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PubMed1997

Modulation of the testicular steroidogenic pathway by cyclosporin A in adult rats pretreated with diethylstilbestrol.

Treatment of male Fischer-344 rats with diethylstilbestrol (DES) induces hyperprolactinemia and alterations in testicular steroidogenesis. Cyclosporin A (CsA), an immunosuppressive drug, is believed to act by opposing the effects of prolactin (PRL) and was reported to influence testicular function. We have examined the effect of CsA on gonadal function in rats pre-treated with DES. Male rats were implanted with DES-containing silastic capsules. After 19 weeks, the capsules were removed, and, starting 2.5 weeks later, rats were treated for 1 week with CsA. At sacrifice, plasma and testes were collected. Testis fragments were incubated with or without 12.5 mlU of human chorionic gonadotropin (hCG)/ml at 32 degrees C for 4 hr. As expected, plasma PRL levels were increased in DES exposed rats, while testicular, seminal vesicle, and prostate weights were reduced. Cyclosporin A treatment did not further modify these parameters. Treatment with CsA and/or DES decreased circulating levels of testosterone, while testosterone content in the testes was not modified. Although CsA did not affect in vitro release of testosterone, it reduced the stimulatory influence of DES pretreatment on testicular responses to hCG in vitro. Plasma and testicular content of progesterone (P) was increased by DES administration but was not affected by CsA. Both CsA and DES administration decreased plasma 17-OH-Progesterone (17-OH-P) levels, but only CsA decreased testicular 17-OH-P contents. Combined exposure to CsA and DES enhanced the stimulatory effect of hCG on the accumulation of 17-OH-P in the media. Media estradiol levels were not affected by treatment with either CsA or DES. The present results indicate that CsA may interfere with the enhancement of the conversion of P to testosterone in DES-treated rats. As CsA did not change plasma PRL or gonadotropin levels, a direct effect of the drug on the testicular function is suspected.

17-alpha-Hydroxyprogesterone↗

PubMed1982

A comparison of diethylstilbestrol- and estradiol-17 beta-induced vitellogenesis in quail.

Japanese quail were injected intramuscularly with .125 to 32 mumole/100 g body weight of estradiol-17 beta (E2) or diethylstilbestrol (DES). During the following 8 days, vitellogenesis was assessed in these birds by measuring plasma concentrations of protein-bound phosphorus (PBP; vitellogenin is a phosphoprotein), calcium, and total protein. Blood packed cell volumes were recorded also. Plasma PBP concentrations of E2-injected male and female quail increased to .83 and .96 mg/ml from control values of .004 and .12 mg/ml, respectively. Doses of 8 to 32 (males) or 4 to 32 (females) mumole E2/100 g body weight induced similar initial rates of vitellogenesis, but the duration of vitellogenesis increased with increasing doses of hormone. In male quail, low doses of DES (.5 to 4.0 mumole/100 g body weight) were more effective than equal doses of E2 in inducing increases in plasma PBP levels. However, the maximum PBP concentrations attained with high doses of DES were less than those attained with equal doses of E2 (.53 and .83 mg/ml, respectively).

Animals↗

PubMed1989

[Liver disorder owing to estrogen therapy in prostatic cancer. The correlation between serum level of cholinesterase and dose of diethylstilbestrol diphosphate].

We have examined the value of cholinesterase (ChE) that indicates the preservation ability of liver function, to assess the liver disorder owing to diethylstilbestrol diphosphate (DES-DP) administration in 25 prostatic cancer patients without castration. The correlation between ChE and the other factors such as age, total dose of DES-DP, duration of administration or ratio (total dose/duration), were studied by means of multiple regression analysis (MRA). In sixteen patients treated for less than 6 months, ChE was correlated with all factors by MRA with the coefficient of 0.645, and the coefficients of simple correlation between ChE and total dose and between ChE and administered duration, were -0.521 (p less than 0.05) and -0.596 (p less than 0.05), respectively. In nine patients treated for more than 6 months, ChE was correlated with all factors by MRA with the coefficient of 0.803, and the coefficient of simple correlation between ChE and ratio was -0.707 (p less than 0.05). According to these results and the permissible range of ChE, the total dose of administration for less than 6 months was estimated to be under 50 gram and its duration was within 100 days. The ratio in patients administered for more than 6 months was under 300 mg/day. Therefore, as far as the long-term hormonal treatment for prostatic cancer and preservation of liver function, we concluded that total dose of DES-DP should be less than 50 gram in less than 100 days for induction therapy and the daily dose of DES-DP should be less than 300 mg/day for maintenance therapy.

