Health care and social service professionals' perceptions of a home-visit program for young, first-time mothers.

INTRODUCTION: Little is known about health care and social service professionals' perspective on the acceptability of long-term home-visit programs serving low-income, first-time mothers. This study describes the experiences and perspectives of these community care providers involved with program referrals or service delivery to mothers who participated in the Nurse-Family Partnership (NFP), a targeted nurse home-visit program. METHODS: The study included two phases. Phase I was a secondary qualitative data analysis used to analyze a purposeful sample of 24 individual interviews of community care providers. This was part of a larger case study examining adaptations required to increase acceptability of the NFP in Hamilton, Ontario, Canada. In Phase II (n = 4), themes identified from Phase I were further explored through individual, semi-structured interviews with community health care and social service providers, giving qualitative description. RESULTS: Overall, the NFP was viewed as addressing an important service gap for first-time mothers. Providers suggested that frequent communication between the NFP and community agencies serving these mothers could help improve the referral process, avoid service duplication, and streamline the flow of service access. The findings can help determine key components required to enhance the success of integrating a home-visit program into an existing network of community services. CONCLUSION: The function of home-visit programs should not be viewed in isolation. Rather, their potential can be maximized when they collaborate and share information with other agencies to provide better services for first-time mothers.

TITRE: Points de vue de professionnels de la santé et des services sociaux sur un programme de visites à domicile destiné aux jeunes mères d'un premier enfant. INTRODUCTION: On sait peu de choses sur ce que pensent les professionnels de la santé et des services sociaux des programmes à long terme de visites à domicile pour les nouvelles mères à faible revenu. Cette étude fait état des expériences et des points de vue de fournisseurs de services communautaires qui orientent les mères participant au Nurse-Family Partnership (NFP) ­ un programme de visites à domicile par une infirmière auprès de cette population cible ­ vers le programme lui-même ou qui interviennent directement dans le cadre de celui-ci. MÉTHODOLOGIE: L'étude s'est déroulée en deux phases. La phase I a consisté en une analyse secondaire de données qualitatives issues d'un échantillon de 24 entrevues individuelles dirigées avec des fournisseurs de soins communautaires, cette démarche s'inscrivant dans le cadre d'une étude de cas plus vaste réalisée à Hamilton (Ontario, Canada) et destinée à examiner les moyens à mettre en oeuvre pour accroître la recevabilité du NFP. La phase II, à laquelle ont pris part 4 participants, a consisté en une description qualitative des 3 thèmes relevés lors de la phase I, thèmes qui ont été approfondis au moyen d'entrevues individuelles semi-structurées menées auprès de certains fournisseurs de soins de santé et de services sociaux communautaires. RÉSULTATS: Le NFP est perçu dans l'ensemble comme un programme comblant une lacune importante dans les services dispensés aux nouvelles mères. Des échanges fréquents entre le NFP et les organismes communautaires offrant déjà des services à ces mères pourraient contribuer à en améliorer le processus d'orientation, à éviter leur chevauchement et à en faciliter l'accès. Ces résultats contribuent à mieux définir les composantes nécessaires au succès de l'intégration d'un programme de visites à domicile au réseau déjà en place de services communautaires. CONCLUSION: Le rôle des programmes de visites à domicile ne doit pas être envisagé isolément. Au contraire, le potentiel de ceux-ci est optimisé par la collaboration et l'échange d'information avec d'autres organismes afin d'offrir de meilleurs services aux mères d'un premier enfant.

Oxidative stress specifically downregulates survivin to promote breast tumour formation.

