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Biomedical subjects

L Tomatis

Publications and source records attributed to L Tomatis.

At least 55 records · Page 3Linked to original sources
PubMed1992

Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol.

There is well documented evidence both in humans and in experimental animals that exposure to diethylstilbestrol (DES) during pregnancy results in an increased incidence of tumours in the progeny. The increased cancer risk has been reported to persist in the second generation descendants of DES-exposed pregnant mice. In the present experiment, female mice of the CBA strain were treated at day 17 of pregnancy with 1 microgram/g body weight of DES. The descendants of DES-treated mothers, described as F1DES, were mated among each other or with untreated animals. The F1DES females were found to be sterile when mated with either F1DES or untreated males. F1DES males were successfully mated with untreated females. In the female offspring so obtained, but not in the male, a statistically significant increased incidence of tumours was observed, in particular of uterine sarcomas, and also of benign ovarian tumours and of lymphomas.

Animals↗
PubMed1992

Diethylstilboestrol: I, Pharmacology, Toxicology and carcinogenicity in humans.

Diethylstilboestrol is still used as an adjunct palliative treatment in certain patients with breast and prostate cancer. Its pharmacological, toxicological and carcinogenic properties are reviewed. In addition to the usual untoward effects following subacute or chronic administration of oestrogens, treatment with diethylstilboestrol has been associated with serious cardiovascular sequelae. Most characteristic are, however, the carcinogenic properties of this drug. Many epidemiological data provide evidence that prenatal exposure to diethylstilboestrol is causally associated with vaginal and cervical clear-cell adenocarcinomas, a very rare type of cancer in the unexposed female population. The intrauterine exposure of males leads to an increased risk of testicular cancer, although the data are less conclusive in this respect. There is some evidence that administration of diethylstilboestrol in large doses to adult women during pregnancy increases the risk of subsequent breast cancer and it probably increases the incidence of endometrial carcinoma, as has been shown with other similar oestrogens given chronically for menopausal symptoms.

Abnormalities, Drug-Induced↗
PubMed1992

Diethylstilboestrol: II, pharmacology, toxicology and carcinogenicity in experimental animals.

Diethylstilboestrol (DES) exerts several toxic effects in experimental animals, by mechanisms which are still unclear. The genotoxicity of the drug has been attributed to a quinone metabolite and is mainly clastogenic, including sister chromatid exchange, unscheduled DNA synthesis, chromosomal aberrations, disruption of mitotic spindle and aneuploidy. There is evidence that genotoxic effects may occur also transplacentally. Intrauterine and early postnatal exposure to DES can cause a variety of dysplasias. In the offspring of female mice exposed to DES during pregnancy, histological changes are observed in the vaginal and cervical epithelium, the endometrium, the ovary, the testis and the epididymis. Prenatal exposure of rats to DES led to decreased litter size and to urethrovaginal cloaca, penile and testicular hypoplasia, and cryptorchidism. Vaginal ridging, vaginal adenosis, testicular hypoplasia and cryptorchidism have been observed in rhesus monkeys following prenatal exposure. There is sufficient evidence that diethylstilboestrol is carcinogenic in experimental animals, after either prenatal or postnatal exposure. Mice show a similar type of carcinogenicity to that observed in humans, target organs being vagina, cervix, uterus, ovary, mammary gland and testis. In rats, prenatal exposure to DES produces mostly mammary and pituitary tumours, but also some tumours of the vagina. Hamsters develop tumours of vagina, cervix, endometrium, epididymis, testis, liver and kidney. DES induces ovarian papillary carcinomas in dogs, and malignant uterine mesotheliomas in squirrel monkeys. Some experimental evidence points to the possibility of a transgenerational carcinogenic effect, since prenatal treatment of mice with DES is followed by an increased incidence of uterine and ovarian carcinomas in the second-generation descendants. Experimental results could have been used to predict the adverse effects of DES observed in humans in the early 1970s: DES had been reported to be carcinogenic in mice in the 1930s, while experiments in the 1960s had provided evidence that exposure during pregnancy could result in an increased cancer risk in the progeny.

Abnormalities, Drug-Induced↗
PubMed1992

Transplacental and transgeneration carcinogenic effect of 7,12-dimethylbenz[a]anthracene: relationship with ras oncogene activation.