Age Factors↗

PubMed2003

[Decrease in anticoagulant factors in patients with prostate cancer treated with diethylstilbestrol diphosphate].

PURPOSE: Estrogen has been highly evaluated as one of the most potent endocrine agents for the treatment of prostate cancer. Unfortunately, a high risk of cardiovascular complications is a clinically important adverse effect of estrogen therapy, and occasionally the complications are fatal. In recent years a high incidence (55%) of thrombotic events has been reported in patients with congenital protein S (PS) deficiency. The aim of this study is to determine the relationship between cardiovascular complications of estrogen therapy and anticoagulant factor levels in the serum of patients with prostate cancer. MATERIALS AND METHODS: Study 1 employed 99 patients with prostate cancer: 39 were untreated, 25 were treated with LH-RH agonist therapy alone, and 35 were treated with oral diethylstilbestrol diphosphate (DESdP) 300 mg per day. We measured the serum levels of anticoagulant factors, parameters antithrombin III (ATIII), protein C (PC), PS, coagulant and fibrinolytic factors in all patients. In study 2, the adverse effects of DESdP therapy on the serum levels of anticoagulant factors were examined in 8 patients with advanced prostate cancer. RESULTS: In study 1, the ATIII and PS levels of the patients treated with estrogen therapy were significantly lower than those in either the untreated patients or the patients treated with an LHRH agonist alone. Especially, both PS antigen (51.5 +/- 16.0%) and PS activity (42.9 +/- 16.0%) were markedly lower in estrogen-treated patients than in the untreated patients (102 +/- 20.8%, 100.6 +/- 20.7%, respectively) or the patients treated with an LH-RH agonist alone (97.9 +/- 16.8%, 91.5 +/- 17.7%, respectively, both p < 0.0001). PS was decreased to below the normal lower limit of normal in 82% (24/35) of the patients on estrogen therapy. In study 2, all 8 cases showed a significant decrease in PS after DESdP therapy. CONCLUSIONS: Our results showed that the PS levels in the oral DESdP group were almost the same as in patients with congenital PS deficiency. We conclude that decreased PS may play a role in the development of cardiovascular complications in prostate cancer patients on estrogen therapy.

Aged↗

PubMed1995

Diethylstilbestrol revisited: a review of the long-term health effects.

PURPOSE: To review the literature on the long-term health effects of exposure to diethylstilbestrol (DES) among women prescribed DES during pregnancy (DES mothers), among their children exposed inutero to the drug (DES sons and daughters) and among the progeny of these exposed sons and daughters (DES grandchildren). DATA SOURCES: English-language articles were identified through MEDLINE and CANCERLIT searches and through review of the bibliographies of identified articles. STUDY SELECTION: All human studies relevant to long-term health effects of exposure to DES were reviewed. DATA EXTRACTION: Descriptive data on existing DES cohorts were extracted from early publications. Risk estimates for health effects were extracted from published reports. DATA SYNTHESIS: An estimated 5 to 10 million Americans received DES during pregnancy or were exposed to the drug in utero. Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, < 2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10,000. The association between DES exposure and testicular cancer in DES sons remains controversial. Exposure to DES has also been linked to reproductive tract abnormalities in DES sons and daughters that consist of immune system disorders and psychosexual effects. No evidence for transgenerational effects currently exists. Recommendations for screening persons exposed to DES are reviewed. CONCLUSIONS: Further research is needed to define long-term health effects related to DES exposure. Such research would provide a basis for counseling persons exposed to DES and would further understanding of environmental and pharmacologic compounds similar to DES.

Animals↗

PubMed1976

Diethylstilbestrol in the treatment of rape victims.

Despite growing controversy surrounding its use as a "morning after pill," diethylstilbestrol (DES) is prescribed liberally for rape victims. Guidelines for its use in these patients is lacking. Of 150 consecutive rape victims treated at a university medical center, 63 (42 percent) received prescriptions for DES. Of the 55 (87 percent) on whom follow-up was obtained, in 40 (73 percent) there were substantial side effects-nausea or vomiting, or both. At least six (11 percent) did not complete therapy because of these side effects. The authors offer guidelines for use of DES for rape victims and a plan for patient education and follow-up.