BACKGROUND: Breast cancer, a heterogeneous disease has been broadly classified into oestrogen receptor positive (ER+) or oestrogen receptor negative (ER-) tumour types. Each of these tumours is dependent on specific signalling pathways for their progression. While high levels of survivin, an anti-apoptotic protein, increases aggressive behaviour in ER- breast tumours, oxidative stress (OS) promotes the progression of ER+ breast tumours. Mechanisms and molecular targets by which OS promotes tumourigenesis remain poorly understood. RESULTS: DETA-NONOate, a nitric oxide (NO)-donor induces OS in breast cancer cell lines by early re-localisation and downregulation of cellular survivin. Using in vivo models of HMLE(HRAS) xenografts and E2-induced breast tumours in ACI rats, we demonstrate that high OS downregulates survivin during initiation of tumourigenesis. Overexpression of survivin in HMLE(HRAS) cells led to a significant delay in tumour initiation and tumour volume in nude mice. This inverse relationship between survivin and OS was also observed in ER+ human breast tumours. We also demonstrate an upregulation of NADPH oxidase-1 (NOX1) and its activating protein p67, which are novel markers of OS in E2-induced tumours in ACI rats and as well as in ER+ human breast tumours. CONCLUSION: Our data, therefore, suggest that downregulation of survivin could be an important early event by which OS initiates breast tumour formation.

The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17beta-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16alpha-hydroxyestradiol, and 4-hydroxyestrone.

Several investigators have suggested that certain hydroxylated metabolites of 17beta-estradiol (E2) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E2 and the effects of genotoxic metabolites of E2 in an in vivo model sensitive to E2-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E2), 4-hydroxyestradiol (4-OH E2), 16alpha-hydroxyestradiol (16alpha-OH E2), or 4-hydoxyestrone (4-OH E1) (equimolar to 2 mg E2). Treatment with 1, 2, or 3 mg E2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E2, 4-OH E2, 16alpha-OH E2, or 4-OH E1 did not induce any detectable mammary tumors. The serum levels of E2 in rats treated with a 1 or 3 mg E2 pellet for 12 weeks was increased 2- to 6-fold above control values (approximately 30 pg/ml). Treatment of rats with E2 enhanced the hepatic microsomal metabolism of E2 to E1, but did not influence the 2- or 4-hydroxylation of E2). In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E2; however, under these conditions 2-OH E2, 4-OH E2, 16alpha-OH E2, and 4-OH E1 were inactive in inducing mammary tumors.

Ectopic uterine stem cell tumors in the hamster kidney. A unique model for estrogen-induced oncogenesis.

Estrogens are intimately involved in the causation of some of the most prevalent cancers afflicting women, particularly, breast, endometrial, cervico-vaginal, and possibly ovarian. Therefore, it has become particularly pertinent to elucidate the molecular mechanisms whereby estrogens elicit their oncogenic actions so that better prevention strategies can be developed. The estrogen-induced Syrian hamster tumors of the kidney have emerged as one of the most intensively studied in vivo models in solely estrogen oncogenesis. An advantage of this model is that the tumors occur in the absence of any intervening morphologic changes, but rather they are the result of the continuous progression of some interstitial stem cells in the kidney leading to tumor formation. Evidence is presented that the origin of these tumors is derived from ectopic "uterine" stem cells, which are responsive to estrogenic hormones. Their steroid receptor and many other gene alterations have been delineated. Importantly, a crucial early event in this solely estrogen-induced oncogenic process is the overexpression and amplification of c-myc and its protein product. Chromosomal instability, in both early and large frank tumors, is another important characteristic of this process. This later feature has commonly been shown in solely estrogen-induced murine mammary tumors, and in ductal carcinomas in situ and in primary invasive ductal breast carcinomas. These changes are considered crucial in eliciting estrogen-induced tumorigenesis.

Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation.

