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Neonatal Estrogen Treatment and Epithelial Abnormalities Inthe [CANCER RESEARCH 41, 721-734, February 1981] 0008-5472/81 /0041-OOOOS02.00 Neonatal Estrogen Treatment and Epithelial Abnormalities in the Cervicovaginal Epithelium of Adult Mice1 John-Gunnar Forsberg2 and Terje Kalland Department of Anatomy, University of Lund, Biskopsgatan 7, S-223 62 Lund, Sweden [J-G. F.], and Institute of Anatomy, University of Bergen, Bergen, Norway IT. K.] ABSTRACT occasionally in the uppermost part of the vagina, there were regions with HCE3 which formed glandular-like downgrowths Female NMRI mice were given injections of different doses into the stroma, resulting in adenosis (13, 19). of 17/8-estradiol, 17a-estradiol, diethylstilbestrol (DES), dienes- Later, it was demonstrated that a synthetic estrogen such as trol, frans-stilbene, progesterone, testosterone, 5a-dihydrotes- DES, injected according to the same schedule as that for tosterone, or olive oil for the first 5 days after birth. When the estradiol, resulted in the same type of changes (15); moreover, females were killed at 8 weeks after birth, all the estrogens, in old females, changes highly suggestive of malignancy de effective at different dose levels (1CT2 to 5 fig/day), had veloped within the regions of adenosis (17, 20). resulted in the display by several of the cervicovaginal prepa While HCE and adenosis were originally described in NMRI rations studied of a heterotopic columnar epithelium (HCE) in mice, the results have later been verified in other strains (51) regions where females given injections of olive oil, testoster regarding localization in the vaginal fornix and the uppermost one, 5a-dihydrotestosterone, progesterone, or frans-stilbene part of the vagina. For the uterine cervix, there is still a had only the normal squamous epithelium. The further fate of discrepancy in results from different strains. the HCE was followed at two later age stages, 36 to 52 weeks After the observation of an association between DES inges and 14 to 17 months. The HCE developed into glandular-like tion during human pregnancy and development of clear cell structures penetrating into the stroma and justifying the des adenocarcinoma in the uterine cervix and vagina of female ignation of adenosis. DES resulted in a more pronounced offspring at puberty (28, 30), as well as the occurrence of a adenosis than did 17/?-estradiol; in both cases, metaplasia was high incidence of adenosis in the vagina after such treatment, a striking component of the adenosis regions. Development of the findings from NMRI mice became attractive as a model for adenosis from HCE was dependent upon presence of the development of cancer in the human situation. The similarities ovaries. Some preparations from 44-week-old females given and dissimilarities between DES-induced changes in mice and DES injections showed signs of a beginning malignant trans humans have been discussed, and the mouse model has been formation in the adenosis regions, more evident in 17-month- pointed out to be of importance for the human situation (2, 15, old females. Among the 23 preparations in the latter group, 8 18, 41, 51 ). The cervicovaginal epithelium of a newborn mouse had changes morphologically indicating malignancy with ex is of a morphologically undifferentiated type. The develop amples of adenocarcinoma, mixed carcinoma, and squamous mental changes taking place during the first week after birth carcinoma. Because of the seemingly low aggressive nature of this malignancy, the term "pseudocarcinoma" is discussed. correspond to morphogenetic steps in the human vaginal epi thelium before the 18th to 20th week of pregnancy. In the Ten- to 12-week-old BALB/c and C57BL/6 females given DES neonatal mouse model, the mother organism and the placenta injections neonatally had HCE in the uterine cervix and vaginal do not interfere with the estrogen treatment. However, DES fornices after neonatal DES injections. Differences in extension passes the placental barrier (59), and female offspring from of HCE were observed after DES injections for three different DES-treated pregnant hamsters or mice develop epithelial 5-day periods in the neonatal and immature stages of NMRI changes in the genital tract similar to those seen after neonatal females. An interaction between different DES-sensitive param treatment (45, 57). eters to result in the pseudocarcinomas is discussed. In this study, we have analyzed the specificity of different estrogens, natural and synthetic, and other sex steroids as INTRODUCTION regards their potential for inducing epithelial aberrations of the HCE type and adenosis. For those substances active in induc The normal cervicovaginal epithelial lining in adult mice is a ing HCE, dose-response experiments were done. Strain differ stratified squamous epithelium which undergoes cyclic ences and critical periods for HCE induction and the ultimate changes related to the estrous cycle. These epithelial condi fate of HCE and adenosis in