Diethylstilbestrol↗

PubMedDate not supplied

The metabolism of diethylstilbestrol in the rhesus monkey and chimpanzee.

Radiolabeled diethylstilbestrol (DES) was administered to one pregnant and three normal female rhesus monkeys. One normal female chimpanzee was also included in the study. Regardless of the mode of presentation (oral versus intravenous), the urine was the principal route of excretion for each species. The urine contained no non-polar radioactivity, and Sephadex LH-20 (MeOH/EtOH-50:50) resolved the radioactivity into five fractions (A, B, C, D, E). Fractions A,B, C, and D were hydrolyzable with beta-glucuronidase, and the principal aglycones were identified with GC/MS as cis-trans DES and dienestrol. The fecal excretory products were extracted with dimethoxy methane/methanol (50:50) and the radioactivity partitioned between benzene and H2O. The polar radioactivity was resolved by LH-20 (MeOH/EtOH-50:50) into chromatographic fractions similar to the urinary conjugates. These fecal conjugates were, however, less sensitive to beta-glucuronidase hydrolysis. The primary non-polar fecal radioactivity was chromatographically similar to DES (LH-20 and HPLC) in both species, and in the rhesus monkey the principal products identified were cis-trans DES and dienestrol.

Animals↗

PubMed2000

Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol.

Prenatal exposure to diethylstilbestrol (DES) is associated with reproductive tract abnormalities, subfertility and neoplasia in experimental animals and humans. Studies using experimental animals suggest that the carcinogenic effects of DES may be transmitted to succeeding generations. To further evaluate this possibility and to determine if there is a sensitive window of exposure, outbred CD-1 mice were treated with DES during three developmental stages: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 microg/kg maternal body weight) during major organogenesis; group II was treated once on day 18 of gestation (1000 microg/kg maternal body weight) just prior to birth; and group III was treated on days 1-5 of neonatal life (0.002 microg/pup/day). DES-exposed female mice (F(1)) were raised to maturity and bred to control males to generate DES-lineage (F(2)) descendants. The F(2) males obtained from these matings are the subjects of this report; results in F(2) females have been reported previously [Newbold et al. (1998) CARCINOGENESIS:, 19, 1655-1663]. Reproductive performance of F(2) males when bred to control females was not different from control males. However, in DES F(2) males killed at 17-24 months, an increased incidence of proliferative lesions of the rete testis and tumors of the reproductive tract was observed. Since these increases were seen in all DES treatment groups, all exposure periods were considered susceptible to perturbation by DES. These data suggest that, while fertility of the DES F(2) mice appeared unaltered, increased susceptibility for tumors is transmitted from the DES 'grandmothers' to subsequent generations.

Animals↗

PubMed2000

Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol.

Women who inherit mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are predisposed to the development of breast and ovarian cancer. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/cB1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129B2+/- mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES). Beginning at 3 weeks of age, BALB/cB1+/-, 129B2+/-, and wild-type female mice were fed a control diet or a diet containing 640 ppb DES for 26 weeks. DES treatment caused vaginal epithelial hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and fibrosis, as well as oviductal smooth muscle hypertrophy. The severity of the DES response was mouse strain specific. The estrogen-responsive 129/SvEv strain exhibited an extreme response in the reproductive tract, whereas the effect in BALB/cJ and C3H/HeN(MMTV-) mice was less severe. The Brca1 and Brca2 genetic alterations influenced the phenotypic response of BALB/cJ and 129/SvEv inbred strains, respectively, to DES in the mammary gland and ovary. The mammary duct branching morphology was inhibited in DES-treated BALB/cB1+/- mice compared with similarly treated BALB/cB1+/+ littermates. In addition, the majority of BALB/cB1+/- mice had atrophied ovaries, whereas wild-type littermates were largely diagnosed with arrested follicular development. The mammary ductal architecture in untreated 129B2+/- mice revealed a subtle inhibited branching phenotype that was enhanced with DES treatment. However, no significant differences were observed in ovarian pathology between 129B2+/+ and 129B2+/- mice. These data suggest that estrogenic compounds may modulate mammary gland or ovarian morphology in BALB/cB1+/- and 129B2+/- mice. These observations are consistent with the hypothesis that compromised DNA repair processes in cells harboring Brca1 or Brca2 mutations lead to inhibited growth and differentiation compared with the proliferative response of wild-type cells to DES treatment.

