Endocrine Disruptors
Abstract:
It can be hypothesized that the ingestion of endocrine disruptor (ED) metabolites (from the water supply and food chain) can result in detrimental outcomes for males and females, such as prostate and breast cancer, infertility and C-sections; either through mechanisms of hormonal imbalance or dysfunctional metabolism. Physiological and biological mechanisms of action thought to be involved include creation of a state of estrogen dominance, and that EDs can alter the morphology and function of sperm and the estrogen receptor. Although further evidence is needed to establish causation between an increased use of the BCP, a high level of metabolites in the water supply, and an increasing number of reproductive diseases, the alarming patterns between these variables warrant additional study.
CONCERNS ABOUT ENDOCRINE DISRUPTORS IN THE WATER SUPPLY AND BIOACCUMULATION
Endocrine disruptors, although detrimental on their own, are not the only concern; there is a) a lack of consistent measurement standards of ED metabolites in the water supply, b) variability in the efficiency of methods that extract EDs and c) a lack of published evidence to link bioaccumulation of reproductive specific metabolites to human disease. Primarily, there is little formal regulation involving monitoring of pharmaceutical metabolites in regional water supplies. Additionally, several countries do not have legislation in place for continuous follow up of these specific chemicals. This variability is also present in treatment facilities. Processes in treatment plants have demonstrated varying removal rates for pharmaceuticals, ranging from less than 20% to greater than 90% (WHO 2011). A report by the International Joint Commission in Windsor showed that pharmaceutical metabolites can exert detrimental effects, such as alterations in the reproductive system of aquatic organisms and humans. Bioaccumulation of EDs has been demonstrated in various environmental compartments, however, their pathological endpoints have not been fully investigated, nor their causative chemical metabolites fully regulated in the United States and Canada (Kemp 2011).
An endocrine disruptor is defined as any natural or synthetic metabolite or compound that alters hormones, enzymes or receptors within the body. Endocrine disruptors can be classified into several categories, two of which will be addressed in this review: a) chemical toxins, and b) pharmaceutical metabolites.
Endocrine Disruptors: Chemical Metabolites
There are several types of toxin related endocrine disruptors, such as polychlorinated biphenyls (PCB), polyvinyl chlorides (PVC), pthalates and parabens that have been correlated with hormonal dysfunction. Bisphenol A (BPA), furans, polybrominated diphenyl ethers (PDBE) and dioxins are well known carcinogens (Kaur 2005). Organochlorines resist biochemical breakdown, have a long half life and also accumulate as EDs in the environment (Fisher 1999).
Food sample analysis in Spain, the USA, and Japan have collectively shown ED levels from 340-3000 parts per trillion (ppt) and have confirmed that all foods containing animal fats had PBDE by-products (Schuhmacher 2007, Seely 2007). It has been estimated that the daily human intake of PBDEs is approximately 0.51 nanograms (Ramos 2006). Further evidence of bioaccumulation was shown in patient fat biopsies that were chemically analyzed following exposure to polychlorinated dioxins, furans and PCBs. Levels of hepta- and octachlorinated furans and dioxins of up to 8400 parts per trillion (ppt) were found in one repeatedly exposed person in comparison to the fat from control group members (from patients with no overtly known exposure to furans or dioxins) that were several 100 ppt (Schecter 1985).
Endocrine Disruptors: Pharmaceutical Metabolites
In addition to toxins, pharmaceutical metabolites accumulate in the water supply and contribute towards physiological dysfunction. These include but are not limited to ethinyl estradiol (EE2), levonorgestrel (LNG) and norethindrone (NET). EE2 is one of the main metabolites of oral contraception, and is also administered as patches, injections and rings. EE2 is more chemically active than other estrogenic metabolites. It is not the largest contributor to estrogen in the water supply, however it has joined other synthetic estrogens, such as those from dairy cows, fertilizers and industrial chemicals (Moore 2011).