Transgeneration transmission of the carcinogenic action of 7,12-dimethylbenz[a]anthracene (DMBA) was studied in two generations of mice using transplacental DMBA initiation followed by postnatal skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) in the first generation (F0) and only promotion in the second generation (F1). Local application of TPA resulted in increased skin tumor yield in both the in utero DMBA-exposed mice and their progeny (P = 0.0002 and P = 0.0941 respectively compared to control). Similarly, lung tumor incidence was increased in the two generations of mice (P less than 0.0001 and P = 0.0080 respectively). The results suggest transgeneration transfer of the effect of DMBA. A to T mutation at the second base of codon 61 of the Ha-ras oncogene was found in skin tumors of DMBA-exposed mice, but not in tumors induced by TPA without initiation. Analysis of Ki-ras codon 61 in seven lung tumors from DMBA-treated mice revealed three types of mutation: two cases with CA[C or G or T], one case with CCA and one case with CTA (the remaining cases having only the wild type). Six of these mice also had skin tumors, which contained A to T mutation at the second base of codon 61 of the Ha-ras gene in five cases. Thus mutations of different ras genes were found in skin and lung tumors from the same animals. In the progeny (F1) of DMBA-exposed F0 mice, only skin tumor samples were available for oncogene analysis and none contained the Ha-ras mutation. The results confirm our previous finding that initiation of skin and lung tumorigenesis can be transmitted transgenerationally. On the other hand, our data from a limited number of skin tumors suggests that ras gene mutation may not be critically involved in this transmission.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Perinatal and multigenerational effect of carcinogens: possible contribution to determination of cancer susceptibility.

Perinatal exposure to carcinogens may contribute to the determination of susceptibility to cancer in two situations: a) exposure in utero of embryonal or fetal somatic cells to carcinogens, and b) prezygotic exposure of the germ cells of one or both parents to carcinogens. Epidemiological as well as experimental studies demonstrate that exposure to carcinogens in utero increases the occurrence of cancer postnatally. Studies with experimental animals suggest that prezygotic exposure of germ cells to carcinogens can result in an increased incidence of cancer not only in immediate but also in subsequent generations. Although several studies suggest a transgeneration effect of carcinogens in human populations, the evidence cannot yet be considered conclusive. In particular, while some hypotheses can be advanced, the mechanism(s) by which increased susceptibility or predisposition to cancer may be transmitted via the germ cells has not yet been clarified. In conjunction with exposure both in utero and prezygotically, it is important to consider postnatal exposure to possible tumor-promoting agents. Results from experimental animals suggest that oncogenes can be activated transplacentally, and human studies indicate that tumor-suppressor gene inactivation may be involved in the transgenerational effect of carcinogens.

Animals↗
PubMed1991

Cancer risks related to electricity production.

The International Agency for Research on Cancer has previously evaluated the cancer risks associated with fossil fuel-based industrial processes such as coal gastification and coke production, substances and mixtures such as coal tars, coal tar pitch and mineral oils, and a number of substances emitted from fossil-fuelled plants such as benzo[a]pyrene and other polycyclic aromatic hydrocarbons, arsenic, beryllium, cadmium, chromium, nickel, lead and formaldehyde. Based on these evaluations and other evidence from the literature, the carcinogenic risks to the general population and occupational groups from the fossil fuel cycle, the nuclear fuel cycle and renewable cycles are reviewed. Cancer risks from waste disposal, accidents and misuses, and electricity distribution are also considered. No cycle appears to be totally free from cancer risk, but the quantification of the effects of such exposures (in particular of those involving potential exposure to large amounts of carcinogens, such as coal, oil and nuclear) requires the application of methods which are subject to considerable margins of error. Uncertainties due to inadequate data and unconfirmed assumptions are discussed. Cancer risks related to the operation of renewable energy sources are negligible, although there may be some risks from construction of such installations. The elements of knowledge at our disposal do not encourage any attempt toward a quantitative comparative risk assessment. However, even in the absence of an accurate quantification of risk, qualitative indication of carcinogenic hazards should lead to preventive measures.

Accidents, Occupational↗
PubMed1991

Correlation of early pathological lesions in the bronchial tree with environmental exposures: study objectives and preliminary findings.

Lung specimens were taken at autopsy from 214 subjects aged 35 years and over who had died from nonpulmonary causes in Athens or the surrounding countryside. The samples were coded and examined for entities thought to be linked to environmental exposures, reflecting epithelial, possibly precancerous, lesions, as well as for morphological features, which were summarized using Reid's index. Of the 214 specimens, 142 were suitable for pathological examination. Next-of-kin of 101 of the dead people were identified and asked about the subject's exposure to active smoking, passive smoking, possible occupational hazards, dietary factors and proxy indicators of air pollution (residence). Preliminary analysis, controlling for age and sex, indicates that active smoking is related, although not statistically significantly, to both the Reid index (difference, 0.28, corresponding to a one-tailed p value of 0.07) and epithelial, possibly precancerous lesions (difference, 16.7, corresponding to a one-tailed p value of 0.09). Nonsignificant differences were found in the preliminary analysis of this ongoing study with respect to the other environmental factors examined.

