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.

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.

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.

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 10<sup>5</sup> –10<sup>6</sup>, 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.

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.

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. 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. Both central and peripheral precocious puberty have been linked to exposure to exogenous estrogenic compounds. These diseases are usually characterized by enlarged testis and can be an indication of peripheral precocious puberty in boys. 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. 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&nbsp;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. 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.

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.

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. increased cancer risk (breast 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. Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse. 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.

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.

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 per year and thus is one of the highest-volume chemicals produced worldwide. 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.

It has been suggested that biphenol A and other xenoestrogens might cause disease to humans and animals.

Bisphenol S (BPS), an analog of BPA, has also been shown to alter estrogenic activity. 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. 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.

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.

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. Endosulfan exposure is known to cause seizures that are the result of hyper-stimulation of the central nervous system (CNS). Upon significant exposure and accumulation in the system, toxicity of the major organs such as the heart, liver and kidneys has been reported and can lead to death within hours.

Brominated flame retardants

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

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. 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.

Zeranol

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

  • 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 carbonization)

See also

References

  • "Our Stolen Future" book about endocrine disruption
  • How to avoid xenoestrogens
  • S. Safe on lack of evidence for any effect