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In this project, I review on the endocrine disrupting chemicals, particularly xenoestrogens, which are compounds that are originated from many anthropogenic sources and possess estrogen-mimicking properties. They are able to imitate or inhibit the activities of endogenous estrogens (17Î²-estradiol) in the endocrine systems by reacting with estrogen receptors, posing many adverse effects in the metabolism, growth, development, reproduction and internal homeostasis of living organisms. Some examples of xenoestrogens are ethynylestradiol, dichlorodiphenyltrichloroethane, nonylphenol, bisphenol-A and di-(2-ethylhexyl) phthalate. Many living organisms can be affected by xenoestrogens, which includes the fishes and reptiles and some aquatic invertebrates.
I have also discussed about the possible effects posed by the xenoestrogens on various species of living organisms. The most prominent effects caused by xenoestrogens are typically in the reproductive development, hormonal responses and immunity functions. The non-specificity of estrogen receptors in accepting these chemicals to bind to the receptors and act agonistically or antagonistically is the main factor that allows xenoestrogens to exert several deleterious effects. The effects includes vitellogenin (egg yolk protein) induction in male and immature organisms, increased egg and embryo production in invertebrates, sex changes that include intersexuality and sex reversal, delayed spawning cycle, inhibition of spermatogenesis and defect spermatozoa quality in males, altered external genitalia, impaired hormonal balance, altered ovarian steroidogenesis, reduced immunocompetence due to reduced leukocyte proliferation, and suppression of phagocytosis. In real environment conditions, the endocrine-disrupting xenoestrogens are acting as mixtures of chemicals whereby they can act in an additive manner to exhibit estrogenic properties. The mixture effects can be predicted accurately by a mathematical model known as concentration addition.
Finally, I review on the modes of action that are required to exert those effects by xenoestrogens. Xenoestrogens can mimic the endogenous estrogen's mode of actions, particularly via genomic and non-genomic mechanisms to act on estrogen receptors. The classical genomic action, which involves the estrogen receptors in the nucleus, is generally associated with or can be independent of estrogen response elements. Association of the receptors with the ligand subsequently leads to a series of reactions such as activation of transcription of target genes and macromolecule-synthesizing response. On the other hand, the non-genomic pathway involves binding of ligand with estrogen receptors on cellular membranes. The receptor-ligand interaction activates various intracellular signaling cascades, where G proteins play a vital role, with or without nuclear participation at the end of actions.
In conclusion, based on the overwhelming effects observed in living organisms, these problems are definitely cannot be ignored and a long term goal of developing strategies and alternatives should be established to reduce the adverse effects of xenoestrogens.
Endocrine-Disrupting Chemicals - Xenoestrogens
In recent years, the increased amount of anthropogenic chemicals from industrial and agricultural activities that result in chemical pollution in the surrounding environments has been receiving concern from many health institutions and international organizations such as the World Health Organization (WHO). Much scientific evidence have been gathered for the potential health effects posed by these chemicals on human and many species of living organisms including fishes, reptiles and invertebrates. These anthropogenic chemicals are believed to adversely disrupt the normal endocrine system functions that regulate bodily metabolisms, growth and development, reproduction and internal homeostasis in living organisms.
As such, these chemicals are scientifically termed "endocrine disrupting chemicals" (EDCs), or commonly called environmental estrogens. EDCs can be classified into two groups: xenoestrogens and phytoestrogens. Phytoestrogens are normally known to be naturally-occurring estrogenic compounds that are derived from plants and food; while xenoestrogens are particularly attention-getting as they are foreign substances that severely affect the normal estrogenic functions of steroid hormones and many alarming news have been reported about their harmful influences.
Xenoestrogens are known to be the anthropogenic compounds which possess estrogen-mimicking properties and are able to simulate or inhibit the activities of endogenous estrogens (Aravindakshan et al., 2004). The xenoestrogens can be either naturally occurring compounds or synthetically derived from various sectors of activities such as manufacturing, agricultural, industrial and residential. Agricultural applications of pesticides, insecticides and herbicides, industrial chemical discharges, sewage effluents from sewage treatment plants, leaching and disposal of household cleaning products and even biogenic hormones that are being released in the form of human waste can be sources of xenoestrogens. Most commonly, xenoestrogens impose greater impacts on the aquatic ecosystems such as rivers and streams. According to Jobling et al. (2003), studies on the disruptive effects of EDCs on wildlife were centered on species inhabited in, or closely related with, the aquatic environment. This is not surprising as many rivers and oceans all over the world have been treated as a repository sites for municipal wastes and discharging sites for large volumes of industrial effluent. This was supported as well by the study of Johnson et al. (2008) which stated that xenoestrogens distribution are often present at estuarine areas where most agricultural and industrial sites as well as sewage treatment are associated. In addition to vertebrates such as fishes, invertebrate populations are also victims of EDCs. They produce vertebrate-like sex steroid hormones and perhaps are sensitive to vertebrate sex steroids and their mimics. An example studied was the molluscs (Jobling et al., 2003).
Xenoestrogens act as EDCs by mediating their effects to interact with normal physiological systems and cause deleterious effects on normal growth and development. Reproductive physiology is particular affected especially on reproduction, whereby altered sexual phenotype and differentiation are observed (Brian et al., 2005; Kuhl et al., 2005). In fact, these chemicals have been implicated in many incidences of reproductive disorders observed in a number of the freshwater fishes. Besides aquatic animals, mammals are also not spared. For instance, Diamanti-Kandarakis et al. (2009) reviewed the possible risks posed by EDCs on reproduction health from a clinical perspective in human and animal models. In some cases, sexual dimorphism could be observed in adult human males and females, while in other studies various reproductive disorders were found, such as intrauterine growth retardation and hypospadias.