There is increasing evidence that both endogenous and exogenously ingested estrogens play a primary role in sporadic breast cancer causation. To establish further that solely estrogen-induced mammary oncogenesis in female ACI rats is an estrogen receptor (ERalpha)-driven process, we show for the first time that concomitant treatment with the antiestrogen, tamoxifen citrate (TAMc), completely prevents the induction of 17beta-estradiol (E(2))-induced mammary gland tumors (MGTs). This finding is also supported by the reduced mammary gland (MG) lobulo-alveolar development and proliferative activity observed in TAMc+E(2)-treated animals compared with MGs from animals treated with E(2) alone. These data also correlated with a marked decrease in the number of MG cells expressing ERalpha and progesterone receptor (PR) in immunostained MG tissue sections from TAMc+E(2)-treated animals. Additionally, a marked decline in the level of expression of ERalpha 47, 56 and 66 kDa forms, and PR-A and PR-B was seen in TAMc+E(2)-treated MGs, compared with MGs treated solely with E(2). Thus, both ERalpha and PR MG profiles in TAMc+E(2)-treated rats essentially revert to their respective receptor profiles seen in untreated control and TAMc-alone-treated rats. The presence of 56 and 54 kDa isoforms in chronically E(2)-treated MGs and in MGTs respectively may contribute to fostering the enhanced E(2)-dependent growth response of both precursor and frank MGT epithelial cells. These findings are consistent with an ERalpha/PR-mediated mg cell proliferation, a prerequisite for generating the high frequency of chromosomal instability seen in E(2)-induced ductal carcinomas in situ and primary MGTs in female ACI rats reported by us previously.

Determination of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione, a novel metabolite of L-histidine, in tissue extracts from sunlight-irradiated rat by capillary electrophoresis.

Exposure of the skin to sunlight results in an increase in the content of epidermal urocanic acid, a key metabolite of L-histidine, and some portions of the metabolite penetrate into the body fluid. S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione (GS(CIE)), an adduct of glutathione and urocanic acid, was proposed to be an origin of a urinary compound, S-[2-carboxy-1-(1 H-imidazol-4-yl)ethyl]-L-cysteine (Cys(CIE)). Various catabolites of Cys(CIE) were also isolated from human urine previously. However, no direct evidence to show the existence of GS(CIE) as a biological material had been found. By using capillary electrophoresis, the glutathione adduct has now been found in the extracts of rat tissues from the kidney, liver, skin and blood when the rat was kept under conditions of sunlight irradiation after the fur on the dorsal skin had been clipped. On the other hand, no or a trace of GS(CIE) was determined in rat tissue extracts when the animal was kept indoor in usual manner. The glutathione adduct was isolated from the kidney extract of the sunlight-irradiated rat using ion-exchangers and high-voltage paper electrophoresis, and determined by fast-atom-bombardment mass spectrometry. These results indicate that GS(CIE) formation actually occurs in the body and that the formation is accelerated by exposing the rat to sunlight irradiation. From these findings, we propose an alternative pathway of histidine metabolism which is initiated by the adduction of urocanic acid to glutathione to form GS(CIE) and terminates with the formation of the urinary compounds via Cys(CIE).

ER and PR in renomedullary interstitial cells during Syrian hamster estrogen-induced tumorigenesis: evidence for receptor-mediated oncogenesis.

The estrogen-induced and -dependent Syrian hamster renal tumor is the most intensively studied model in estrogen carcinogenesis. Yet, it remains confounding that the kidney of this species behaves as an estrogen target tissue. As both reproductive and urinary systems arise from the same germinal ridge, we propose that some of the germinal cells, normally destined for the uterus, migrate and establish themselves in the renal corticomedullary region in this hamster strain. These ectopically located germinal cells remain dormant unless exposed to estrogen. Supporting this contention, a subset of renal interstitial cells, primarily located in the corticomedullary region, express PR after only 2 wk and ER alpha after 1.5--3.0 months of estrogen treatment. As treatment continues, groups of cells of the renal interstitium and small and large renal tumors show ER alpha(+) and PR(+) staining. Although ER alpha and PR isoform profiles in estrogen-treated hamster kidneys are distinctly different from corresponding uterine patterns, both receptor isoform profiles in primary renal tumors closely resemble those seen in hamster uteri. Renal ER alpha protein and mRNA expression increased after 2.0 and 4.0 months of estrogen treatment and in all renal tumors examined. Using nuclear image cytometry, both early small and large renal tumors were highly aneuploid, indicating that genomic instability is probably a critical early event in estrogen carcinogenesis.

Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster.

There is strong evidence that estrogens are involved in the etiology, promotion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-dependent renal neoplasm is a well-established animal model used to elucidate the cellular and molecular mechanisms involved in solely estrogen-induced carcinogenic processes. G(1) cell cycle progression was studied in estrogen-induced early renal tumor foci and in large kidney tumors of castrated male hamsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins were higher in these renal neoplasias than in adjacent uninvolved renal tissue and kidneys from untreated, age-matched animals. Of particular interest is the presence of a predominant 35 kDa cyclin E protein variant form in primary renal tumors. In addition, amounts of the phosphorylated forms of cyclin-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27(kip1) (p27), a cyclin-dependent kinase inhibitor, were markedly higher in early and frank renal tumors than in adjacent uninvolved renal tissue and kidneys of untreated, age-matched animals. These changes in cell cycle components coincided with a rise in renal tumor cell proliferation. Binding of the elevated p27 protein to cyclin E, cdk2 and cdk4, however, was not impaired, suggesting that this cell cycle suppressor protein is functional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kinase activities were also lower in these estrogen-induced renal neoplasms than in untreated, age-matched kidneys. Interestingly, when compared with untreated kidney tissue, early and frank renal neoplasms had less of the 62 kDa native form of E2F1 and contained a 57 kDa variant form. Thus we have characterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-driven kidney tumor cell proliferation and may contribute to the early genomic instability found.

Overexpression and amplification of c-myc in the Syrian hamster kidney during estrogen carcinogenesis: a probable critical role in neoplastic transformation.

An estrogen receptor-driven, multistep process for estrogen carcinogenesis in the Syrian hamster kidney is proposed. Because in this species the reproductive and urogenital tracts arise from the same embryonic germinal ridge, it is evident that the kidney has carried over genes that are responsive to estrogens. Using in situ hybridization, overexpression of early estrogen-response genes, i.e., c-myc and c-fos, has been shown to be localized preferentially in early renal tumor foci after 3.5-4.0 months of estrogen treatment. This event coincides with an increased number of S-phase proliferating cell nuclear antigen-labeled cells in these tumor foci, along with a rapid rise in aneuploid frequency in the kidney. Western blot analyses of c-MYC and c-FOS protein products support the overexpression of these genes. Amplification of c-myc, 2.4-3.6-fold, but not of c-fos, was detected in 67% of the primary renal tumors examined, by Southern blot analyses. Consistent chromosomal gains, common to both diethylstilbestrol- and estradiol-induced renal neoplasms, were observed in chromosomes 1, 2, 3, (6), 11, (13), 16, 20, and 21 (chromosome number alterations are indicated in parentheses). Using fluorescence in situ hybridization, the c-myc gene was localized to hamster chromosome 6qb. Chromosome 6 exhibited a high frequency of trisomies and tetrasomies in the kidney after 5.0 months of estrogen treatment and in primary renal tumors. The data presented indicate that estrogen-induced genomic instability may be a key element in carcinogenic processes induced by estrogens.

Prevention of estrogen carcinogenesis in the hamster kidney by ethinylestradiol: some unique properties of a synthetic estrogen.

Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.

Promotion of estrogen-induced mammary gland carcinogenesis by androgen in the male Noble rat: probable mediation by steroid receptors.

