User:Habaker930/Xenoestrogen

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, 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.

Effects[edit]

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, where each species is more or less sensitive to certain substances than the other specie.

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. Breast cancer are fueled by hormonal fluctuations and xenoestrogen acts as a catalyst for cancer growth because it increases the proliferation of the breast tissue.

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.

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.

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

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. However, recent studies have shown that chemical exposure to environmental estrogen disruptors the HPG axis and result in precocious puberty. In 1999, US Food and Drug Administration has recommended to not take estrogen in food of more than 0.43 ng/day for boys and 3.24 ng/day for females. 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.

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. 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.

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, increased cancer risk (breast and endometrial for girls and testicular for boys). Precocious puberty is linked with other gynecologic disorders such as endometriosis, adenomyosis, polycystic ovarian syndrome and infertility. Premature pubertal growth spurt and accelerated bone maturation will result in premature closure of distal epiphysis which causes reduced adult height and short stature. 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[edit]

Non-human animal studies have shown that exposure to environmental contaminants with estrogenic activity can accelerate the onset of puberty. A potential mechanism has been described in rats exposed to DDT or beta-estradiol in which GnRH pulsatile secretion was found to be increased. 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. Exposure to xenoestrogens such as nonylphenol (NP), genistein (GEN), and bisphenol A (BPA) during development are shown to hinder the development and functionality of metabolic systems in mice. Because metabolic systems are largely responsible for endocrine signaling, dysregulation of metabolism has been shown to effect growth and neuronal development as well. A study of NP exposure in developing mice indicated that NP may dysregulate the formation of adipose tissue in male mice by acting their endocrine systems. As NP acts disrupts endocrine signaling, it changes the expression levels of RNA related to adipose development leading to abnormalities in fat formation.

Disruption of developmental endocrine signaling has also been linked to deficits in cognitive abilities later in life. Exposure to GEN and BPA was shown to dysregulate amino acid metabolism, resulting in changes in cognitive ability. This is because exposure may disrupt the development of neuronal systems or imbalance neurochemistry in adult mice, by acting on the microbiome-gut-brain to change neurochemical expression. The livers of oviparous vertebrates play a role in sexual reproduction by secreting hormones that facilitate egg formation and production, and hormones that contribute to sexual dimorphism. Environmental estrogens that act on the livers of oviparous vertebrates are shown to increase rates of liver diseases in chickens, and disrupt egg production in fishes. 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.

Xenoestrogens with environmental relevance disrupted spermatogenesis of zebrafish. Xenoestrogens disrupted the HPG axis and imbalanced the hormone levels. Xenoestrogens enhanced proliferations but induced apoptosis in the germ cells. Xenoestrogens have been a subject of concern due to their potential to disrupt the endocrine system of various organisms, including fish. Zebrafish (Danio rerio), with their transparent embryos and rapid development, have become a valuable model for studying the effects of xenoestrogens on aquatic organisms. Exposure to these compounds can lead to a myriad of adverse effects in zebrafish, ranging from developmental abnormalities and reproductive dysfunction to altered behavior and impaired immune function. For instance, studies have shown that exposure to xenoestrogens such as bisphenol A (BPA), phthalates, and certain pesticides can interfere with the normal development of zebrafish embryos, leading to malformations in organs such as the brain, heart, and gonads. Moreover, xenoestrogens have been found to disrupt the reproductive physiology of adult zebrafish, affecting gamete production and fertility. Additionally, exposure to these compounds has been linked to changes in behavior, such as increased anxiety-like behavior and impaired shoaling, which could have implications for survival in natural environments. Furthermore, xenoestrogens can modulate the immune response in zebrafish, potentially rendering them more susceptible to infections and diseases. Overall, the study of xenoestrogen-induced effects in zebrafish provides valuable insights into the potential risks posed by these compounds to aquatic ecosystems and highlights the importance of regulating their use to protect environmental and human health.