Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz, Luisa; Hacker, Hans Jörg; Klingmüller, Dietrich; Bannasch, Peter; Pfeifer, U; Dombrowski, Frank

doi:10.1016/s0002-9440(10)65033-x

Cited by 5 publications

(10 citation statements)

References 28 publications

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“…They were housed as previously described. 17 All experiments were performed in line with the guidelines of the Society for Laboratory Animals Service (GVSolas).…”

Section: Methodsmentioning

confidence: 99%

“…The gonadal tissue of donor animals was obtained as previously described. 17 The ovaries were dissected into small fragments, suspended in ice-cold Hanks' balanced solution (pH 7.2) (Sigma, Heidelberg, Germany), and transplanted via the portal vein into the right part of the liver (i.e., the right lobe, the right part of the middle lobe, and the caudate lobe), secured by previous clamping of the left branch of the portal vein. Each animal received the same amount of gonadal tissue; all ovarian fragments were from one donor animal.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were killed after 6, 12, 18, 24, and 30 months and were fixed via perfusion as previously described in detail. 17 After fixation, the livers were removed and cut into slices. From every liver, 10 specimens of 2 ϫ 2 mm were postfixed with OsO 4 and embedded in Epon.…”

Section: Methodsmentioning

confidence: 99%

“…[18][19][20] Preliminary data also indicated that some of these lesions progress to hepatocellular neoplasms. 17 However, dietary administration of the natural estrogen estradiol did not show any hepatocarcinogenic effect in contrast to similarly administered synthetic estrogens in another study. 21 Thus, the carcinogenic potential of endogenous estradiol in the liver still needs to be clarified.…”

mentioning

confidence: 88%

“…15,16 We have previously shown that high local levels of endogenous estrogens, derived from hormonally stimulated ovarian fragments after their intrahepatic transplantation in ovariectomized rats, exert characteristic focal alterations in the downstream liver parenchyma. 17 The changes in these foci of altered hepatocytes (FAH) included loss of glycogen, cytoplasmic amphophilia, nuclear enlargement, a strong increase in peroxisome density, and an increase in proliferative activity, as well as apoptotic elimination and changes in the activities of certain key enzymes of the energy metabolism. The phenotype of these FAH resembled in many respects that of amphophilic preneoplastic foci that appear after long-term administration of different chemical hepatocarcinogens.…”

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Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

et al. 2006

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Intrahepatic transplantation of ovarian fragments in ovariectomized rats results in morphological abnormalities. The liver acini draining blood from ovarian grafts show alterations resembling chemically induced amphophilic hepatocellular preneoplasias. We investigated the long-term development of these estrogen-induced foci of altered hepatocytes (FAH). We divided 451 Lewis rats into one main group (MG) and 11 (7 female, 4 male) control groups and observed them for up to 30 months. MG animals were ovariectomized and received ovarian transplants into the right liver part. Different combinations of castration, transplantation of ovarian or testicular fragments, and administration of antiestrogenic toremifene were used in controls. In the MG, transplants showed signs of gonadotropic stimulation, and estrogen levels were strongly increased in the downstream liver acini. After 6 and 12 months, O ral contraceptive steroids contribute to the development of hepatocellular adenoma (HCA) in humans, and a recent meta-analysis has also shown an increased incidence of hepatocellular carcinoma (HCC) in women of a low-risk population (low hepatitis B and C prevalence). 1 These observations correspond to findings in animal experiments that have demonstrated an enhancement of hepatocarcinogenesis after administration of various synthetic estrogens such as ethinyl estradiol and diethylstilbestrol. [2][3][4][5][6] Simultaneous administration of tamoxifen inhibited part of the carcinogenic effects of ethinyl estradiol, indicating that they were most likely mediated by the estrogen receptor. 7 These observations suggest that estrogens are not only genotoxic 8,9 but may also act as hepatocarcinogens by altering cell signaling and metabolism, including nuclear and mitochondrial gene expression and cell proliferation. 10,11 Estrogens also interact with other hepatocellular mitogens such as epidermal or hepatocyte growth factor and transforming growth factor ␣ (TGF-␣). [12][13][14] Although the carcinogenic effects of synthetic estrogens on the liver have been extensively studied, little is known about the hepatocarcinogenic potential of endogenous estrogens, although increased levels of circulating estrogens bear a risk for the