Adult↗
PubMed1991

[Activation of the Ha-ras oncogene in tumors induced in mice by transplacental exposure to 7,12-dimethylbenz(a)anthracene].

A study of tumors induced in mice by transplacental exposure to 7,12-dimethylbenz(a)anthracene (DMBA) alone or in combination with postnatal tissue-specific promotion showed skin and liver tumor development to be associated with cellular Ha-ras oncogene activation in a large percentage of cases. As shown by Xba I RFLP, oncogene activation was caused by T for A substitution at the second position of codon 61. The said mutation was traced in DMBA-induced tumors of the liver alone but not in spontaneous hepatomas. The results of the study showed the role of oncogene activation in cancer development to be tissue-specific.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks.

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.

Aflatoxin B1↗
PubMed1990

Tissue-specific activating mutations of Ha- and Ki-ras oncogenes in skin, lung, and liver tumors induced in mice following transplacental exposure to DMBA.

Transplacental carcinogenesis represents a good model in which to study the involvement of tissue-specific oncogene activation in carcinogenesis because a single exposure to a carcinogen induces tumors at various sites. We tested tumors of the skin, liver, and lung produced in mice after transplacental 7,12-dimethylbenz[a]-anthracene (DMBA) exposure for possible activation of ras genes. XbaI restriction fragment-length polymorphism analysis has shown that exposure to DMBA in utero may result in appearance of A----T transversion at the second position of codon 61 of Ha-ras oncogene in skin and liver tumors but not in lung tumors. Moreover, DNA samples isolated from spontaneous and DMBA-induced lung and liver tumors were analyzed for mutations at the same position of Ki-ras oncogene using differential hybridization with specific oligonucleotides. Among five spontaneous lung tumors, three cases of A----G transition, and one case of A----T transversion were found, whereas four of ten lung tumors of DMBA-treated animals were positive for A----T mutation. No Ki-ras mutation was detected in one spontaneous and four DMBA-induced hepatomas. In two cases, we revealed Ki-ras A----T mutation in the lung tumor and Ha-ras mutation in the liver tumor taken from the same animal. These results indicate first that DMBA treatment may induce A----T mutation at the second position of codon 61 both in Ha-ras and in Ki-ras and, second, that the role of different activated oncogenes in carcinogenesis may differ, depending on the tissue in which the tumor develops.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Tumour incidence in the progeny of male rats exposed to ethylnitrosourea before mating.

BDVI male rats were given a single i.p. dose of 80 mg/kg b.w. ethylnitrosourea (ENU), and each rat was then mated at weeks 1, 2, 3, 4 and 5 after treatment with 3 untreated females. A decrease in the fecundity of the treated males was observed, particularly when they were mated 5 weeks after ENU treatment. The average litter size was lower in the treated group, especially for females mated in week 4. No significant differences in pre- or post-weaning mortality were noted between control and treated groups. A slight, non-significant increase in the incidence of brain tumours was observed in the progeny of treated males compared with the controls. The incidence of thyroid tumours was significantly higher in controls but this difference disappeared when adjustment was made for litter effect and intralitter dependence.

Animals↗
PubMed1989

5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats.

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.

Animals↗
PubMed1989

Human carcinogens so far identified.

The massive exploitation of natural resources, of which tobacco and asbestos are two conspicuous, though very different examples, and the synthesis of industrial chemicals have generated new hazards and new carcinogens which have been added to older ones. The majority of the over 50 agents that have been firmly identified so far as being human carcinogens belong to the relatively new hazards, that is environmental chemicals or chemical mixtures to which humans have been exposed only during the last century and a half. They are of more importance for cancer occurring in men than in women, and there is no evidence so far that they are related to cancers occurring at some of the most common target sites in either sex. It would be mistaken to believe that complete cancer prevention could be achieved solely by controlling these new, or relatively new, carcinogenic agents, but it would be similarly wrong to deny the importance of trying to control them and of continuing to do so. The experimental approach for the identification of carcinogens has an irreplaceable role to play in preventing the dispersal into our environment of new hazards and in identifying among the chemicals already in use, those that are carcinogenic. That a closer integration between the epidemiological and the experimental approaches may succeed in substantially reducing the size of the unknown region within the spectrum of cancer-causing factors, is today's hope that awaits confirmation. At the same time, advances in the understanding of the mechanisms underlying the different steps of the process leading to the clinical manifestation of cancer may help in the uncovering of agents and risk factors that the approaches used, at least in the way they have been used until now, may not have been apt to identify.

Animals↗