الفهرس 
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Abstract
Caffeine is the most widely consumed behaviorally active substance in the world. Caffeine is present in a number of dietary sources, i.e., tea, coffee, cocoa beverages, chocolate bars, and soft drinks. Caffeine absorption from the gastrointestinal tract is rapid and reaches a high level in humans in a limited time after ingestion. The hydrophobic properties of caffeine allow its passage through all biological membranes in adults or foeti. In pregnancy, caffeine is the most widely consumed xenobiotic with the potential to adversely affect the developing fetoplacental unit. Maternal caffeine intake has been reported to be associated with a reduction in birth weight but the precise level of intake above which the risk is increased remains unknown. Caffeine is rapidly absorbed and crosses the placenta freely and the cytochrome P450 1A2 which is the principal enzyme involved in caffeine metabolism is absent in the placenta and the fetus.
Vitamin A (all-trans-retinol), a fat-soluble vitamin, is an essential nutrient for humans because it cannot be synthesized de novo. The vitamin is a group of unsaturated nutritional organic compounds that includes retinol, retinal, retinoic acid and several provitamin A carotenoids, among which beta-carotene is the most important. The molecule is involved in all normal cellular proliferation and differentiation processes. Particularly, vitamin A and its derivatives are required for several processes, including embryogenesis, vision, reproduction, skeletal development and maintenance of epithelial tissues. The vitamin is stored primarily in the liver and it is transported in plasma bound to a small protein molecule the retinol-binding protein. The combination of relatively rapid absorption with a low clearance can produce acute toxicity within hours after a sufficiently high dose and chronic toxicity after prolonged intake of substantially smaller doses. Excessive administration of vitamin A and its derivatives can lead to fibrosis in the Disse space and obstruction of sinusoidal blood flow, causing non-cirrhotic portal hypertension and hepatocellular dysfunction.
from the data above, it is clear that both of caffeine and vitamin A sharing: - 1) A rapid absorption and decreased clearance during pregnancy and in new born 2) Ease of placental transfer without degradation 3) Adverse effects on fetoplacental unit, skeleton and visceral organ. So, the aim of the present study was to find out further details relationship effects to resolve the controversy between the psychoactive-ergogenic food item (caffeine) and hypervitaminosis A in developing embryos and neonates as their dams consume these substances during pregnancy and lactation. Also, early feed pups were included as they become fed independently. To achieve this goal, experimental design was conducted in which pregnant animals were dosed with caffeine, retinoic acid either separate or in combination at the beginning of the second trimester. At the onset of the third trimester and at the end of pregnancy, embryos were obtained and processed for examination at both the morphological, histological and immunohistochemical study to follow up skeleton, liver and kidney development at the prenatal period of study. Also, liver and kidney of postnatal up to six weeks were included.
Results did not revealed morphological abnormalities in either caffeine or retinoic acid in the developing embryos at 14th day of gestation whose mother’s administered caffeine (2 mg/100g b. w.) or whose mother’s treated with retinoic acid even at 4mg/kg b. w. dose during the onset of the second trimester of pregnancy. However, dose-dependent retinoic acid treatment initiate chondrocyte vacuolation, depression of PAS +ve intracellular inclusions and depression of nuclear fluorescence that concomitant with downregulation of TGFβ2 expression in the perichondrium of the developing vertebrae. Co-administration of caffeine was found to ameliorate the effects of low 2 mg/kg b. w. rather than the high dose 4 mg/kg b. w. of retinoic acid. At 18th day of gestation the uterine horns appeared normal without any signs of fetoresorption in all treatments. However, the effect of both caffeine (2 mg/100g b. w.) and retinoic acid at both doses 2&4 mg/kg b. w. in Alizarin Red stain of whole mount revealed malformed phalanges of the developing limbs either in separate or in combined treatments.
In the liver, the study revealed that the fetal liver at 14th day of gestation, at the histological level can be compared to adult bone marrow, hyperchromatic hemopoietic progenitor and the polyploidy megakaryocytes (the platelet forming cells) were well observed. Caffeine and retinoic acid dosing during pregnancy results in altered and dose-dependent deformation of megakaryocyte differentiation and function as expressed in H&E and PAS stained sections. Concomitant fluorescence depression of hepatoblastes and downregualated expression of TGFβ2 in the developing liver were noted that relatively recovered in combined treatment with caffeine and retinoic acid in a dose-dependent manner in the prenatal period at 14,18 days of development. At postnatal during suckling and after weaning in control increased percentages of binucleated hepatocytes from the 3rd to the 6th week were noted. Decreased percentages of binucleated hepatocytes were observed in all treatments with concomitant polyploid giant nuclei induction compared to control. Giant nuclei inductions in either caffeine, retinoic acid or in the combined treatments reflect their ability to suppress cell proliferation through inducing incomplete cytokinesis resulting in polyploidy. However, the present study revealed that caffeine administration from the 3rd to the 6th week during the independent feeding induces inflammatory cell infiltration and deposition of collagen. A drawback effect of caffeine that is controlled in co-treatment with retinoic acid at both doses used in the present study. Concomitantly, in either the pre- or the postnatal period of study, caffeine was able to perturb carbohydrates, increase calcium and decrease iron those accompanied with downregulated expression of TGFβ2 in hepatic tissue as compared to control. Treatment with retinoic acid at both doses in the present study either separate or combined with caffeine upregulate calcium against suppression of iron. Moreover, TGFβ2 show biphasic effect that severely downregulated during gestation and extended to express intranuclear at postnatal in liver tissue.