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“…They were housed as previously described. 17 All experiments were performed in line with the guidelines of the Society for Laboratory Animals Service (GVSolas).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 88%

mentioning

confidence: 99%

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Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

et al. 2006

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Estradiol Administration Improves Splanchnic Perfusion Following Trauma-Hemorrhage and Sepsis

Kuebler

Jarrar²,

Tóth³

et al. 2002

Arch Surg

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Hypothesis: The female sex steroid 17␤-estradiol improves immune functions following trauma-hemorrhage in rodent models. Therefore, we hypothesized that 17␤estradiol administration following trauma-hemorrhage would also improve cardiac output, splanchnic perfusion, and oxygen utilization, even after the induction of subsequent sepsis. Setting: A university laboratory. Intervention: Male rats underwent midline laparotomy (ie, soft tissue injury). They were bled to a mean arterial pressure of 35 to 40 mm Hg for 90 minutes and resuscitated over 60 minutes with lactated Ringer solution. At the beginning of resuscitation, 17␤-estradiol (l mg/kg) or a vehicle was administered. At 20 hours after resuscitation, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Main Outcome Measures: At 5 hours after CLP, cardiac performance (via a left ventricular catheter), cardiac output, and organ blood flow were determined using strontium 85 microspheres. Blood samples were collected from the femoral artery and jugular, portal, and renal veins to determine systemic and regional oxygen delivery and consumption. Moreover, circulating levels of 17␤-estradiol, its adrenal precursor dehydroepiandrosterone (DHEA), and corticosterone were assessed by enzyme-linked immunosorbent assay. Results: Hemorrhage and subsequent sepsis significantly depressed cardiac performance, cardiac output, organ perfusion, and oxygen consumption. Estrogen did not restore cardiac output or systemic oxygen consumption; nonetheless, it restored the depressed intestinal perfusion. Rats treated with estrogen had significantly elevated levels of plasma 17␤-estradiol, but the levels of DHEA or corticosterone were not affected. Conclusions: The increase in gut perfusion could represent a potential mechanism for the salutary effects of 17␤-estradiol following trauma-hemorrhage. Because 17␤estradiol improves systemic and intestinal perfusion after trauma-hemorrhage and induction of subsequent sepsis, this agent appears to be a promising adjunct for the treatment of trauma victims.

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Different Effects of the Liver Mitogens Triiodo-Thyronine and Ciprofibrate on the Development of Rat Hepatocellular Carcinoma

et al. 2003

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Previous work has shown that treatment with thyroid hormone (T3) decreased the incidence of rat hepatocellular carcinoma (HCC). The present study was designed to determine whether the inhibitory effect of T3 on HCC development was limited to early steps of the carcinogenetic process or, whether a similar effect could also be exerted by starting T3 treatment at later stages. Hepatic nodules were induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3 groups: group 1 was maintained on basal diet: group 2 was fed a diet containing 4 mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA administration: group 3 was exposed to cycles of T3 starting 8 months after initiation. Results demonstrate that inhibition of HCC development was essentially similar in rats exposed to T3 starting either 9 weeks or 8 months after initiation (50% inhibition compared to control rats). We have previously shown that T3-induced nodule regression and HCC inhibition occurred in spite of its mitogenic effect. Therefore, we next wished to determine whether a similar antitumoral effect could be exerted by other liver mitogens, such as peroxisome proliferators. Rats exposed to the initiation-promotion protocol described previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented diet, each cycle consisting of 7 days/month: the incidence of HCC and lung metastases was determined 13.5 months after initiation. Results showed that although treatment with T3 strongly inhibited HCC development (only 31% of T3+ rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same number of HCC as T3-untreated rats. In conclusion, the results of this study showed that the anticarcinogenic effect of T3 is maintained also when treatment begins late in the process, and its antitumoral property appears to be specific and may not be shared by other liver mitogens.

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Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Cited by 5 publications

References 28 publications

Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats†

Estradiol Administration Improves Splanchnic Perfusion Following Trauma-Hemorrhage and Sepsis

Different Effects of the Liver Mitogens Triiodo-Thyronine and Ciprofibrate on the Development of Rat Hepatocellular Carcinoma

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