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, 34 (2), 119-28

A Human Fetal Prostate Xenograft Model of Developmental Estrogenization

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A Human Fetal Prostate Xenograft Model of Developmental Estrogenization

Camelia M Saffarini et al. Int J Toxicol.

Abstract

Prostate cancer is a common disease in older men. Rodent models have demonstrated that an early and later-life exposure to estrogen can lead to cancerous lesions and implicated hormonal dysregulation as an avenue for developing future prostate neoplasia. This study utilizes a human fetal prostate xenograft model to study the role of estrogen in the progression of human disease. Histopathological lesions were assessed in 7-, 30-, 90-, 200-, and 400-day human prostate xenografts. Gene expression for cell cycle, tumor suppressors, and apoptosis-related genes (ie, CDKN1A, CASP9, ESR2, PTEN, and TP53) was performed for 200-day estrogen-treated xenografts. Glandular hyperplasia was observed in xenografts given both an initial and secondary exposure to estradiol in both 200- and 400-day xenografts. Persistent estrogenic effects were verified using immunohistochemical markers for cytokeratin 10, p63, and estrogen receptor α. This model provides data on the histopathological state of the human prostate following estrogenic treatment, which can be utilized in understanding the complicated pathology associated with prostatic disease and early and later-life estrogenic exposures.

Keywords: animal models; developmental pathology; environmental toxicology; prostate; reproductive system.

Figures

Figure 1
Figure 1
Dosing paradigm used in this study to examine the early and later-life effects following estrogen exposure on human prostate xenografts. (A) Human fetal prostates from spontaneous pregnancy losses were obtained, and implanted under the renal subcapsular space of an immunodeficient rat host (day 1). Following xenograft surgery, rat hosts were given a subcutaneous injection of either corn-oil (control) or 250 μg/kg of β-estradiol 3-benzoate (treatment) on days 1, 3, and 5. To explore the initial effects of estrogen, a subset of xenografts were collected on days 7, 30, and 90 (primary collection). (B) An additional subset of rat hosts was administered silastic capsules on day 90, containing either empty capsules (control) or β-estradiol 3-benzoate and testosterone capsules (secondary treatment), for a total of 110 days. To examine the effects of paired early and later-life estrogen exposure, some rat hosts were collected on day 200 (primary and secondary collection), while a subset of animals had treatment removed and were subsequently collected on day 400 (recovery group).
Figure 2
Figure 2
Histology of 7-, 30-, and 90-day human prostate xenografts that received an early exposure to estradiol. (A–B) At day 7, both control (corn-oil) and estrogen-treated prostate xenografts have primordial small ducts with basal cell hyperplasia. (A) The stroma in the corn-oil group is composed of a busy cellular mesenchyme, representative of normal fetal prostate stroma, while the (B) treated group shows better stromal maturation with immature smooth muscle cells. (C) In 30 days post-implantation, the corn-oil xenografts present with immature ducts, but a better-developed stroma, while (D) treated xenografts show similar epithelial features as the controls but an immature edematous and hypocellular stroma. (E&F) Both corn-oil and estradiol-treated xenografts appear morphologically similar at 90 days, demonstrating mature ducts with proper secretory function and stromal maturation similar to the adult prostate. Prior to implantation, the gestational age of the human fetal prostate was 23.7 weeks. (Hematoxylin and Eosin staining; scale bar = 50 μm).
Figure 3
Figure 3
Histology of human prostate xenografts at 200 days post-implantation that was given initial (corn-oil or estradiol) and secondary (empty or estradiol and testosterone silastic capsules) treatments to evaluate the effects of early and later-life exposures to estradiol. Controls for the secondary treatment were empty silastic capsules. (A) Control human prostate xenografts (corn-oil/empty) present with normal, phenotypically adult prostatic ducts encompassed by a cellular stroma. (B) Human prostate xenografts given only an early dose of estradiol with no subsequent exposure (estradiol/empty) appear similar to control xenografts, with adult glands and a mature stromal environment. (C) Xenografts given only a later dose of estradiol (corn-oil/estrogen and testosterone) present with atrophic ducts incapable of secretory function. (D) Xenografts that received both early and later doses of estradiol (estradiol/estradiol and testosterone) demonstrate significant glandular hyperplasia, with no apparent changes to the stroma. (A–D) Gestational age of human prostate before implantation was 21 weeks, and treatment conditions are depicted as primary/secondary exposure. CO: corn-oil, and E&T: estradiol and testosterone. (Hematoxylin and Eosin staining; scale bar = 50 μm).
Figure 4
Figure 4
Histology of a human prostate xenograft at 400 days post-implantation that was exposed to both early and later doses of estradiol (E/E&T) followed by a recovery period of 200 days. Estrogen-related treatment effects persist in the epithelial compartment after a 200-day recovery period as demonstrated by the presence of ductal hyperplasia. Gestational age of human prostate before implantation was 22 weeks. E&T: estradiol and testosterone. (Hematoxylin and Eosin staining; scale bar = 100 μm).
Figure 5
Figure 5
Immunohistochemical staining of cytokeratin 10 (squamous metaplasia), p63 (basal cell), and estrogen receptor-α (hormone receptor) markers in 200- and 400-day E/E human prostate xenografts at 200 and 400-days post-implantation. (A, D) The epithelia show a similar pattern of CK10 staining at 200- and 400-days post-implantation, suggesting that squamous metaplasia is a persistent consequence of estrogen exposure. (B) At 200 days post-implantation, xenografts display a mature phenotype with epithelial hyperplasia and one layer of basal cells. (E) After 200 days of recovery, epithelial hyperplasia is still present, along with some areas of significant basal cell hyperplasia. (C) ERα shows strong epithelial and stromal staining after 200 days, (F) while there is residual epithelial but less stromal staining at 400 days. Gestational age of human prostate before implantation is 17 weeks (A–C), and 22 weeks (D–F). Counterstain is Hematoxylin (A&D), and methyl green (B, C, E, &F). (Scale bar = 50 μm)

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