old females (oldest stage studied, tions are changed in adult females given estrogen injections 17 months) were investigated. neonatally. Thus, in 1962, it was demonstrated that such a treatment may result in persistent vaginal cornification (61, 62, MATERIALS AND METHODS 64). Forsberg (13) in 1969 described another type of perma nent epithelial aberration induced by estradiol neonatally (NMRI The majority of the mice used belong to a closed, outbred mice); mainly localized to the uterine cervix and vaginal fornix, stock of NMRI mice. In some experiments, inbred females of the BALB/c or C57BL/6 strains were used. The animals were ' This investigation was supported by grants from the Norwegian Cancer fed a standard pellet diet and given water ad libitum. Apparently Society (Landsforeningen mot Kreft) and the Norwegian Research Council for Science and Humanities. 2 To whom requests for reprints should be addressed. 3 The abbreviations used are: HCE, heterotopic columnar epithelium; DES, Received July 3, 1980; accepted October 31, 1980. diethylstilbestrol; DHT, 5a-dihydrotestosterone; CCC, common cervical canal. FEBRUARY 1981 721 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1981 American Association for Cancer Research. J-G. Forsberg and T. Kailand pregnant mothers from breeding cages were put into separate columnar type (Fig. 1D). Interspersed in this region were small cages to give birth to their litters. Within 24 hr after birth, areas where hyperplastic nodules of cuboidal cells were seen newborn females were separated from newborn males. Fe under the columnar epithelium (Fig. 1£).Caudally in the vagina, the basal zone was hyperplastic. In the group receiving 10~2 males from several litters were pooled, and every mother animal was allowed to suckle 7 to 9 females. fig DES, both normal and affected preparations were repre In most experiments, the neonatal females were given s.c. sented. injections for 5 days, starting within 24 hr after birth, of varying The results of the mitotic rate studies are demonstrated in doses of the test substances in 0.025 ml olive oil. Pressure Fig. 1, C and D, and Chart 2. There was a progressive decrease was kept on the injection site for about 15 to 20 sec after in mitotic rate activity related to the daily DES dose. A dose as small as 10~5 fig reduced the proliferative activity. The curve withdrawal of the needle to avoid leakage. In some experi had a tendency to flatten out at 10~3 and 10~2 ¡ig,only later to ments, the injections started later after birth (Day 4 or 6) but still covered a 5-day period. Finally, in one experiment, females turn down steeply to almost zero level at 10"' and 1 fig DES. were given injections of 5 jug DES for 5 days neonatally, Histology of Cervicovaginal Epithelium from 8-Week-old ovariectomized at 8 weeks, and killed at 51 weeks. Controls NMRI Females. Epithelial abnormalities were recorded from 3 were given injections of the vehicle (olive oil) only. different regions: uppermost part of the vagina; vaginal fornix; The test substances used were DES, dienestrol, frans-stil- and CCC. "Abnormal" epithelium is defined as HCE, in direct bene, 17/î-estradiol, 17a-estradiol, progesterone, testoster contact with the basal membrane, and interspersed in areas one, and DHT. The purity of the 17a-estradiol batch used was normally lined with squamous epithelium (Fig. 2). checked in a gas chromatography system." Contamination with In Chart 3 is plotted the extension of columnar epithelium in 17/?-estradiol was found to be less than 0.5%. Stock solutions of the different substances (obtained from Sigma Chemical uterine horn Co., St. Louis, Mo.) were prepared by dissolving an appropriate amount of the test substance in a minimal amount of ethanol and adding olive oil. -JtiuL-/:./.—cervical part The animals were killed by cervical dislocation at different sq.-c.j. ages from 8 weeks to 17 months. Most test groups comprise common preparations from at least 3 different litters, no litter being cervical represented with less than 2 preparations. The whole uterine canal cervix and upper part of the vagina were dissected out in foto [cccj (Chart 1). The preparations were fixed in Bouin's solution, dehydrated in alcohol, and embedded in paraffin. The prepa rations were serially sectioned in 7-/tm-thick sections. All sec tions were stained in hematoxylin and eosin. Neonatal NMRI females were given different daily injections of DES for a 5-day period; on Day 6 they were given a s.c. injection of 1 fig colchicine in Tyrode's solution and killed 4 hr later (24 hr after the last DES injection). The test groups at this age were pooled from only 2 litters. Histological sections (7 Chart 1. A schematic illustration of the anatomy of the region studied. Only the upper part of the vagina was included in the preparations. The region between firn) were prepared from the upper part of the vagina and the the 2 dashed lines represents the normal variation for the level of the squamo- uterine cervix.
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