The Endocrine System
The endocrine system is a sophisticated network of neural, glandular and organ tissues, which are responsible for maintaining homeostasis and the regulation of many vital bodily functions, including: energy metabolism, tissue growth and repair, cognitive development, osmoregulation, immunology and reproduction. Communication between the different parts of the body is accomplished with the release of various chemical messengers and their subsequent binding to specific receptors. Increasing incidences of autoimmune disorders, obesity, and infertility around the world has brought with it an increased concern regarding the impact endocrine disrupting chemicals (EDCs) have on the human body. According to the U.S. Environmental Protection Agency, EDCs are defined as: exogenous agent(s) that interfere(s) in synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental processes. This article will consist of an in-depth discussion about the numerous deleterious effects EDCs may have not only on those individuals who are directly exposed, but also any potential future offspring that one may have.
Endocrine Disrupting Chemicals
Endocrine disruption can occur due to both natural and man-made compounds. Flavonoids, coumestands, lignans, and stilbenes are the four main groups of naturally occurring plant compounds known as phytoestrogens. Phytoestrogens are found to be structurally similar to naturally occurring estradiol; in one study blood concentrations of genistein and daidzein were found to be 1000 times higher in infants exposed to diets high in beans and legumes, compared to endogenous estrogens. The main source for phytoestrogen exposure in humans is through the consumption of various fruits, vegetables, and legumes. The majority of compounds listed in the Endocrine Disruptor Knowledge Base consist of man-made chemicals such as pesticides, PCBs, dioxins, plasticizers, flame-retardants and others. Although many have been banned from use since the late 1970s, though their residues and metabolites are still widespread in the environment and can still be found in humans. A large number of known EDCs are still used today, some of which individual production exceeds six billion pounds per year.
Exposure to EDCs
Humans are exposed to a numerous EDCs each day through food, water, inhalation, skin absorption, and even in utero through the placenta. Much of the research regarding endocrine disrupting chemicals and their affects on human health is based on animal studies. The increased incidence of immune system, developmental, and reproductive disorders in humans within the past 50 years may be seen as circumstantial evidence, though it is intriguing. The degree to which the prevalence of such disorders has increased is said to be too fast to be explained by genetic mutations alone. In the past few decades, there has been a dramatic increase in number of individuals diagnosed with allergies, eczema, and other autoimmune diseases. Increased rates of reproductive system development and fertility issues have also been observed worldwide. For example, researchers found a doubling in rates of cryptorchidism in England between 1962 and 1981. In a more recent study, undescended testes further increased in prevalence by 65% in the past 20 years. A doubling in frequency of hypospadias in males over the past 40 years, and a worldwide change in semen quality for the worse has also been observed. While causation is still up for debate in humans, similar outcomes in animals can be seen in the laboratory as a direct result of exposure to various endocrine disrupting chemicals.
EDC Storage in White Adipose Tissue
Some EDCs are hydrophilic and are rapidly absorbed, metabolized, and excreted through the urine. Others are lipophilic, which are stored in white adipose tissue (WAT) and deemed persistent organic pollutants; these are resistant to biological degradation and can build up in the body. Until recently, WAT was thought of as a passive organ and its function was simply to store accumulated energy. It has become increasingly apparent that WAT is actually a major endocrine organ; it is regulated by sympathetic innervation and responds to various hormones, including insulin, thyroid and steroid hormones, as well as catecholamines. In addition, WAT secretes numerous cytokines, which have effects on inflammation, blood pressure, body weight, as well as insulin sensitivity and resistance. There is evidence of biomagnification of EDCs, which is a term used to describe the process of increasing concentrations of chemicals in WAT, the higher the organism is on the food chain.
Mechanism of Action
Endocrine disrupting chemicals utilize one or many different mechanisms in order to produce their observed effects, some of which include: binding to receptors and mimicking or antagonizing the effects of natural endocrine hormones, changing the number of hormone receptors within the cell, modifying the production or degradation of natural hormones, or by interfering with the chemical signals in which the various components of the endocrine system communicate. To add to the complexity, many EDCs alternate their mechanisms of interaction along with the effects they produce depending on the circumstance. For example, an EDC may be agonistic in one area of the body while being antagonistic of that same receptor in another, or may have completely different effects based on the age or stage of development of an individual when exposed.
