toxsci/kfh042. PMID 14657511.
- vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV (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". Toxicol Ind Health 14 (1–2): 239–60. doi:10.1177/074823379801400115. PMID 9460178.
- Aravindakshan J, Gregory M, Marcogliese DJ, Fournier M, Cyr DG (September 2004). "Consumption of xenoestrogen-contaminated fish during lactation alters adult male reproductive function". Toxicol. Sci. 81 (1): 179–89. doi:10.1093/toxsci/kfh174. PMID 15159524.
- 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". Mol. Cell. Endocrinol. 178 (1–2): 39–45. doi:10.1016/S0303-7207(01)00416-6. PMID 11403892.
- Rozati R, Reddy PP, Reddanna P, Mujtaba R (December 2002). "Role of environmental estrogens in the deterioration of male factor fertility". Fertil. Steril. 78 (6): 1187–94. doi:10.1016/S0015-0282(02)04389-3. PMID 12477510.
- 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". Environ. Health Perspect. 103 (12): 1136–43. doi:10.1289/ehp.951031136. PMC 1519239. PMID 8747020.
- Dallinga JW, Moonen EJ, Dumoulin JC, Evers JL, Geraedts JP, Kleinjans JC (August 2002). "Decreased human semen quality and organochlorine compounds in blood". Hum. Reprod. 17 (8): 1973–9. doi:10.1093/humrep/17.8.1973. PMID 12151423.
- Palmlund I (June 1996). "Exposure to a xenoestrogen before birth: the diethylstilbestrol experience". J Psychosom Obstet Gynaecol 17 (2): 71–84. doi:10.3109/01674829609025667. PMID 8819018.
- Olea N, Olea-Serrano F, Lardelli-Claret P, Rivas A, Barba-Navarro A (1999). "Inadvertent exposure to xenoestrogens in children". Toxicol Ind Health 15 (1–2): 151–8. doi:10.1177/074823379901500112. PMID 10188197.
- Li DK, Zhou Z, Miao M, He Y, Wang J, Ferber J, Herrinton LJ, Gao E, Yuan W (February 2011). "Urine bisphenol-A (BPA) level in relation to semen quality". Fertil. Steril. 95 (2): 625–30.e1–4. doi:10.1016/j.fertnstert.2010.09.026. PMID 21035116.
- Rogan WJ, Ragan NB (July 2003). "Evidence of effects of environmental chemicals on the endocrine system in children". Pediatrics 112 (1 Pt 2): 247–52. doi:10.1542/peds.112.1.S1.247. PMID 12837917.
- Williams DE, Lech JJ, Buhler DR (March 1998). "Xenobiotics and xenoestrogens in fish: modulation of cytochrome P450 and carcinogenesis". Mutat. Res. 399 (2): 179–92. doi:10.1016/S0027-5107(97)00255-8. PMID 9672659.
- Vajda AM, Barber LB, Gray JL, Lopez EM, Woodling JD, Norris DO (May 2008). "Reproductive disruption in fish downstream from an estrogenic wastewater effluent". Environ. Sci. Technol. 42 (9): 3407–14. doi:10.1021/es0720661. PMID 18522126.
- 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)". Aquat. Toxicol. 49 (3): 159–170. doi:10.1016/S0166-445X(99)00083-1. PMID 10856602.
- Golden RJ, Noller KL, Titus-Ernstoff L, Kaufman RH, Mittendorf R, Stillman R, Reese EA (March 1998). "Environmental endocrine modulators and human health: an assessment of the biological evidence". Crit. Rev. Toxicol. 28 (2): 109–227. doi:10.1080/10408449891344191. PMID 9557209.
- 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". J Appl Toxicol 27 (1): 67–77. doi:10.1002/jat.1200. PMID 17121429.
- 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): 1567–78. doi:10.1093/carcin/bgi339. PMID 16474171.
- Darbre PD (March 2006). "Environmental oestrogens, cosmetics and breast cancer". Best Pract. Res. Clin. Endocrinol. Metab. 20 (1): 121–43. doi:10.1016/j.beem.2005.09.007. PMID 16522524.
- Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS (2004). "Concentrations of parabens in human breast tumours". J Appl Toxicol 24 (1): 5–13. doi:10.1002/jat.958. PMID 14745841.
- 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): 5388–96. doi:10.1210/en.2005-0565. PMID 16123166.
- 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.
- Murray DW, Lichter SR (April 1998). "Organochlorine residues and breast cancer". N. Engl. J. Med. 338 (14): 990–1. doi:10.1056/nejm199804023381411. PMID 9527611.
- Sharpe RM, Skakkebaek NE (May 1993). "Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?". Lancet 341 (8857): 1392–5. doi:10.1016/0140-6736(93)90953-E. PMID 8098802.
- Sharpe RM (February 2003). "The 'oestrogen hypothesis'- where do we stand now?". Int. J. Androl. 26 (1): 2–15. doi:10.1046/j.1365-2605.2003.00367.x. PMID 12534932.
- Vidaeff AC, Sever LE (2005). "In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence". Reprod. Toxicol. 20 (1): 5–20. doi:10.1016/j.reprotox.2004.12.015. PMID 15808781.
- It's official: Men are the weaker sex 7 December 2008. The Independent.
- Mouritsen A, Aksglaede L, Sørensen K, Mogensen SS, Leffers H, Main KM, Frederiksen H, Andersson AM, Skakkebaek NE, Juul A (April 2010). "Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty". Int. J. Androl. 33 (2): 346–59. doi:10.1111/j.1365-2605.2010.01051.x. PMID 20487042.