Animals↗

PubMed1999

Acute effects of estradiol and of diethylstilbestrol: pro- or antioxidant potential?

This study was aimed to examine the effects of a single high dose of natural and synthetic estrogens on the antioxidant defense enzymes in liver and blood. Female Wistar albino rats, four to six months old, were divided into three groups, and received either i.p. injections of diethylstilbestrol (DES ; 150 mg kg(-1) b.w.) or s.c. injections of estradiol (E2; 25 mg kg(-1) b.w.), and the third group (control) was injected the solvent. Animals were killed under light ether anesthesia three hours after injection. Cu-Zn superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (Cat) enzyme activities and fluorometric malondialdehyde (MDA) determination were performed in liver tissue homogenates and in blood. Acute estradiol injection caused a significant increase in both MDA levels and GPx activity in liver tissue when compared to the controls, (p <0.05 and p <0.02; respectively). Changes in both enzyme activities and MDA concentration were unremarkable following acute DES injection. In blood, only Cu-Zn SOD activity was significantly altered in blood following E2 injection. Although the significance of alteration in GPx activity remains unclear, it is most likely related to enhanced generation of lipoperoxides. A significant increase in MDA concentrations in liver tissue is indicative of pro-oxidative damage rather than an antioxidant action by E2.

Animals↗

PubMed2000

Inhibition of disease flare with diethylstilbestrol diphosphate and chlormadinone acetate administration for two weeks prior to slow-releasing leuprolide acetate in prostatic cancer patients.

To determine whether administration of estrogen or gestagen prior to luteinizing hormone-releasing hormone (LH-RH) agonist prevents disease flare in prostate cancer patients, we pretreated the patients with either diethylstilbestrol diphosphate (DES-P) 300 mg daily (N = 17) or chlormadinone acetate (CMA) 100 mg daily (N = 16) or none (N = 16) for two weeks before the initial injection of leuprolide acetate (L). Blood samples for prostatic specific antigen (PSA), testosterone (T), and luteinizing hormone were collected before CMA and DES-P administration, before and at 2, 7, 14, 28, 56, and 84 days after the first administration of leuprolide. The treatment with DES-P and CMA prior to LH-RH agonist induced an early decline of PSA. The mean PSA level showed no significant secondary rise in those patients with pretreatment after L administration. In the patients pretreated with DES-P or CMA, the mean serum T level never exceeded the pretreatment baseline after L administration. On the other hand, in the patients without DES-P or CMA, both serum T and PSA levels increased after the first administration of L. These results clearly demonstrate that pretreatment with DES-P 300 mg daily or CMA 100 mg daily for 2 weeks is quite effective to prevent disease flare after the first administration of L in patients with prostatic cancer.

Aged↗

PubMed2000

[Synthetic estrogen as a endocrine disruptor--diethylstilbestrol and oral contraceptives].

Recently, considerable attention has been focused on certain environmental contaminants, endocrine disruptors, of industrial origin that may mimic the action of estrogen. Oral contraceptives containing ethynylestradiol, a synthetic estrogen, have been suspected to have adverse environmental effects since prenatal exposure to diethylstilbestrol, another synthetic estrogen, was reported to be associated with clear cell adenocarcinoma of the vagina in female offspring. In terms of magnitude and extent, such exposures to synthetic estrogens are now considered virtually insignificant compared with the secretion and excretion of natural estrogens from humans. However, as is the case with all other chemicals, continuous and rational risk assessment and risk management of these synthetic estrogens must be made.

Adenocarcinoma, Clear Cell↗

PubMedDate not supplied

Suppression of androgen action and the induction of gross abnormalities of the reproductive tract in male rats treated neonatally with diethylstilbestrol.