Effects on Fertility and Reproductive Development
Concern has grown over the effect to which endocrine disrupting chemicals may have on fertility and various stages of reproductive development in humans. Fetuses are thought to be especially susceptible to the harmful effects EDCs because of their small size, fast rate of growth and their inability to sufficiently detoxify harmful substances on their own. Fat mobilization during pregnancy is frequent, which results in fetal exposure to high levels of EDCs. This has been associated with a decrease in gestational age, lower birth weight, and delayed psychomotor and cognitive functions. Plastic derived compounds, which include bisphenol-A (BPA) and a variety phthalates, are of particular concern due to their widespread use and frequency of exposure. These chemicals can be found in water bottles, dental fillings, eyeglass lenses, household electronics, medical equipment, latex adhesives and cosmetics, and begin to leach out of such products with repeated use.
Bisphenol-A is one of the better-studied compounds regarding its numerous deleterious effects on humans. Over 5 million tons of BPA were produced in 2010, and it has been estimated that over 1 million pounds are released into the environment each year. BPA can be found in the follicular and amniotic fluid, as well as the foetal and umbilical cord serum in over 90% of U.S. and Canadian citizens. It can be absorbed orally, dermally, or through inhalation, though researchers estimate that 90-99% of exposure in children and adults is through ingestion. BPA has been shown to have estrogenic properties and competes with endogenous estradiol by binding to estrogen receptors. Estrogen plays an important role in many bodily functions, has strong influences on the sexually dimorphic sexual development of the fetus, and mediates baseline physiology for many organ systems in children and adults.
The mechanisms by which BPA interacts with the endocrine system are complex and many. BPA not only binds to estrogen receptors, but binds to the glucuronide receptor, suppresses thyroid hormone receptor transcription, increases the rate of fatty acid oxidation and prolactin release, decreases the rate at which cholesterol transports through the mitochondrial membrane, and impairs aromatase expression. Direct exposure to BPA is associated with the promotion of obesity and metabolic diseases, and is correlated with increased rates of cancer and diabetes. Direct effects of BPA exposure may be an altered date of pubertal onset, the disruption of estrous cycles, prostate neoplasia, and abnormal mammary gland development. In males, exposure to BPA has adverse effects on testicular function; a reduction in the secretion of luteinizing hormone from the pituitary and Leydig cell steroidogenesis has been demonstrated. It has been suggested that this may lead to incomplete masculinization with resulting malformations in the reproductive tract of males. In addition, it has been suggested that BPA exposure is associated with female infertility and implantation failure. Studies suggest that BPA is toxic to the ovaries, and may reduce the quality and number of female gametocytes.
The health effects of EDCs, including BPA, are often delayed and may take long time spans before becoming apparent, as they act selectively depending on the stage of development and may only manifest in later generations. When a pregnant female is exposed during the period of gonad sex determination, not only does she experience the effects, but the fetus and any fetal germ cells in the process of development are also exposed. Studies suggest that the female offspring of BPA-exposed mothers are at risk for meiotic chromosome nondisjunction. This and other errors may continue to be passed down through generations because of seemingly permanent methylation properties of imprinted DNA. BPA is just one of the many plastic derived compounds that may directly affect the individual exposed as well as any subsequent future offspring.
Phthalates (PAEs) are also widely used and are found in PVC plastics, pacifiers, perfumes, teething rings, soft squeeze toys, shampoo, nail polish, aftershave, artificial leather, cellulose film, food containers and more. They can also be found in tablecloths, shower curtains, vinyl upholstery and various construction materials. PAEs make up from 10-60% of plastic but are not chemically bonded to resin, resulting in the subsequent release of phthalates into the environment. Studies have found detectible levels of PAEs in samples of water, soil and dust, as well as in human food and mother’s breast milk. Phthalates are believed to be of low acute toxicity and are generally metabolized and released by the body within 48 hours of exposure. The main concern is that with PAEs is that humans are chronically exposed and therefore concentrations of such chemicals remain detectable in the blood despite the short half-life of 6-12 hours.
