Transplacental effect of nitrosamines in Syrian hamsters

Summary The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4–6 h after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F₁- than in the P-generation and comparatively longer latencies were also observed in the F₁-generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.

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Transplacentare Wirkungen von Nitrosaminen bei HamsternIV. Metaboliten von dipropyl- und dibutylnitrosamin

Zusammenfassung Die Untersuchungen haben gezeigt, daß angenommene sowie gefundene Metaboliten des Dipropyl- und Dibutylnitrosamins die Feten Syrischer Hamster via Placenta nach subcutaner (s.c.) Behandlung der Muttertiere (14. Tag der Tragzeit) erreichen. Die Verbindungen (2-hydroxypropylpropylnitrosamin, HPPN; 2-oxopropylpropylnitrosamin, OPPN; methylpropylnitrosamin, MPN; N-nitrosobis(2-hydroxypropyl)amin, BHP; 4-hydroxybutylbutylnitrosamin, HBBN) waren noch 4–6 Std nach subcutaner Injektion in den untersuchten Geweben (mütterliches Blut, Placenta, Fetus, Fruchtwasser) nachweisbar. Die allgemeine Tumorhäufigkeit transplacentar induzierter Tumoren war geringer in der F₁- als in der P-Generation, während vergleichsweise die Latenzzeiten verlängert waren. Darüber hinaus fanden sich jedoch Geschwülste in geringer Häufigkeit bei einigen Gruppen, die bei Muttertieren nicht gefunden wurden (Nasenhöhle: BHP, HBBN; Trachea: HBBN; Lunge: HPPN, BHP, HBBN; Leber: OPPN, MPN, BHP, HBBN). Für den Laryngo-Tracheal-Trakt erhöhte sich die transplacentare carcinogene Wirkung nach Behandlung am 14. Tag der Tragzeit in Vergleich zur Exposition an einem früheren Zeitpunkt der Gestation. Tumoren anderer Organe wurden nicht auf eine transplacentare Wirkung der untersuchten Nitrosamine bezogen.

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Supported by U.S. Public Health Service Contract NO1 CP33278 from the Division of Cancer Cause and Prevention, National Cancer Institute

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We thank Nancy Hays for technical assistance and Mardelle Susman for editorial aid.     

Transplacental oncogenic effect of ethylnitrosourea in rabbits (author's transl)]

50 mg/kg ethylnitrosourea (ENU) per dose, diluted in a 0.9%NaCl/1%NaH2PO4 solution (pH 6.2) were administered intravenously to three pregnant rabbits. The injections were carried out on the following days of gestation: 21., 26., and 30./21., 25., and 31./22., 25., and 30. From the total offspring (22), 16 rabbits could be raised. In 12 animals, kidney tumours were observed after a latent period of 2--2 1/2 years. The induced tumours are generally composed of both epithelial and mesenchymal tissue elements. Two tumours of the series are of a pure epithelial or a pure mesenchymal nature respectively. In most of the mixed tumours, classified as Adenocarcino-Sarcomas (10), the epithelial and mesenchymal elements are closely integrated, sometimes one component predominated over the other one. Histologically the ENU-induced mixed tumours of kidney in rabbits and the "dysontogenetic" kidney tumours of children (WILMS) show comparable structural characteristics.     

Transplacental transmission and fetal parasitosis of Trypanosoma cruzi in outbred white Swiss mice.

Two strains of Trypanosoma cruzi, isolated from humans and assayed for their biological capacity to kill outbred white Swiss mice (HaM/CR-CD) following reticuloendothelial system blockade with thorium dioxide, were used in these experiments: the Maria Cristina strain, which killed all blocked mice at a rate following a rectangular dose-response curve, and the José Cardoso strain, which did not kill blocked mice at comparable dosages. When inoculated into pregnant HaM/CR-CD mice, the non-pathogenic José Cardoso strain did not cross the placental barrier, in either blocked or unblocked mice, to cause fetal parasitosis. The pathogenic Maria Cristina strain did not cross the barrier in non-blocked mice, but in thorium-dioxide blocked mice it produced an incidence of fetal parasitosis of 8.9% (7 of 79 fetuses). These results indicate that the transplacental transmission of T. cruzi was dependent on two restrictions: pathogenicity of the strain of T. cruzi, and blockade of phagocytic activity by thorium dioxide, suggesting that transplacental transmission of T. cruzi is related to interference with the phagocytic activity of the placenta.     

