Adverse effects of prolonged administration of caffeine on rat fetus

doi:10.1016/0041-008X(72)90252-9

Toxicology and Applied Pharmacology

Volume 22, Issue 3, July 1972, Pages 449-457

https://doi.org/10.1016/0041-008X(72)90252-9 Get rights and content

Abstract

Caffeine was mixed in a diet at 0.25 or 0.50% by weight and given to rats throughout or during each of selected periods of gestation. Near term fetuses were examined for external, visceral and skeletal abnormalities. Fetal blood obtained from the umbilical vein was examined for nucleated red blood cells. Maternal blood obtained from the abdominal aorta was also examined for cholesterol concentration. The major findings were as follows: (1) the effects of caffeine on the fetus appeared dependent on the time of administration during gestation; (2) a high incidence of fetal resorption and occurrence of certain types of gross, visceral and skeletal abnormalities of live fetuses were found when the compound was given throughout or during the middle stage of pregnancy; (3) generalized edema was present in the majority of fetuses when caffeine was given throughout or during the late stage of pregnancy. The severity and frequency of edema were clearly dose dependent; (4) ossification was delayed in all the treatment groups, and the delay was more severe in the fetuses with edematous change; (5) increase of normoblasts in the fetal blood was found in the group where fetal edema was manifested; and (6) the average cholesterol concentration in the maternal blood serum measured near term was higher in the animals treated throughout pregnancy than in the controls, although the difference was not significant.

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The teratogenic effect of caffeine has been clearly demonstrated in rodents. The sensitivity of different animals species is variable. Malformations have been demonstrated in mice at 50–75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats. However, when caffeine is administered in fractioned amounts during the day, 330 mg/kg/day are necessary to reach teratogenicity in rats. In rodents, the most frequently observed malformations are those of the limbs and digits, ectrodactyly, craniofacial malformations (labial and palatal clefts) and delays in ossification of limbs, jaw and sternum. Nevertheless, even in rodents, caffeine can be considered as a weak teratogenic agent, given the quite large quantities of caffeine necessary to induce malformations and the small number of animals affected. In humans, caffeine does not present any teratogenic risk. The increased risk of the most common congenital malformations entailed by moderate consumption of caffeine is very slight. However, caffeine potentiates the teratogenic effect of other substances, such as tobacco, alcohol, and acts synergistically with ergotamine and propranolol to induce materno-fetal vasoconstrictions leading to malformations induced by ischemia. Therefore, even though caffeine does not seem to be harmful to the human fetus when intake is moderate and spread out over the day, some associations, especially with alcohol, tobacco, and vasoconstrictive or anti-migraine medications should be avoided.
Maternal consumption of caffeine affects brain composition, especially in case of a low-protein diet and also seems to interfere with zinc fixation in brain. Maternal exposure to caffeine induces also long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety in rat offspring, whereas in humans, more studies are needed to ascertain long-term behavioral effects of caffeine ingestion by pregnant mothers.
Ossification of the vertebral column in the offspring of rats exposed to alcohol, acetaldehyde and caffeine
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The embryopathic effects of alcohol have been widely studied in humans and laboratory animals. However, the role of risk factors remains largely unknown. Whereas skeletal abnormalities are often present in the offspring of alcoholic mothers, these have not been fully documented. This report is concerned specifically with the development of the vertebral column in rats exposed in utero to ethanol, its primary metabolite acetaldehyde, and caffeine. Our results indicate a possible causal association between alcohol abuse and ossification anomalies of the vertebral column. Maternal treatment with caffeine accelerated ossification in the sacro-caudal vertebrae. Caffeine combined with ethanol only moderately affected the development of the centra and arches.
Behavioral and biochemical consequences of perinatal exposure of mice to instant coffee: A correlative evaluation
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In the present study, the lasting effects of prepartum and perinatally consumed instant coffee by female mice on the behavior as well as on the level of activities of certain enzymes in the tissues of their male offspring have been investigated. The behavioral observations of nonsocial investigation, defense, displacement, latency to threat and naso-nasal contact has decreased significantly in offspring of treated mothers, while the threat, attack, latency to threat and attack and number of fights have increased significantly. Hence, coffee has proven to be an inducer of hyperactive behavior in these offspring. Such effects are both dose dependent and duration-of-treatment dependent. Moreover, variations were detected in the level of AChE activity in the brain tissues of these offspring together with variations in the levels of AcPase and AlPase activities in their liver, kidneys and testes. Such variations in these organs have developed in utero, making these enzymes convenient markers in teratological studies.
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Rats whose mothers had been treated with 1 microgram of arginine vasopressin (AVP) or oxytocin (OXT), 15 mg of caffeine, or saline on days 13–19 of gestation were given training on a passive avoidance response as adults. Female rats whose mothers had been exposed to either AVP or caffeine demonstrated enhanced retention of the response. No effects were found for male rats or for exposure to oxytocin. These results suggest that prenatal exposure to AVP or caffeine produced sexually dimorphic effects on learning and that the effects are specific to the structure of AVP.
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1987, Toxicology Letters
Caffeine metabolism to 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was studied in the isolated, perfused rat liver. The [2-¹⁴C]-labelled drug and metabolites were separated by thin-layer chromatography or high-pressure liquid chromatography. The chemical structure of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was confirmed by mass spectrometry and it was quantitatively determined by liquid scintillation counting. 6-Amino-5-[N-methylformylamino]-1,3-dimethyluracil is one of the major metabolites of caffeine found in the perfusion medium. The kinetics of caffeine elimination and of the uracil metabolite formation were studied up to 2 h perfusion time using livers from control rats and rats pretreated with phenobarbital, β-naphthoflavone or 3-methylcholanthrene. Phenobarbital pretreatment did not modify the rate of caffeine elimination or the extent of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil formation. In contrast, there was a highly significant inducing effect on both drug elimination and formation of the uracil metabolite in perfusions of livers from β-naphthoflavone- and 3-methylcholanthrene-pretreated animals.

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Adverse effects of prolonged administration of caffeine on rat fetus

Abstract

Jap. J. Pharmacol.

J. Nutr.

Amer. J. Ophthalmol.

Toxicol. Appl. Pharmacol.

Sur un effect tératogène systématique et spécifique de la caféine chez les Rongeurs

C. R. Soc. Biol.

The teratogenic effect of the steroid nucleus in the rat

J. Dent. Res.

A note on the staining of the skeleton of cleared specimens with alizarin red S

Stain Technol.

Caffeine and nicotine penetrate the pre-implantation blastocyst

Nature (London)

Beitrage zur Frage der Fruchtschadigung beim Kaninchen

Z. Mikrosk. Anat. Forsch.

Teratogenic actions of some methylated xanthines in mice

Okajimas Folia Anat. Jap.