Exposure to phthalates is believed to result in the accumulation of lipids in fat cells, and may lead to toxicities in the developmental and reproductive organs in humans. DBP is a phthalate that is added to plastics to increase flexibility. Pregnant females exposed to high levels of DBP causes a reduced rate of fetal survival, a reduction in birth weight for those offspring that do survive, skeletal malformations, and reproductive abnormalities in both sexes. Similar to in cases of BPA exposure, phthalates may also induce epigenetic transgenerational inheritance of disease; this can be seen in cases of exposure during critical stages of fetal development, usually within weeks 7 to 12. Ancestral phthalate exposure may increase the chances for adult onset-obesity, further leading to higher rates of polycystic ovarian disease, amenorrhea and infertility. In animal studies, exposure to DBP resulted in the proliferation of fetal Leydig cells; surprisingly this was accompanied with a reduction of testicular levels of testosterone, rather than the expected increase. Researchers Svechnikov et al. (2010) hypothesized that this increase was a compensatory change in response to a reduced ability for the Leydig cells to produce sufficient levels of testosterone.
Not only can phthalate exposure have detrimental effects on fertility and hormonal homeostasis, but it can also affect the immune system. Studies have found PAEs to have stimulatory effects on the immune system by increasing immunoglobulin production and influencing cytokine secretion from T helper cells, enhancing enzyme and histamine release, and through increasing the phagocytic abilities of monocytes and macrophages. Monocytes reside in the bone marrow and are released into the blood stream, and along with macrophages are responsible for a variety of functions including tissue repair and modulating inflammation. Immune cells release cytokines and chemokines, such as tumour necrosis factor and interleukin-1, which are proinflammatory; elevated levels of these cytokines have been found in many autoimmune disorders. Additionally, a positive association between allergy, eczema, asthma and other autoimmune diseases has been found with PAE exposure.
In addition to the plastic derived chemicals discussed above are a variety of other types of EDCs, all with distinct mechanisms of action – some of which are anti-androgens. DDT deriviatives, procymidone, linuron and vinclozolin are pesticides that are antagonists of the androgen receptor. A positive correlation has been demonstrated in men between DDT exposure and insulin sensitivity, as well as serum testosterone levels. In animal studies, exposure during pregnancy is found to result in a variety of reproductive abnormalities and is suggested to play a role in the high rate of cryptorchidism found in the Florida panther. Procymidone may induce hypergoandotropism; large amounts can be found in tomatoes, grapes, wine, and unhusked rice. Furthermore, both linuron and vinclozolin exposure result in a variety of reproductive delays and hormonal alterations in animal studies.
EDCs: A Danger to Our Health
Bisphenol-A, phthalates and the pesticides discussed above are only a few of the potentially 58,000 potentially endocrine disrupting chemicals listed in the EDKB that humans are frequently exposed to. The rising incidence of developmental, reproductive, and autoimmune disorders seen in humans within the last few decades, paired with growing evidence in animal and human research supporting claims that EDC exposure may directly and indirectly lead to such disorders, highlights the importance of continued research. Not only does more research need to be completed regarding how individual EDCs interact with the human body and the effects they produce, but also to determine whether or not concomitant exposure to multiple EDCs produces compound effects, which the scientific community is currently unaware of. The chronic low-dose exposure to a variety of endocrine disrupting chemicals, and the delay in observable deleterious effects, make this a difficult but necessary task.
- Adeniyi, A., Dayomi, M., Siebe, P. & Okedeyi, O. (2008). An assessment of the levels of phthalate esters and metals in the Muledane open dump, Thohoyandou, Limpopo Province, South Africa. Chemistry Central Journal, 2(9). doi: https://doi.org/10.1186/1752-153X-2-9
- Band, P., Le, N., Fang, R. & Deschamps, M. (2002). Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer. The Lancet, 360(9339), 1044-1049.
- Bornehag, C. & Nanberg, E. (2010). Phthalate exposure and asthma in children. International Journal of Andrology, 33(2), 333-345. doi: https://doi.org/10.1111/j.1365-2605.2009.01023.x
- Cappiello, A., Famiglini, G., Palma, P., Termopoli, V., Lavezzi, A. & Matturri, L. (2014). Determination of selected endocrine disrupting compounds in human fetal and newborn tissues by GC-MS. Analytical and Bioanalytical Chemistry, 406, 2779-2788. doi: https://doi.org/10.1007/s00216-014-7692-0
- Danzo, B. (1998). The effects of environmental hormones on reproduction. CMLS Cellular and Molecular Life Sciences, 54, 1249-1264.
