Biomedical subjects
Publications and source records attributed to H Tuchmann-Duplessis.
The development of the mammalian embryo can be impaired by physical and chemical exogenous agents, leading to congenital malformations or tumours. These accidents represent at present the main cause of perinatal mortality and postnatal morbidity. The principles of teratogenicity and of transplacental cancers are analysed and the therapeutical implications of the prenatal pathology are examined.
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Most studies for determining the reproductive toxicity of a chemical have to be conducted with whole animals. Test procedures used to investigate parts or the whole of the reproductive cycle are described in current guidelines. Other techniques, such as in vitro methods, and those for investigating specific events in the cycle, are under development. Epidemiological studies can give valuable information, although they are difficult to perform and interpret in practice. There is a need for more epidemiological studies of exposed populations and for recording and quantifying the concentrations of chemicals to which such populations are exposed. It is suggested that animal experiments should be programmed in a stepwise manner, and should take into account effects seen in previous toxicity studies. The programme of tests for determining reproductive toxic potential should be established on a case-by-case basis, since many factors will influence the choice of studies and the sequence in which they should be performed.
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Reproduction can be impaired in animals and man by drugs and various environmental agents. Depending on the time of exposure--from fertilization through the fetal period and eventually during lactation--the consequences can range from embryotoxicity, gross malformations and a large variety of more subtle morphological, biochemical, and functional abnormalities. The high susceptibility of the embryo to exogenous agents is due to cellular multiplication and differentiation and to the lack of development of the enzyme systems necessary for the detoxification of chemicals. At present, developmental impairments represent the main cause of perinatal mortality and postnatal morbidity. After a review of prenatal physiology and teratogenic principles, the action of selected drugs and environmental agents is analyzed. The potential danger of environmental factors during intrauterine development is of particular concern because of its irreversible nature.
A study of the potential biological effects of veralipride was conducted in female rats. A definite stimulating action on the mammary gland was noted, but doses of 5 to 20 mg/kg/day are required to produce secretion, which is varying from one animal to another. Follicular maturation is preserved, though there is an increase in the number of corpora lutea with more marked development in some of them. Progesterone impregnation of the uterus occurs in a variable way and then only at doses of 5 + 0 20 mg/kg/day. Vaginal mucification, from a reduction in estrogen in relation to progesterone impregnation, is noted after 1 mg/kg/day (though 25 p. cent of the animals still demonstrate vaginal keratinization after 20 mg/kg/day). Finally, degranulation of the carminophile cells of the anterior pituitary gland, occurs after 5 mg/kg/day.
When orally administered, 5-(3-diméthylamino propyliden)-benzofuro [2,3-c] benzoxepin-1, which antagonizes several biogenic amines, is slightly sedative and has also endocrinological properties in the Rat, induces the appearance of localized lesions of uterine stroma in 2 to 16% of the animals. The cytological picture could suggest a tumorogenesis. In fact, these lesions represent a non-tumoral reactional hyperplasia with nuclear abnormalities due to a hormonal stimulation.
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Maternal, foetal and peri- and post-natal toxicity studies of a hypolipidaemic agent, 2-[p-(2,2-dichlorocyclopropyl)phenoxy]-2-methyl propionic acid (WIN 35833), were performed on different animal species during animal evaluation of this new drug. In teratology studies in rats, mice and rabbits, no adverse effects were detected following drug exposure during the organogenesis period. In peri-natal studies, a neonatal abnormality related to treatment just before term was shown in rats. This modification, previously observed with other hypolipidaemic drugs, seems to be species specific and characteristic of compounds in the aryloxyalkanoic acid series.
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Prostaglandin F2alpha is not teratogenic in the Rat. The frequency of abortions increases after implantation. Between day 9-14, 100% of abortions are observed. Progesterone, aspirine, or indomethacine are incapable of preventing the abortions induced by prostaglandin F2alpha.
Prostaglandin F2alpha determines a high proportion of abortions in the mouse when administered before implantation at a dose level of 2 mg/kg. After implantation between days 6-8 or 7-9, doses 20 times higher are necessary to produce the effect. Daily progesterone administration, 5 mg per animal, from day 1 to day 17 allow the evolution of pregnancy in 60% of the mice even when 120 mg/kg prostaglandin is given. This dose determines usually 100% abortions. No teratogenic effect has been observed.
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Acetylsalicylic acid (ASA) administration (200 mg/kg/day) during the last six days of pregnancy in the rat has been observed to result in: (a) a prolongation of the duration of pregnancy; (b) a prolongation of the parturition time; (c) the appearance, in some individuals, of dystocia with possible secondary death of foetuses in utero.
Suramine, a trypanocidal drug, has an embryo-lethal and teratogenic action in Rodents. Like Triton W.R. 1339 suramine modifies the lysosomes of the visceral yolk sac. In the mouse the attempts to correct the embryolethal action by a simultaneous progesterone treatment failed while the hormonal treatment is capable to suppress the embryolethality in Triton W.R. 1339 treated mice.