Transplacental transfer of human antinuclear antibodies in mice by injection of lupus IgG in pregnant animals

Pregnant female Balb/c mice were injected with IgG fractions from patients with systemic lupus erythematosus, in order to study the in vivo passage of antinuclear antibodies (ANA) across the placenta. After injection of monospecific sera directed against nDNA, Sm, nRNP, Ro(SSA) and La(SSB), ANA were found in fetal circulation and trapped in the liver, spleen kidney and skin of fetus. Also, ANA were demonstrated in placental tissue and cord. The placental IgG-Fc receptors apparently played a major role in ANA entry into the fetus. Our study demonstrates that human ANA can be passively transferred into experimental animals to study their kinetics during pregnancy.     

Transplacental effect of nitrosamines in Syrian hamsters. IV. Metabolites of dipropyl- and dibutylnitrosamine.

The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4--6 h after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F1- than in the P-generation and comparatively longer latencies were also observed in the F1- generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.     

Transplacental effects of nitrosamines in Syrian hamsters

Summary The aliphatic nitrosamines dimethylnitrosamine (DMN), diethylnitrosamine (DEN), dipropylnitrosamine (DPN), and dibutylnitrosamine(DBN) reached fetal tissue in quantitatively measurable amounts after subcutaneous administration to pregnant Syrian hamsters. The compounds were present for at least 2 h in maternal blood, placenta, fetus, and amniotic fluid; DBN was still measurable after 6 h. Only a weak or borderline transplacental effect was seen when incidences and latencies of neoplasms in the respiratory and digestive tracts of the F₁-generation were compared with those of the P-generation after exposure to a single dose of DMN or DPN. However, some tumor types occurred at relatively high rates in the young, but were seen only occasionally in their mothers or in this hamster colony in general.

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Transplacentare Effekte von Nitrosaminen in Syrischen HamsternIII. Dimethyl- und Dipropylnitrosamin

Zusammenfassung Die aliphatischen Nitrosamine Dimethylnitrosamin (DMN), Diäthylnitrosamin (DEN), Dipropylnitrosamin (DPN) und Dibutylnitrosamin (DBN) erreichen nach subcutaner Verabreichung an trächtige, Syrische Hamster in quantitativ bestimmbaren Mengen das fetale Gewebe. Die Verbindungen waren im mütterlichen Blut, in Placenta, Fetus und Fruchtwasser wenigstens 2 Std nachweisbar; DBN zeigte meßbare Werte noch nach 6 Std. Der Vergleich der Häufigkeit und Latenzzeit der Tumoren, die in den Luftwegen und im Verdauungstrakt der F₁-Generation gefunden wurden, mit denen in der P-Generation nach Behandlung mit einer Einzeldosis von DMN oder DPN ließ nur eine schwache oder grenzwertige, transplacentare Wirkung erkennen. Jedoch entwickelten sich bei den Jungen einige Tumorarten, die nur gelegentlich bei den Müttern oder anderen Hamstern dieser Kolonie gefunden wurden.