- Dickerson, E., Sathyapalan, T., Knight, R., Maguiness, S., Killick, S., Robinson, J. & Atkin, S. (2011). Endocrine disruptor & nutritional effects of heavy metals in ovarian hyperstimulation. Journal of Assisted Reproduction and Genetics, 28, 1223-1228. doi: https://doi.org/10.1007/s10815-011-9652-3
- Ding, D., Xu, L., Fang, H., Hong, H., Perkins, R., Harris, S., Bearden, E., Shi, L. & Tong, W. (2010). The EDKB: an established knowledge base for endocrine disrupting chemicals. BMC Bioinformatics, 11(6): S5. doi: http://www.biomedcentral.com/1471-2105/11/S6/S5
- Eichenlaub-Ritter, U. & Pacchierotti, F. (2015). Bisphenol A Effects on Mammalian Oogenesis and Epigenetic Integrity of Oocytes: A Case Study Exploring Risks of Endocrine Disrupting Chemicals. BioMed Research International, 2015: 698795. doi: http://dx.doi.org/10.1155/2015/698795
- Facemire, C., Gross, T. & Guillette Jr., L. (1995). Reproductive impairment in the Florida panther: nature or nurture?. Environmental Health Perspectives, 103(4), 79-86.
- Hansen, J., Bendtzen, K., Boas, M., Frederiksen, H., Nielsen, C., Rasmussen, A. & Rasmussen, U. (2015a). Influence of Phthalates on Cytokine Production in Monocytes and Macrophages: A Systematic Review of Experimental Trials. PLoS ONE, 10(3):e0120083. doi: https://doi.org/10.1371/journal.pone.0120083
- Hansen, J., Nielsen, C., Brorson, M., Frederiksen, H., Hartoft-Nielsen, M., Rasmussen, A., Bendtzen & Feldt-Rasmussen, U. (2015b). Influence of Phthalates on in vitro Innate and Adaptive Immune Responses. PLoS One, 10(6): e0131168. doi: https://doi.org/10.1371/journal.pone.0131168
- Howdeshell, K., Hotchkiss, A., Thayer, K., Vandenbergh, J. & vom Saal, F. (1999). Exposure to bisphenol A advances puberty. Nature, 401, 763-764.
- Manikkam, M., Tracey, R., Guerrero-Bosagna, C. & Skinner, M. (2013). Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations. PLoS ONE, 8(1):e55387.
- Mullerova, D. & Kopecky, J. (2007). White Adipose Tissue: Storage and Effector Site for Environmental Pollutants. Physiological Research, 56(4), 375-380.
- Olujimi, O., Fatoki, O., Odendaal, J. & Okonkwo, J. (2010). Endocrine disrupting chemicals (phenol and phthalates) in the South African environment: a need for more monitoring. Water SA, 36(5), 671-682.
- Rauch, S., Braun, J., Boyd, B., Calafat, A., Khoury, J., Montesano, M., Yolton, K., & Lanphear, B. (2012). Associations of Prenatal Exposure to Organophosphate Pesticide Metabolites with Gestational Age and Birth Weight. Environmental Health Perspective, 120(7), 1055-1060.
- Reinli, K. & Block, G. (1996). Phytoestrogen content of foods – a compendium of literature values. Nutrition and Cancer, 26(2), 123-148.
- Setchell, K., Zimmer-Nechemias, L., Cai, J. & Heubi, J. (1997). Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet, 350(9070), 23-27.
- Stefanidou, M., Maravelias, C. & Spiliopoulou, C. (2009). Human Exposure to Endocrine Disruptors and Breast Milk. Current Drug Targets, 9, 269-276.
- Svechnikov, K., Izzo, G., Landreh, L., Weisser, J. & Soder, O. (2010). Endocrine Disruptors and Leydig Cell Function. Journal of Biomedicine and Biotechnology, 2010, 1-10. doi: http://dx.doi.org/10.1155/2010/684504
- Yan, S., Chen, Y., Dong, M., Song, W., Belcher, S. & Wang, H. (2011). Bisphenol A and 17b-Estradiol Promote Arrhythmia in the Female Heart via Alteration of Calcium Handling. PLoS ONE, 6(9): e25455.
- Yuan, M., Bai, M., Huang, X., Zhang, Y., Liu, J., Hu, M., Zheng, W. & Jin, F. (2015). Preimplantation Exposure to Bisphenol A and Triclosan May Lead to Implantation Failure in Humans. BioMed Research International, 2015: 184845. doi: http://dx.doi.org/10.1155/2015/184845