Both endogenous and exogenous estrogen exposure is associated with an increased breast cancer risk. In some studies, elevated serum testosterone levels have also been linked to an increased breast cancer risk. Estrogen alone or combined with progesterone induces high mammary tumor incidences in various strains of both male and female rats. Mammary gland ductal adenocarcinomas were induced after 17beta-estradiol (E2) and testosterone propionate (TP) treatment in male Noble rats. Tumor incidence was 100% after 8-9 months of treatment. Such neoplasms were not detected after either estrogen or androgen exposure alone within this time period. TP alone caused disruption of mammary gland ducts and proliferation of stromal tissue, while E2 treatment alone induced both ductal epithelial growth and nodular atypical hyperplasia. To study the interaction of these hormones in mammary tumorigenesis, sex hormone receptors were characterized in mammary glands of Noble rats. Estrogen receptor-alpha (ER) was detected in age-matched, untreated mammary gland epithelium; in most early atypical hyperplastic lesions appearing after E2 and E2 + TP treatment and in E2 + TP-induced mammary tumors. Two major ER putative isoforms, 116 and 120 kDa, were detected in E2- and E2 + TP-treated mammary glands, and in the induced tumors. A 54 kDa ER protein was found in untreated and TP-treated mammary glands, and in the induced tumors. Both progesterone receptor-B (PR-B) and PR-A2, as well as androgen receptor-B (AR-B) and AR-A isoforms were markedly elevated in all E2 + TP-induced mammary tumors. However, the levels of both PR and AR were very low in mammary glands of E2- and E2 + TP-treated male rats. Low and moderate levels of AR and PR, respectively, were detected in most atypical hyperplastic lesions induced by E2- and E2 + TP-treated mammary glands. These results suggest that androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced tumors to effect the reduction in latency period, enhance tumor size, and increase incidence to 100%.

Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage.

We have proposed that an early step in estrogen carcinogenesis in the hamster kidney is tubular damage followed by reparative cell proliferation. This tubular injury is progressive and increases in severity with continued estrogen treatment; one pertinent feature is a marked rise in the number of both secondary and tertiary lysosomes. Data presented herein indicate that cathepsin D, an estrogen-responsive lysosomal proteolytic enzyme, is increased in the kidney following estrogen treatment in the hamster. Three isoforms of cathepsin D were detected in estrogen-treated kidneys, 52, 31, and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen treatment, 52-kDa cathepsin D content increased 1.4- to 1.6-fold. These changes coincided with a rise in renal estrogen receptor levels during the same estrogen treatment periods. More pronounced rises in cathepsin D levels, 2.7- and 3.5-fold, were seen after 4 and 5 months of estrogen treatment, respectively. A concomitant, 3.0- to 4.0-fold rise in estrogen receptor content was also observed. At 5 months of estradiol or DES treatment, both 27- and 31-kDa isoforms were present in hamster kidneys, in addition to the 52-kDa form. Neither progesterone nor DHT treatment affected the untreated levels of cathepsin D. Interestingly, either concomitant tamoxifen or DHT and estrogen treatment prevented the rise in cathepsin D and estrogen receptor content observed after estrogen treatment alone. Primary estrogen-induced renal tumors and their metastases exhibited markedly elevated levels of all three isoforms of cathepsin D. Immunohistochemical analysis of cathepsin D in kidney sections confirmed the Western blot findings. These data suggest a novel role for estrogen-induced cathepsin D in the hamster kidney during tumorigenesis; that is, mediating renal tubular damage as a prelude to reparative cell proliferation, thus initiating a multi-step estrogen-driven process which leads to renal tumor formation.

Glutathione S-transferase Yc cDNA from Syrian hamster kidney.

A cDNA encoding alpha-class glutathione S-transferase Yc (GSTYc) has been isolated from a Syrian hamster kidney library, and its nucleotide sequence (968 bp) has been determined. Analysis of the deduced amino acid sequence revealed a high level of identity between Syrian hamster GSTYc, rat GST Yc1 and Yc2 and mouse GSTYc. Northern-blot experiments demonstrated that Syrian hamster GSTYc expression is tissue-specific. A GSTYc mRNA of approx. 1 kb is expressed in liver, kidney, vas deferens and epididymis. Expression of the GSTYc transcript was not detected in testis or uterus.

Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen carcinogenesis.

Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancers. We have proposed a sequential multistage scheme involving tubular cell damage, regenerative cell proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene alteration, and amplification as essential steps for estrogen carcinogenesis in this model. A systematic study was undertaken to assess the expression of nuclear proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by Northern blot analysis to further support this scheme. Hamster kidney RNA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated castrated male hamsters and corresponding age-matched untreated controls was used in these studies, as well as primary estrogen-induced renal tumor RNA, for reference. Although no significant changes in the expression of these proto-oncogenes were detected in the first 4 months of estrogen treatment relative to age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar estrogen-exposed hamsters. Although no significant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal tumor. In contrast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in WT-1 expression was observed in the primary renal tumor. It is evident that two WT-1 transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney. In summary, the estrogen-induced inappropriate gene expression, including p53, reported herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain proximal tubular interstitial cells necessary for estrogen-driven tumor formation in the hamster.

Estrogen carcinogenesis in the hamster kidney: a hormone-driven multistep process.

It is proposed that the kidney cytotoxicity or tubular damage and the subsequent regenerative cell proliferation elicited by estrogens after chronic hormone treatment is driven specifically by the intrinsic estrogenic property of these agents. The sequence of events leading to estrogen-induced renal tumorigenesis in the hamster is presented in Figure 2. There are a number of events that occur rapidly and nearly simultaneously. First, there is an alteration in kidney proximal tubule (PCT) cells that is manifested by an elevation in both ER and PR at about 1.5 and 3 months, respectively. This clearly demonstrates an increased responsiveness of the kidney tubule to estrogen. Second, there is a progressive PCT cytotoxicity or cell injury, occurring as early as 1.5 months, which increases in severity with continued estrogen exposure. Initially, when the tubular damage is not severe, the reparative hyperplasia occurs mainly in the mature proximal tubules. Third, with increased severity in renal tubular cell damage, committed epithelial interstitial stem cell populations, shown to be the origin of this tumor, begin to proliferate in an effort to repair the increasing cell damage induced by chronic estrogen treatment. As a consequence of this regenerative cell proliferation, in both mature proximal tubules (limited) and primitive interstitial stem cells, aneuploid cells in both dividing mature and primitive kidney cells are significantly elevated. This view is consistent with the specific estrogen-induced cell proliferation in culture cited earlier. Evidence has recently been provided in our laboratory that suggests that chromosomal instability as a result of nonrandom chromosomal alterations (trisomies, tetrasomies, monosomies) as well as other chromosomal aberrations contribute critically to early events in renal tumorigenesis in the hamster. Moreover, overexpression of protooncogenes and suppressor genes occurs as early as 4 months of estrogen treatment. Therefore, the nongenotoxic estrogen-induced neoplastic transformation in the hamster kidney is suggested to occur in a series of discrete molecular events that is now believed to be primarily hormonally driven and hormonally dependent.

Carcinogenic activities of various steroidal and nonsteroidal estrogens in the hamster kidney: relation to hormonal activity and cell proliferation.

