Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.
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 (in which estrogenic action is an intended effect, as in the drug ethinylestradiol used in contraceptive pills), but other chemicals may also have estrogenic effects. Xenoestrogens have been introduced into the environment by industrial, agricultural and chemical companies and consumers only in the last 70 years or so, but archiestrogens exist naturally. Some plants (like the cereals and the legumes) are using estrogenic substances possibly as part of their natural defence against herbivore animals by controlling their fertility.
The potential ecological and human health impact of xenoestrogens is of growing concern. The word xenoestrogen is derived from the Greek words ξένο xeno 'foreign', οἶστρος oistros 'sexual desire', and γόνο gono 'to generate', and it 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 hormone disruptive effects on both wildlife and humans.
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.
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.
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.
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.
There is a concern that xenoestrogens may act as false messengers and disrupt the process of reproduction. Xenoestrogens, like all estrogens, can increase growth of the endometrium, so treatments for endometriosis include avoidance of products which contain them. Likewise, they are avoided in order to prevent the onset or aggravation of adenomyosis. Studies have implicated observations of disturbances in wildlife with estrogenic exposure. For example, discharge from human settlement including runoff and water flowing out of wastewater treatment plants release a large amount of xenoestrogens into streams, which lead to immense alterations in aquatic life. With a bioaccumulation factor of 105 –106, fish are extremely susceptible to pollutants. 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 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. 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.
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), 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. Ninety-nine percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.It's official: Men are the weaker sex 7 December 2008. The Independent.
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.
Precocious puberty
Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function. 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.
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 accelerated 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. Both central and peripheral precocious puberty have been linked to exposure to exogenous estrogenic compounds.
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. 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.