Research suggests that like other vertebrates, humans are also susceptible to endocrine disruption by exogenous chemicals. This is highlighted by the case of DES, which failed to fulfil its purpose of preventing miscarriage and was found to cause reproductive disorders and cancers in children born to DES mothers. Indeed, clear cell adenocarcinoma, abnormalities of the cervix, uterus and fallopian tubes, as well as increased likelihood of miscarriage, ectopic pregnancies and premature birth were observed in daughters (Hotchkiss et al., 2008). Effects were also reported in sons, including hypospadias (the abnormal placement of the male urethral orifice) and cryptorchidism (undescended testes), as well as reductions in sperm count, the number of motile sperm and sperm with normal morphology, although fertility appeared
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unaffected (Toppari et al., 1996). The link to these disorders is supported by studies in rodents, where similar effects were observed, such as cancers, reduced fertility and reproductive tract malformations (Newbold, 2001). These studies also demonstrated transgenerational inheritance of cancers through epigenetic changes in the maternal germ line, which has caused concern for the health of DES granddaughters (Newbold
et al., 2006). In addition to DES, some environmental chemicals have also been
associated with endocrine disorders following occupational exposures or poisoning events. For example, cryptorchidism in male newborns has been associated with occupational pesticide exposure of mothers involved in agriculture and gardening in Norway and Denmark (Weidner et al., 1998; Kristensen et al., 1997). Hypospadias and other congenital anomalies have been associated with proximity to hazardous waste sites in Europe (Dolk et al., 1998), whilst in Minamata, Japan, methylmercury poisoning of residents consuming contaminated fish resulted in severe neurological problems (Ekino et al., 2007).
Like wildlife populations, humans globally are constantly exposed to pollutants in food, soil, water, air and dust, which can enter the body by inhalation, ingestion and dermal contact (WHO/UNEP, 2013). In 1951, the detection of DDT in human fat and milk was first reported in non-occupationally exposed mothers (Laug et al., 1951). Since then it has become increasingly appreciated that the general human population has a body burden of a wide range of contaminants, which has led to an increase in biomonitoring. Of particular concern is the presence of these contaminants in pregnant women, since chemicals are capable of crossing the placenta into the foetus and have been detected in amniotic fluid, umbilical cord blood and meconium (Woodruff et al., 2011; Barr et al., 2007). Indeed, the ubiquitous exposure to some environmental chemicals was demonstrated in the US Health and Nutritional Examination Survey conducted from 2003-4. Here, certain PCBs, organochlorine pesticides, perfluorinated compounds, phenols, PBDEs, phthalates, polyaromatic hydrocarbons (PAHs), and perchlorate were detected in 99–100% of the 268 pregnant women studied (Woodruff et al., 2011). Some of the chemical classes detected in a subsample of this study are shown below in Figure 1.4.
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Figure 1.4 The number of chemicals detected by chemical class in a subsample of 54
pregnant US women from the Health and Nutritional Examination Survey conducted from 2003-04 (from Woodruff et al., 2011). Each vertical bar represents one study participant.
Although much of the evidence for endocrine disruption in humans comes from accidental or occupational exposures to adverse chemicals, such as DES, there is evidence for increasing trends in hormone related disorders in the general human population. Indeed, EDCs may be contributing to the increasing trends in reproductive disorders, hormone related cancers, neurobehavioral disorders and even obesity, which have been observed in a number of countries in the last century (WHO/UNEP, 2013). In males, increasing trends in the incidence of testicular germ cell cancers, cryptorchidism and hypospadias, as well as reductions in semen quality have been observed in a number of countries and are well characterised in Europe (Jørgensen et
al., 2006; Richiardi et al., 2004; Sharpe and Irvine, 2004; Toppari et al., 2001). Since
these disorders have been associated as risk factors of one another, they have been hypothetically linked as symptoms of a single, underlying condition termed testicular dysgenesis syndrome (Skakkebæk et al., 2001). In humans, the symptoms may vary dependant on the severity of the condition and although genetic factors can be involved, a majority of newborns with malformations of the genitalia were found to have no known genetic defects. This, combined with the speed of increased incidence of these symptoms, suggests that lifestyle and environmental factors, such as EDCs, are
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likely to be involved (Skakkebæk et al., 2001). In fact, testicular dysgenesis syndrome is thought to have a foetal origin, resulting from disruption to prenatal testicular development during the androgen programing window. This is the point during foetal development in which androgens induce masculinisation of the reproductive tract and when disruption of androgen control can lead to abnormal development (Welsh et al., 2008). Indeed, in mammalian studies, disruption of androgen production and/or androgen action at the receptor by EDCs has been shown to induce these disorders in the male offspring of exposed pregnant females (Wilson et al., 2008; Earl Gray Jr. et
al., 2006). For example, di (n-butyl) phthalate caused a dose dependent induction of
cryptorchidism, hypospadias and impaired spermatogenesis (Sharpe and Skakkebaek, 2008). In humans, prenatal exposure to phthalates, BPA and p,p’-DDE were also associated with lower ano-genital distance (Miao et al., 2011; Torres-Sanchez et al., 2008; Swan et al., 2005). This measurement is normally higher in males than females and so a decrease indicates demasculinisation. As a result, whilst it was originally considered that these effects could be a result of exposure to environmental oestrogens, it now seems more likely they are caused by disruption of the oestrogen- androgen balance. Critically, the increase in focus on the role of androgens also implicates environmental anti-androgenic chemicals, which are capable of disrupting endogenous androgens (Sharpe, 2003). From this perspective, a cumulative risk assessment of 15 AR antagonists, including pesticides, phthalates and parabens was conducted to determine their possible impact on human reproductive health. Based on the median intake of these chemicals in the general human population and the concentrations required to cause adverse effects in rodent models, this study found that adverse effects were unlikely to occur in the general human population. In comparison, for individuals at the high end of the exposure range the cumulative risk from the combination of these chemicals was determined to exceed an acceptable level (Kortenkamp and Faust, 2010). However, when a mixture of 22 AR antagonists were combined at levels observed in human plasma, they failed to produce an anti- androgenic effect in vitro. This indicates an explanation gap between the cause and effects of testicular dysgenesis syndrome, which suggests that other as yet unknown chemicals would need to be contributing to the observed effects (Kortenkamp et al., 2014).
Adverse female reproductive health trends include increases in the incidence of endometriosis, the preterm birth rate, uterine fibroids and difficulty in achieving or maintaining pregnancy, as well as the earlier onset of puberty (WHO/UNEP, 2013). As with male reproductive health issues, it is thought that EDCs could play a role in
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inducing these effects through disruption of the hormonal control of development and function of the female reproductive system. Indeed, the human body burden of some pesticides has been associated with shorter menstrual cycle, earlier age of menarche and later menopause (Farr et al., 2006; Ouyang et al., 2005; Farr et al., 2004). Exposure to p,p’-DDE in early life is also considered to be a risk factor for breast cancer in later life (Cohn et al., 2007). In addition, thyroid disruption and effects on neurodevelopment in males and females have also been observed in animal models following exposure to chemicals such as brominated flame retardants, PBDEs, BPA and PCBs (Boas et al., 2012; Zoeller, 2010; Legler, 2008). There is concern that these could be linked to increasing incidence of attention deficit/hyperactivity disorder (ADHD). Indeed, in the US there is evidence that children with higher serum concentrations of polyfluoroalkyl chemicals, such as PFOS and PFOA, have greater odds of having ADHD (Hoffman et al., 2010). There is also evidence of a link between organochlorines and behavioural deficits in children following prenatal exposure (González-Alzaga et al., 2013).