There are numerous studies that identify how contraceptives are: a) found in the water supply, and b) pose health hazards to wildlife and other species in the food chain. The Songhua River and Harbin drinking water study charted the removal rates of estrogenic activity, which was 34.6% to 50.5% in Harbin, and revealed that estrogenic pollutants in source water were not efficiently removed in treatment plants (Shao 2009). The Endocrine Society released a statement that low level, chronic exposure to environmental endocrine disruptors has caused or contributed to adverse human health effects (Diamanti-Kandarakis 2009). A collective of in vitro, animal and a few human studies has provided compelling evidence that exposures to either birth control pill (BCP) or estrogen metabolites through the water supply had biological consequences. This has been corroborated by the discovery of inter sex fish near sewage plants in various parts of the world, such as the U.S.A, Europe and Japan (Iwanowicz 2009, Jobling 2004). Another interesting animal study showed that chronic exposure to levonorgestrel (LNG) caused oxidative stress to Dreissena polymorpha (Contardo- Jara 2011). A human study showed that an insecticide altered sperm function by altered membrane depolarization and membrane dipole potential; this lowered water molecular dynamics in the superior part of the external membrane (Silvestroni 1997). It should be noted, however, that unlike other chemical toxic metabolites, comprehensive evidence of quantified bioaccumulation of BCP metabolites in humans is lacking to date.
TRENDS IN ENDOCRINE DISRUPTOR LEVELS AND GENITOURINARY DISEASE Increased Use of the Birth Control Pill
There has been a rise in the utilization of contraception, more specifically an overall trending to an increased use of the birth control pill (BCP) through recent decades (Moore 2011). The BCP was released into the Canadian market 50 years ago. The Canadian Contraception Study determined that 84 % of Canadian women use or have used the BCP (Fisher 2002, O’Malley 2001). Eighty three percent of the “effluent” sewage samples had EE2 from the BCP (0.07 to 2.6 ng/L); and induced estrogenic responses in fish (Tyler 2009).
There is an average daily dose range of 30 to 35 μg to 1 mg of EE2/ pill. Human urine is the major source of natural and synthetic estrogens in the water supply (Wise 2010). Of the 38.2 million women in the USA using contraception in 2006–2008, the pill accounts for about 28% of contraceptive users, and the percent of women aged 15-44 currently using the pill is 17% (Martinez 2012).
The Use of the Birth Control Pill and Reproductive Cancers
There is direct evidence for an increased risk of breast and cervical cancers with the use of BCPs (Burkman 2004). Several studies including but not limited to a 2003 analysis by the International Agency for Research on Cancer (IARC) and a systematic review by Lancet found an increased risk of cervical cancer with longer use of BCPs (Moreno 2002, Smith 2003). The results from a breast cancer study showed that the highest risk was found in women aged 20-34, who used BCPs within 5 years prior to diagnosis of disease (Althuis 2003). Evidence for indirect risk (through ingestion of BCP related EDs through the water supply) of reproductive female cancers is lacking, although intriguing patterns have been published for male cancers.
Male reproductive diagnoses, such as prostate cancer have recently been etiologically investigated. It was theorized that BCPs were excreted in the urine and travelled into the water supply; concurrently, scientific findings have suggested that low levels may cause cancer, including prostate cancer (Ubelacker 2011). They further postulated that in countries where BCP use was higher, prostate cancer had a greater incidence. A more recent study showed that BCP use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.53), respectively; p<0.05 for all) and with BCP use in Europe (r=0.545, p<0.05), whereas other contraceptives did not correlate with prostate cancer incidence nor mortality (Margel 2011). Although these findings do not necessarily infer causation, these aligning trends should not be ignored, and further studies are warranted.