Comparison of Xenoestrogens with Endogenous Estrogens
Endogenous estrogens are generally steroid hormones which are produced mainly in the ovaries, and to a lesser extent in the brain, testis, adipose tissue and adrenal glands (Alonso-Magdalena et al., 2011). They are formed from the aromatization of androgen, a male sex hormone, by aromatase enzyme which is coded by cyp19 gene, a member of the cytochrome P450 superfamily,. This enzyme is expressed in the brain, liver and gonads (Kuhl et al., 2005). Indeed, aromatization of androgen is an important source of estrogen production that plays an important role particularly in reproduction and development among vertebrates. 17Î²-estradiol (E2) is generally the most potent estrogen among several estrogens that are synthesized throughout life and this hormone is common in many species of vertebrates and some invertebrates in which it plays a role in regulating reproductive activities and it also involves in neuro-endocrine feedback control in the hypothalamic-pituitary-gonadal axis (Alonso-Magdalena et al., 2011; Sayed et al., 2012).
According to Segner et al. (2003), endogenous estrogens as steroids can act through a common mechanism because they exhibit phylogenetic conservatism, whereby they can bind to either or both cytoplasmic and nuclear estrogen receptors to form ligand-receptor complexes that subsequently stimulate and activate transcription of steroid-responsive genes. Endogenous estrogens are commonly found in vertebrates as these are the chemical mediators in regulation of reproductive and somatic cell functions, governing development of female secondary sexual characteristics, activating sexual maturation cycle and sexual differentiation, controlling mating and breeding behaviors, regulating calcium and water homeostasis, as well as exerting significant actions in many systems such as bone, brain, cardiovascular, liver, pancreas and skeletal muscle (Alonso-Magdalena et al., 2011; Jobling et al, 2003; Segner et al., 2003). Jobling and coworkers (2003) also pointed out that estrogens have been reported to be involved in sexual maturation and egg production in most invertebrates such as snails, in contrary to vertebrates in which estrogens have direct effect on the folliculogenesis, leading to both proliferative and differentiation of effects on the follicular somatic cells.
A big difference of xenoestrogens as compared to endogenous estrogens is that they are biologically functioning like estrogens but are not physiologically normal hormone. As their name implies, "xeno-" means foreign. These, these foreign chemicals have been believed to cause threats on hormone-sensitive organs such as breast, brain, testis and ovary (Fernandez and Russo, 2010). In fact, these chemicals, called endocrine disrupting chemicals, act similarly (as agonist) or antagonistically to endogenous endocrine factors (Kuhl et al., 2005). They may mimic the actions of endogenous estrogens, such as estradiol (E2) via competitive interaction with estrogen receptors, as evidenced in the study of Alo' et al. (2005), Alo' et al. (2005) reported which stated that xenoestrogens could interfere with neuroendocrine-related brain mechanism and exert their estrogenic actions at the brain level via G-protein-coupled neuronal systems which contain estrogen receptor sites. In a similar review by Alonso-Magdalena et al. (2011) which showed that some endocrine disrupting chemicals can interrupt the classical estrogen-triggered pathways using estrogen receptors as transcription factors binding to estrogen responsive elements in the DNA, whereas some endocrine disrupting chemicals disrupt non-classical estrogen activated pathways through binding to cytoplasmic estrogen receptors.
Either individually or exist in a mixture of compounds, xenoestrogens are acting via the same mode of action, albeit with different physio-biochemical properties and chemical potencies to exert their effect. Furthermore, some of these compounds are persistent and can bio-accumulate in water body or living organisms, posing more adverse effect by acting additively to disrupt the endocrine systems when they exist together (Johnson et al., 2008). Xenoestrogens are synthetic steroids used in many industries which include plasticizers and phthalates, for instance bisphenol-A and di-(2-ethylhexyl) phthalate (DEHP), pesticides, for example dichlorodiphenyltrichloroethane (DDT) and alkylphenol polyethoxylates (APEs), as well as ingredients in many pharmaceutical products. In fact, many of these compounds are differ in structures but they all have in common the hydrophilic phenol rings and other hydrophobic components (Figure 1). This is the structural similarity in which they share this feature with steroid hormones and related nuclear receptor-activating compounds in the body of many living organisms (Watson et al., 2006).
Types of Xenoestrogens
According to Kuhl et al. (2005), DDT is a well-known synthetic pesticide which has been banned in the United States since 1972 due to its deleterious effects on the aquatic organisms. The estrogen agonist constituting between 10 and 25% of manufactured DDT is the o,p-DDT (Figure 1D). This chemical is a very hydrophobic compound which readily dissolves in non-polar solvents. Consequently, it has the ability of bioaccumulation and biomagnification in lipid matter, causing increasing concentrations in both higher-level organisms and aquatic environments. In addition, o,p-DDT targets reproductive system of certain fish species, whereby it causes feminization of males. This is possible due to the fact that this chemical can dissolve into yolk in the eggs, in which it can be transferred maternally from an exposed mother to the embryo. Direct exposure of o,p-DDT from the contaminated aquatic environment can also result in feminization (Kuhl et al., 2005).