The link between environmental chemicals and male infertility has been widely appreciated since 1962 with the publication of Rachel Carson s book, Silent Spring
, which highlighted the effects of dichlorodiphenyltrichloroethanes (DDTs) on infertility in birds and other wildlife. While human studies examining altered male reproduction in relation to environmental chemicals were initially limited, evidence has emerged over the years that suggests a link between hormonally active toxicants and developmental reproductive abnormalities [29
]. Studies have raised the possibility that EDCs may be contributing to a decline in the human sperm count that has been observed over the last 50–60 years [30
]. A review of 61 international studies involving 14,947 men between 1938 and 1992 showed that the average sperm count had dropped from 113 million/ml in 1940 to 66 million/ml in 1990, in addition to alterations in sperm morphology and motility [33
]. Many epidemiological studies suggest a link between non-persistent (or contemporary-use ) pesticide exposure and altered semen quality [34
] suggesting that EDCs may be the proximate cause. Two recent studies based on occupational reports involving simultaneous exposure to several pesticides found associations between pesticide exposures representative of that seen in the general population and reduced semen quality [35
In addition to altered semen quality, other male reproductive tract anomalies potentially attributable to EDCs have emerged with increased frequency over the past few decades that together have been described as testicular dysgenesis syndrome [37
]. These disorders in the human population, which include increased incidences in cryptorchidism, hypospadias, oligospermia, and testicular germ cell cancer, have been linked in some studies to prenatal endocrine-disruptor exposure [37
]. It is interesting to note that the so-called testicular dysgenesis syndrome has geographical specificity which emphasizes the likelihood that environmental factors contribute to these reproductive tract abnormalities [44
]. Although not all cases of these disorders are a result of EDC exposures and have separate etiologies, a unifying hypothesis that links these disorders provides an intriguing and compelling argument that requires further investigation. Other male reproductive abnormalities that have been associated with EDCs that have AR disruptor activity in both human epidemiology studies as well as in animal models included delayed puberty [45
] and reduced anogenital distance in newborn boys [46
Another area of male reproductive health potentially linked to EDC exposures is cancers of the reproductive tract, specifically testicular and prostate cancers. Testicular cancer rates have increased worldwide over the past 35 years with the greatest increase observed in certain European populations. Although direct evidence for increased testicular cancer due to EDC exposures is very limited, there are several reports [47
] that suggest a link. In utero
diethylstilbestrol exposure has been associated with an increased risk of testicular cancers [49
] while maternal levels of chlorinated chemicals suggests a link for these compounds with mixed estrogenic and antiandrogenic activity to testicular cancer rates in sons [50
]. Further, a rabbit model for testicular cancer identified exposure to di-n
-butylphthalates with antiandrogenic action to testicular carcinoma in situ
]. There is compelling data for increased prostate cancer risk and exposure of farmers to pesticides, some which are inhibitors of p450 enzymes involved in steroid metabolism [42
]. Epidemiologic studies of occupational exposure to PCBs revealed a strong exposure-response relationship for prostate cancer risk [Ritchie, 2003 #3204; Charles, 2003 #3205] and prostate cancer mortality [54
]. While estrogenic activity of these compounds is a suspected mode of action, there is also evidence that some PCBs may behave as antiandrogens.
While there are many sites of action for chemicals to interfere with androgen signaling, available evidence primarily classifies these compounds into two broad categories; (i) interference with androgen biosynthesis or metabolism to indirectly modulate androgen function (nonreceptor-mediated disruptors) and (ii) interaction with the androgen receptor to interfere with the ligand-dependent transcriptional function (receptor-mediated disruptors). Furthermore, it has been shown that some pesticides can act by reducing androgen receptor expression [4
]. For the purposes of this review, we here look at the exposure to endocrine-disrupting pollutants with identified antiandrogenic toxicity, mostly through binding of the androgen receptor to alter proper folding of its ligand-binding domain (LBD), blocking recruitment of co-activators and preventing transcriptional initiation. Androgen-disruptors acting via this mechanism include vinclozolin, DDT, procymidone, linuron, lindane, dieldrin/aldrin, methoxychlor, nonylphenol, and bisphenol-A [7
]; ). These chemicals will be discussed individually in the following section based upon their chemical classifications.
Endocrine-disrupting pollutants with antiandrogenic toxicity through binding of the AR.