This study evaluated whether androgen action is altered in rats treated neonatally with diethylstilbestrol (DES) at a dose that induced reproductive tract abnormalities. Rats were treated on alternate days 2-12 with 10 microg DES and studied on Day 18. DES-induced abnormalities included a 70% reduction in testis weight, distension and overgrowth of the rete, distension and reduction in epithelial height of the efferent ducts, underdevelopment of the epididymal duct epithelium, reduction in epithelial height in the vas deferens, and convolution of the extra-epididymal vas. In DES-treated rats, androgen receptor (AR) immunoexpression was virtually absent from all affected tissues and the testis, whereas AR expression in controls was intense in epithelial and stromal cells. The DES-induced change in AR immunoexpression was confirmed by Western analysis for the testis. In rats treated neonatally with 1 microg DES, reproductive abnormalities were absent or minor, except for a 38% reduction in testis weight; loss of AR immunoexpression also did not occur in these rats. Treatment-induced changes in AR expression were paralleled by changes in Leydig cell volume per testis (91% reduction in the 10-microg DES group; no change in the 1-microg DES group). To test whether suppression of androgen production or action alone could induce comparable reproductive abnormalities to 10 microg DES, rats were treated neonatally with either a potent gonadotropin-releasing hormone antagonist (GnRHa) or with flutamide (50 mg/kg/day). These treatments reduced testis weight (68% for GnRHa, 40% for flutamide), and generally retarded development of the reproductive tract but failed to induce the abnormalities induced by 10 microg DES. GnRHa and flutamide caused no detectable change in AR immunoexpression in target tissues, with the exception of minor changes in the testes of flutamide-treated males. GnRHa treatment caused a reduction (83%) in Leydig cell volume comparable to that caused by 10 microg DES. Immunoexpression of estrogen receptor alpha (ER alpha) in the efferent ducts and of ER beta in all tissues studied were unaffected by any of the above treatments. Neonatal coadministration of testosterone esters (TE; 200 microg) with 10 microg DES prevented most of the morphological abnormalities induced by 10 microg DES treatment alone, though testis weight was still subnormal (46% reduction in DES + TE vs 72% in DES alone and 49% with TE alone) and some lumenal distension was still evident in the efferent ducts. Coadministration of TE with DES prevented DES-induced loss of AR immunoexpression (confirmed for testis by Western blot analysis). It is concluded that 1) reproductive tract abnormalities induced in the neonatal male rat by a high (10 microg) dose of DES are associated with reduced AR expression and Leydig cell volume; 2) these changes are largely absent with a lower dose of DES (1 microg); 3) treatments that interfere with androgen production (GnRHa) or action (flutamide) alone failed to induce reproductive tract abnormalities or alter AR expression as did 10 microg DES; 4) a grossly altered androgen:estrogen balance (low androgen + high estrogen) may underlie the reproductive tract abnormalities, other than reduced testis weight, induced by high doses of DES.

Androgen Antagonists↗

PubMedDate not supplied

PROGINS polymorphism of progesterone receptor is increased in female offspring with maternal exposure to diethylstilbestrol.

DES (Diethylstilbestrol) was used for the treatment of corpus luteum insufficiences in early pregnancy. Prenatal exposure to DES leads to an increased frequency of vaginal cancer in female offspring. DES causes persistent alterations of steroid hormone binding in the vaginal tissue. The frequency of a polymorphism (PROGINS) of human progesterone receptor (hPR) gene which is associated with an increased risk of sporadic ovarian cancer was tested in DES-exposed offspring with vaginal dysplasia. Genomic DNA was isolated from the serum of 15 US Caucasian DES-offspring. PROGINS analysis was performed using sequencing, gel-electrophoresis and SSCP-PCR. The results demonstrated that the frequency of PROGINS is increased in DES-offspring (DES: 6.7% homozygous, 26.7% heterozygous, normal US Caucasians: 3.3% homozygous, 15% heterozygous). Mutation screening of PROGINS is an important advantage for the clinical management of screening and can give additional information to prevent or find vaginal cancer in early stages in DES-offspring.

Carcinogens↗

PubMedDate not supplied

Neonatally administered diethylstilbestrol retards the development of the blood-testis barrier in the rat.

Newborn rats were treated with 10 microg of diethylstilbestrol (DES) on alternate days from the 2nd to the 12th postnatal day, and the testes were sequentially examined up to 105 days of age by light, electron, and confocal laser microscopy. In control rats, spermatozoa and step 19 spermatids were observed in stage VIII seminiferous tubules at 56 days of age. Spermatogenic cells in DES-treated rats differentiated normally from birth until 21 days of age, after which differentiation continued only to the pachytene-spermatocyte stage. From this age onward, spermatogenic cells older than pachytene spermatocytes were not found until 56 days of age. After this point, the cells resumed differentiation and finally became spermatozoa by 91 days of age; that is, 35 days later than control rats. Electron and confocal laser microscopy showed that in the normal rat, the formation of the ectoplasmic specialization between adjoining Sertoli cells was observed as early as 20 days of age. In contrast, the specialization was not formed until 56 days of age in DES-treated rats. Furthermore, the delay in functional maturation of this structure as the blood-testis barrier was confirmed by intercellular tracer experiments. It is clear that neonatal administration of DES delayed the establishment of the blood-testis barrier for 4 weeks. Consequently, during this period, pachytene spermatocytes were exfoliated from the seminiferous epithelium without completion of meiosis.

