Congenital malformations and transplacental cancers.

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.

Identification and assessment of the effects of chemicals on reproduction and development (reproductive toxicology).

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.

Oxetorone-induced hyperprogesteronemia and the development of uterine decidual lesions in rats.

Application of the deciduoma formation test showed that 3-benzofurol[3,2-c][1] benzoxepin-6(12H)-ylidene-N,N-dimethyl-l-propanamin-(E )-2-butenedioate (1:1) (oxetorone, L-6257, Nocertone) stimulated secretion of progesterone by the ovaries in rats and that this hyperprogesteronemia resulted from an increased secretion of prolactin. The studies carried out also showed that the apparition of uterine decidual lesions observed in certain animals undergoing chronic oxetorone treatment was linked to this hyperprogesteronemia. In view of the specific physiology of prolactin in rodents, such uterine lesions can only develop in these animals and cannot occur in man.

The teratogenic risk.

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.

[Effect of veralipride on the estral cycle, genital tract, mammary gland and pituitary gland in female rats (author's transl)]. / Etude de l'action du véralipride sur le cycle oestral, le tractus génital, la glande mammaire et l'hypophyse de la ratte.

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.

[Pseudotumoral uterine reaction in the rat treated with a benzofuro-benzoxepin]. / Réaction utérine pseudo-tumorale chez le rat soumis à l'action d'une benzofuro-benzoxepine.

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.

Post natal side effects in rats induced by hypolipidaemic treatment during pregnancy.

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.

[Action of prostaglandin F2 alpha on pregnancy in mice. Prevention of its abortive property by progesterone]. / Action de la prostaglandine F2alpha sur la gestation de la Souris. Prévention du pouvoir abortif par la progestérone

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.

[Endocrinotropic actions of the benzamide sultopride (author's transl)]. / Propriétés endocrinotropes d'une benzamide, le sultopride

The influence on the pituitary hypothalamic system of Sultopride are different of those of a chemically related compound, Sulpiride. In the mammary gland the development of the acini is associated with an increase of the connective tissue. The processus of secretion, lactogenesis is quiet not stimulated. The changes on the anterior lobe of the pituitary involve the carmino and eosinophilic cells. This modification seems to reflect a stimulation of the secretion of LT and an inhibition of the release of STH. In the juvenile rat, Sultopride determines an inhibition of the somatic growth.

[The effect of prostaglandin F2alpha on pregnancy in rats and attempts to counteract its abortifacient action]. / Action de la prostaglandine F2alpha sur la gestation de la Ratte et essais de prévention du pouvoir abortif

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.