- Parent AS, Rasier G, Gerard A, Heger S, Roth C, Mastronardi C, Jung H, Ojeda SR, Bourguignon JP (2005). "Early onset of puberty: tracking genetic and environmental factors". Horm. Res. 64 Suppl 2 (2): 41–7. doi:10.1159/000087753. PMID 16286770.
- 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.
- Guillette EA, Conard C, Lares F, Aguilar MG, McLachlan J, Guillette LJ (March 2006). "Altered breast development in young girls from an agricultural environment". Environ. Health Perspect. 114 (3): 471–5. doi:10.1289/ehp.8280. PMC 1392245. PMID 16507474.
- The National Health and Nutrition Examination Survey III (NHANES III) and the Pediatric Research in Ofﬁce Settings (PROS)
- 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". Environ. Health Perspect. 113 (8): 1100–7. doi:10.1289/ehp.7615. PMC 1280355. PMID 16079085.
- Den Hond E, Schoeters G (February 2006). "Endocrine disrupters and human puberty". Int. J. Androl. 29 (1): 264–71; discussion 286–90. doi:10.1111/j.1365-2605.2005.00561.x. PMID 16466548.
- 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". Environ. Health Perspect. 108 (9): 895–900. doi:10.1289/ehp.00108895. PMC 2556932. PMID 11017896.
- Rogan WJ, Ragan NB (October 2007). "Some evidence of effects of environmental chemicals on the endocrine system in children". Int J Hyg Environ Health 210 (5): 659–67. doi:10.1016/j.ijheh.2007.07.005. PMC 2245801. PMID 17870664.
- Massart F, Meucci V, Saggese G, Soldani G (May 2008). "High growth rate of girls with precocious puberty exposed to estrogenic mycotoxins". J. Pediatr. 152 (5): 690–5, 695.e1. doi:10.1016/j.jpeds.2007.10.020. PMID 18410776.
- Cesario SK, Hughes LA (2007). "Precocious puberty: a comprehensive review of literature". J Obstet Gynecol Neonatal Nurs 36 (3): 263–74. doi:10.1111/j.1552-6909.2007.00145.x. PMID 17489932.
- Partsch CJ, Sippell WG (2001). "Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens". Hum. Reprod. Update 7 (3): 292–302. doi:10.1093/humupd/7.3.292. PMID 11392376.
- Grün F, Blumberg B (May 2009). "Endocrine disrupters as obesogens". Mol. Cell. Endocrinol. 304 (1–2): 19–29. doi:10.1016/j.mce.2009.02.018. PMC 2713042. PMID 19433244.
- Genuis SJ (September 2006). "Health issues and the environment--an emerging paradigm for providers of obstetrical and gynaecological health care". Hum. Reprod. 21 (9): 2201–8. doi:10.1093/humrep/del181. PMID 16775159.
- 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 B 364 (1526): 2097–113. doi:10.1098/rstb.2008.0268. PMC 2873014. PMID 19528058.
- Nikaido Y, Yoshizawa K, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, Tsubura A (2004). "Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring". Reprod. Toxicol. 18 (6): 803–11. doi:10.1016/j.reprotox.2004.05.002. PMID 15279878.
- Hotchkiss AK, Rider CV, Blystone CR, Wilson VS, Hartig PC, Ankley GT, Foster PM, Gray CL, Gray LE (October 2008). "Fifteen years after "Wingspread"--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go". Toxicol. Sci. 105 (2): 235–59. doi:10.1093/toxsci/kfn030. PMC 2721670. PMID 18281716.
- 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): 5592–8. doi:10.1210/en.2008-0113. PMID 18635664.
- 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): 116–27. doi:10.1210/en.2006-0561. PMC 2819269. PMID 17023525.
- Acerini CL, Hughes IA (August 2006). "Endocrine disrupting chemicals: a new and emerging public health problem?". Arch. Dis. Child. 91 (8): 633–41. doi:10.1136/adc.2005.088500. PMC 2083052. PMID 16861481.
- Patisaul HB, Adewale HB (2009). "Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior". Front Behav Neurosci 3: 10. doi:10.3389/neuro.08.010.2009. PMC 2706654. PMID 19587848.
- Degen GH, Bolt HM (September 2000). "Endocrine disruptors: update on xenoestrogens". Int Arch Occup Environ Health 73 (7): 433–41. doi:10.1007/s004200000163. PMID 11057411.
- 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". Environ. Health Perspect. 113 (8): 926–33. doi:10.1289/ehp.7713. PMC 1280330. PMID 16079060.
- Watson CS, Jeng YJ, Guptarak J (October 2011). "Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways". J. Steroid Biochem. Mol. Biol. 127 (1–2): 44–50. doi:10.1016/j.jsbmb.2011.01.015. PMC 3106143. PMID 21300151.
- Nilsson R (2000). "Endocrine modulators in the food chain and environment". Toxicol Pathol 28 (3): 420–31. doi:10.1177/019262330002800311. PMID 10862560.
- US Food and Drug Administration. "21CFR522.2680". Retrieved 14 June 2014.
- Health Canada. "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).
- 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. Retrieved 14 June 2014.
The use of zeranol for growth promotion in food animals was banned in the EU in 1985.
- Pair call for public discourse on treating wastewater contaminated with birth control pill chemicals, Phys.org
- "Our Stolen Future" book about endocrine disruption
- How to avoid xenoestrogens
- S. Safe on lack of evidence for any effect
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