The therapeutic use of estrogens has been associated with an increased risk of some of the most predominant, as well as less prevalent, cancers in women. The estrogen-induced renal tumor is one of the primary animal models to evaluate the carcinogenic properties of estrogens. Correlations were made with various estrogens by using parameters of estrogenicity end points such as competitive binding, progesterone receptor induction, and alterations in prolactin levels; in vitro renal proximal cell proliferation; and in vivo estrogen-induced carcinogenicity. The most potent estrogens were Moxestrol (MOX), diethylstilbestrol (DES), and 17 beta-estradiol, followed by indenestrol B, 16 alpha-hydroxyestrone, and 11 beta-methoxyestradiol with moderate estrogenic activities, whereas 11 beta-methylestradiol, 17 alpha-estradiol, indanestrol, and deoxoestrone were all relatively weaker. As expected, hydrolyzed Premarin (unconjugated estrogens) was strongly estrogenic. Of the estrogens tested, MOX was the most potent carcinogenic estrogen in the hamster kidney. Both 16 alpha-hydroxyestrone and 11 beta-methoxyestradiol induced intermediate tumor incidences with distinctly lower frequencies of renal tumor foci compared to the most potent carcinogenic estrogens. However, hamsters treated for 9.0 months with 11 beta-methylestradiol, 17 alpha-estradiol, deoxoestrone, and indanestrol exhibited no tumors. In contrast, treatment with estrone, equilin plus d-equilenin, and hydrolyzed Premarin for the same time period resulted in 100% renal tumor incidences and numerous tumor foci. Cell proliferation studies of cultured hamster kidney proximal tubule cells were carried out at varying estrogen concentrations (0.01-100 nM). Exposure to MOX resulted in consistently high renal cell proliferative response over a concentration range of 0.1-10 nM. Strongly carcinogenic estrogens such as estrone had a maximal renal cell proliferation response (2.4-fold above untreated control levels) between 0.1 and 10 nM, DES and 17 beta-estradiol responded at 1.0 nM, and 4-hydroxyestradiol responded at 10 nM. Interestingly, exposure to ethinylestradiol, a potent estrogen, at similar or higher doses as those used for DES and 17 beta-estradiol, yielded only a 10% renal tumor incidence and induced only a 1.7-fold increase in proximal tubule cell proliferation. In contrast, 17 alpha-estradiol, deoxoestrone, indanestrol, and 11 beta-methylestradiol, all weakly estrogenic and noncarcinogenic agents, had relatively little effect on tubule cell proliferation. The hydrolyzed Premarin exhibited a maximal 2.0-fold cell proliferative response at 10 nM. The present results provide clear evidence that, in the hamster kidney, the degree of carcinogenicity of a given estrogen correlates with its ability to induce proximal tubule cell proliferation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of parental alcoholism and life stress on Hispanic and Non-Hispanic Caucasian adolescents: a prospective study.

Investigated ethnicity and parental alcoholism as factors that might influence the stress vulnerability of adolescents. It extended an initial cross-sectional study of this same sample by adding two annual assessments which allowed for additional cross-sectional analyses and longitudinal tests. Hispanic and Caucasian adolescents (N = 306 at Time 1) completed measures of their own life stress, family conflict, and alcohol use. Their parents reported on adolescents' internalizing and externalizing symptoms. Cross-sectional analyses at Time 2, and prospective analyses involving Time 1 and Time 2 measures were, for the most part, consistent with the original study's results. Caucasian adolescents and children of alcoholic parents appeared to be more vulnerable to stress than Hispanic adolescents and children of nonalcoholic parents. Family conflict was a partial explanation for this increased vulnerability.

Induction of chromosome aberrations in Syrian hamster renal cortical cells by various estrogens.

Estrogens, both natural and synthetic, have been implicated in carcinogenesis at different organ sites in a variety of animals, including man, for more than six decades. However, the molecular mechanism(s) involved in the carcinogenic action of estrogens still remains both controversial and elusive. Cytogenetic damage in the hamster kidney has been studied after in vivo treatment with either potent or weak estrogens for varying periods. Compared to age-matched untreated control, diethylstilbestrol (DES) treatment resulted in significant increases in the number of chromatid gaps and breaks, chromosome breaks, and endoreduplicated cells in hamster renal cortical cells. These chromosomal aberrations (CA) were cumulative with continued hormone exposure from 1.0 to 5.0 months. However, chromosome exchanges as a result of the breaks were not elevated. After 5.0 months of hormone treatment, potent estrogens such as 17 beta-estradiol and Moxestrol exhibited similar frequencies of CA in the hamster kidney to that found for DES, whereas weak estrogens such as 17 alpha-estradiol and beta-dienestrol exhibited CA frequencies that were not significantly different from untreated levels. Ethinylestradiol treatment for a similar period resulted in significant increases in chromatid gaps, although these did not evolve into increases in either chromatid or chromosome breaks, and in a rise in endoreduplicated cells. These results raise the possibility that the CA generated after estrogen treatment may be involved in renal tumorigenic processes.