Developmental Exposure to Diethylstilbestrol DES

There is an extensive literature concerning the long-term effects of exposure to high doses of potent manmade estrogens, such as DES, during fetal/neonatal life in human [219, 222] and animal [130,223, 224] studies, some of which is discussed above in Sect. 4. While the focus of most studies of DES has been the re-

Table 7. Abnormalities in males subsequent to prenatal exposure to diethylstilbestrola

Abnormality

Organ

Outcome in humans (References)

Outcome in rodents (References)

Cancer

Testis

Positive [63,250] or inconclusive [64, 65, 251]

Adenocarcinoma of the rete testes, interstitial cell carcinoma [266,267]

Prostate

No data available

Squamous cell cancer of dorsolateral prostate [268]

Other

Penis

Reduced size; hypospadias

Hypospadias [130,270]

genital tract

[252, 255,258,269]

changes

Testis

Cryptorchidism, hypertrophy, capsular induration, epididymal cysts [68, 69, 255,258,269]

Cryptorchidism [128,270,271], epididymal cysts [128, 130]

Prostate

Hyperplasia and metaplasia of prostatic ducts [229,230]

Abnormal development, squamous metaplasia of prostatic and coagulating gland ductal epithelium [128,167,213,231,232,268]

Adverse

Impaired semen quality

Impaired semen quality and sperm

reproductive

and sperm concentration;

concentration; impaired fertility

outcomes

impaired fertility inconsistent [254-258,269]

[130,270]

a Adapted from Newbold [130].

a Adapted from Newbold [130].

productive organs, effects on other tissues, such as bone, have been noted [225]. The overwhelming proportion of this research, at least in humans, has been conducted in the female offspring, with ongoing follow-up of thousands of DES daughters. Follow-up on the DES sons, on the other hand, has been limited to cohorts of only a few hundred exposed males. Therefore, while the consequences of prenatal DES exposure to females are now well established, the effects on human males are less certain. As seen in Table 7, the reproductive consequences of prenatal DES exposure are highly similar in mouse and man, and when the appropriate exposure window is considered, the effective doses are of the same order of magnitude. The high doses of DES used in animal studies have been selected to be similar to the doses that were administered to pregnant women during the 1950s and 1960s, and thus have clinical relevance. DES has a higher potency than estradiol during development [226, 227], due to limited binding by DES to plasma estrogen binding glycoproteins (sex hormone binding globulin in humans and alphafetoprotein in rodents) [147,228].

Typically, estrogenic EDCs have a lower intrinsic estrogenic activity than DES [147,171,183,196]. Since the very high doses of DES that have been used in prior animal studies were chosen for their clinical relevance, findings from these studies may not predict effects seen with environmentally relevant doses of estrogenic EDCs. However, the DES studies do provide valuable information linking effects in controlled animal studies with clinical outcomes of DES exposure in humans. Thus, information concerning exposure in early life to DES provides a link between animal and human responses to a man-made estrogen and identifies the types of clinical outcomes that should be examined when assessing effects from an EDC exposure.

Treatment of pregnant females with high doses of DES interferes with the action of Mullerian inhibiting hormone on Mullerian duct regression in male mice [128] and humans [229]. The utricular remnant within the prostate, which is of Mullerian origin, is enlarged and there is marked hyperplasia and metaplasia of prostatic ducts in the central zone of the adult prostate [229,230]. As mentioned above, exposure of the neonatal mouse to high doses of DES has been shown to interfere with normal development of the prostate [213, 231, 232]. Squamous metaplasia of prostatic and coagulating gland (dorsocranial prostate) ductal epithelium in male mice and rats has also been reported after exposure to exogenous estrogen or estrogenic chemicals during early life [128]. This endpoint is also characteristic of the effect of estrogen on rat prostatic cells in culture [200]. Exposure of rats and mice to high doses of DES during development also alters testis development, leading to a decrease in testis size, sperm numbers, undescended testes, and epididymal cysts and infertility [130].

In some studies, the effects of exposure to DES during development were not noticeable prior to the animals reaching old age. For example, treatment of male rats with DES during the first month after birth did not result in observable malignancies at 6-9 months of age, but by 20 months (old age), squamous cell cancer was detected with involvement of the dorsolateral prostate, coagulating glands (dorsocranial prostate) and ejaculatory ducts [233]. There are not yet reports of prostate abnormalities in men exposed to DES during fetal life. However, DES was used in pregnancy during 1947-1971, with peak use in the 1950s and 1960s, so most DES sons are 40-50. Since few of these men have reached the age at which benign prostatic hyperplasia (BPH) or prostate cancer increases in frequency, prostate abnormalities in DES sons have not yet been studied and it is important that this cohort be monitored for these endpoints.

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