Aging↗

PubMed1975

The confirmation of diethylstilbestrol residues in beff liver by gas chromatography-mass spectrometry.

A confirmatory test for the presence of the growth-promoting hormone, diethylstilbestrol (DES), in beef liver is described, Samples are subjected to a published electron capture gas chromatographic method that involves the formation and measurement of the bis-dichloroacetyl derivative of DES. The presence of the derivative is then confirmed by gas chromatography-mass spectrometry, using a repetitive scanning technique to maximize response. The isotope pattern of the tetrachlorinated molecular ion greatly facilitates the confirmation.

Adipose Tissue↗

PubMed2001

[Consequences of diethylstilbestrol during pregnancy; 50 years later still a significant problem].

Since the 1940s, diethylstilbestrol (DES) has been administered to about three million pregnant women in the United States and in the Netherlands, between 1947 and 1975, to about 220,000. The most important consequences described are: for DES mothers an increased risk of mammary carcinomas and for DES daughters a 1 in 1000 chance of clear cell adenocarcinoma (CCAC) as well as an increased risk of (pre)malignant abnormalities of the stratified epithelium in the vagina and cervix. In addition to this, DES daughters frequently have developmental disorders of the cervix and corpus uteri. In connection with this fertilisation disorders have been described as well as unfavourable outcomes of pregnancy: more ectopic pregnancies, abortion and premature birth. DES sons exhibit an increased frequency of several benign abnormalities of the genitalia. The DES problem continues to be an important issue. The entire cohort of DES mothers is in the age group with a high risk of mammary carcinoma. The youngest DES daughters will be of childbearing age for at least another 15 years; the risk of ectopic pregnancies and pre-term labour is increased. The oldest DES daughters are now reaching postmenopausal age. The incidence of CCAC of the vagina and cervix in the population is bimodal, with a second peak at older age. It is still unknown if at this age DES daughters will have an increased incidence of these malignancies. From animal experiments it becomes clear that DES administration to pregnant mice results in an increased incidence of genital tumours not only in the second generation but also in the third. This has yet to be investigated in humans and deserves special attention. The legally imposed destruction of patient files after a period of ten years is a serious threat to patient care and scientific investigation, notably in obstetrics and child medicine.

Adenocarcinoma, Clear Cell↗

PubMed1979

Effects of transplacental exposure to diethylstilbestrol on carcinogenic susceptibility during postnatal life in hamster progeny.

Prenatal exposure to a single dose of diethylstilbestrol (DES) produced a significant increase in carcinogenic response of hamster progeny that were subsequently subjected to the carcinogenic stimulus of 7,12-dimethylbenz(a)anthracene (DMBA) during postnatal life. The compounds were administered according to the following schedules. The pregnant animals (second group) received a single dose of DES, 10 mg/kg, on Day 14 of gestation. Postnatally, at 6 weeks of age, the progeny were given DMBA, 25 mg/kg p.o., twice weekly for 8 weeks. The first group received DMBA at 6 weeks of age, 30 mg/kg p.o., twice weekly for 18 weeks. The progeny exposed to DES prenatally and DMBA postnatally (DES-DMBA-exposed progeny) developed a greater multiplicity of tumors per tumor-bearing animal (p less than 0.001) and higher rates of neoplasms of the reproductive tract, e.g., ovarian and uterine tumors, mammary gland and forestomach tumors, and dermal melanomas. The prenatally DES-exposed progeny also had significantly higher incidences of malignant tumors, e.g., carcinomas of the mammary gland (p less than 0.001) and carcinomas of the forestomach (p less than 0.001), than did the hamsters given DMBA alone during postnatal life. Endocrine imbalance produced by exposure in utero may heighten the sensitivity of the progeny to development of neoplasms after a challenge with carcinogenic stimuli in adult life. The significance of these experimental data to the human situation is discussed.

9,10-Dimethyl-1,2-benzanthracene↗