The Impact of Endocrine Disruptors on Infertility and Caesarean Sections
Recent human studies have elucidated that decreasing fertility could be due to environmental toxic metabolites; biochemically (hormones) or molecularly (cell interactions). One study in males from an infertility clinic demonstrated that an elevation in urinary BPA concentration was associated with decreases in sperm concentration, motility, and morphology of 23% (95%CI -40%, -0.3%), 7.5% (-17%, +1.5%), and 13% (-26%, -0.1%), respectively; this was also associated with a 10% (0.03%, 19%) increase in sperm DNA damage (Meeker 2010). A study of female exposure to the chemical pentachlorophenol, utilized as a lumber preservative, showed altered hypothalamic activity, and was thought to cause low level impaired ovarian function and hormonal insufficiency (Gerhard 1999).
There has also been a notable increase in Caesarean sections (C-section) in recent decades. The Canadian Institute for Health Information stated that the C-section rate has risen; up to 26% of babies born in hospitals in 2005, compared to 23% five years earlier and 17% in 1993 (Hall 2009). Some of the causes can be attributed to technological intervention, position of labour and birth complications; however, chemical causes through bioaccumulation may have been overlooked. Estrogen induces labour by increasing the expression of pro-contraction genes in cells of the myometrium around the time of delivery. The induction of contraction-related gene expression is modulated by signalling outside the nucleus (ERK/MAP) through the estrogen receptor (ER)α (Welsh 2011). Therefore, it can be postulated that dysfunctional estrogen metabolism, signalling and concentration that are caused by synthetic estrogens from ED could result in changes in labour patterns. Several mechanisms can be hypothesized: a) synthetic estrogens may not stimulate the ER with affinity that is sufficient to upregulate signalling, b) high levels of EDs in humans over time may downregulate the estrogen receptor by number or potency, and c) reactive oxygen species from ED accumulation may result in altered gene expression/protein production. Although published evidence between ED bioaccumulation in humans and rates of C-sections is lacking, the putative link and associated mechanisms of action deserve consideration.
RELEVANT BIOCHEMICAL AND MOLECULAR MECHANISMS OF ACTION
Hormone Metabolism
The release of EDs into the water supply is thought to create a state of estrogen dominance (associated with cancer, fibroids and endometriosis). Estrogen (comprised of 17 carbons), is hydroxylated at either C2, C4 or C16 positions; C4 and C16 are thought to be activated by EDs and are associated with breast cancer (Kabat 1997). Hormonal dysfunction is also seen in male reproductive hormones; studies have confirmed inverse associations between ED concentrations and testosterone levels (Meeker 2010).
Infertility
The mechanisms of action by which ED may cause male infertility consist of altered sperm count, altered quality of semen, dysfunctional cell signalling and DNA damage. A reduction in the sperm count and quality can be attributed to PI3K/c-Src/FAK and MAPK signalling on a molecular level, and anatomically, a destruction of cellular junctions by reactive oxygen species (Wong 2011). Regarding mechanisms of female infertility, the binding of EDs to the ER and activation of secondary messenger kinases, as well as calcium influx are at play (Robins 2011). During pregnancy, ED’s may alter meiotic spindle formation (Fujimoto 2011).
CONCLUSION
Although there is an overall lack of causal evidence linking estrogenic metabolites from birth control pills to reproductive diagnoses, there are critical trends and disease patterns identified: increased use of the birth control pill in recent decades, a rise in male and female reproductive cancers, infertility and caesarean sections. More importantly, it may be too early to witness the full effects of increased EDs in the water supply at this point in time, as a critical threshold concentration for detrimental effects may not have been reached for some diseases. Bioaccumulation may dredge up these detrimental effects over time. This principle is evident from the rise in the incidence of various cancers across the globe today that are thought to originate from exposures to toxins in previous decades. Research must include a focus on the past and the future, rather than waiting for the tipping point at present; observation should include searching the past for patterns and trends that may allude to disease incidence, and looking to the future to anticipate prophylactic strategies of modulating chemical toxins and pharmaceutical metabolites in the environment.
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