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Supported by U.S. Public Health Service Contract NO1 CP33278 from the National Cancer Institute, NIH

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The authors thank K.Muffly and D. Ogrowsky for technical assistance, J. Villareal for graphic illustration and M. Susman for editorial help     

Transplacental Passage of Foetal Blood Cells

With the brightly fluorescent Y chromatin as a marker, the proportion of foetal lymphocytes in maternal blood was found to be 0.02 - 0.16 % in 7 of 11 primigravidae bearing a boy, but not a single XY mitosis was found among 112,000 leucoagglutinin-stimulated mitoses from the same women. The proportion of foetal lymphocytes did not change appreciably during pregnancy (first appearance detected at 15 weeks' gestation), nor were there any unequivocal foetal erythrocytes in spite of ABO and Rh compatibility. These findings suggest that foetal lymphocytes pass actively into the mother's blood relatively early during pregnancy. The cells are protected from immunological elimination, and therefore may remain in the maternal blood for long periods. They are a valuable potential source of material for antenatal foetal diagnosis.     

Transplacental transport of N-acetylcysteine in an ovine model

STUDY OBJECTIVE: Acetaminophen freely crosses the placenta, and acetaminophen ingestion is the most frequent intentional overdose in pregnancy. Although most patients do well after maternal treatment with the antidote N-acetylcysteine (NAC), fetal death with massive hepatic necrosis has occurred. It has never been shown whether NAC crosses the placenta to yield fetal plasma levels equal to those associated with hepatoprotective effects in human beings. Our study objective was to evaluate this in a widely accepted large animal model for maternal-fetal research. DESIGN AND TYPE OF PARTICIPANTS: A nonblinded experiment was performed using four domestic sheep at near-term gestation. INTERVENTIONS: NAC 150 mg/kg IV was administered to the ewe over 15 minutes. After induction of anesthesia, the fetal head was delivered surgically and a neck vein cannulated for blood sampling. Maternal and fetal blood samples were obtained at the end of NAC infusion, at 30- and then at 60-minute intervals for four hours. Plasma NAC levels were determined by gas chromatography/mass spectroscopy (detection limit, 2 micrograms/mL; quantification limit, 5 micrograms/mL). RESULTS: Maternal peak plasma NAC levels were 619, 631, 1,757, and 2,512, micrograms/mL, respectively, within 30 minutes of infusion. However, NAC was only minimally detectable in plasma of two fetal animals and transiently reached quantifiable levels in two others. None of the fetal animals attained serial plasma NAC levels that equalled those associated with therapeutic dosing or hepatoprotective effects in human beings. CONCLUSION: Transplacental transport of NAC is clinically insignificant in a mammalian model resembling the human being. These findings suggest that the human fetal liver is not protected from acetaminophen toxicity by maternal NAC therapy.     

Transplacental passage of autoantibodies to triiodothyronine.

Autoantibodies to T3 (T3Ab) were detected by immunoprecipitation in a 18-year-old female patient affected by Graves' disease. The presence of these antibodies was constantly confirmed during a 7-year follow-up period, independently of therapy and functional thyroid status. Antithyroid microsomal antibodies (McAb) and TSH binding-inhibiting antibodies (TBII) were also present. The title of AbT3, McAb and TBII fluctuated, at times, independently of one another. The patient became pregnant; during pregnancy T3Ab concentration fell and went up again 4 months after delivery. A normal baby was born. T3Ab were present in the cord blood and declined during the following 2-8 months. The T3Ab of both mother and child belonged to the IgG class. The concentrations and the binding affinities of T3Ab in mother and child were identical. The presence of T3Ab in the child did not affect his thyroid function.     

Hypoglycaemic effect of AICAriboside in mice

Summary We have previously demonstrated that in isolated hepatocytes from fasted rats, AICAriboside (5-amino 4-imidazolecarboxamide riboside), after its conversion into AICAribotide (AICAR or ZMP), exerts a dose-dependent inhibition on fructose-1,6-bisphosphatase and hence on gluconeogenesis. To assess the effect of AICAriboside in vivo, we measured plasma glucose and liver metabolites after intraperitoneal administration of AICAriboside in mice. In fasted animals, in which gluconeogenesis is activated, AICAriboside (250 mg/kg body weight) induced a 50% decrease of plasma glucose within 15 min, which lasted about 3 h. In fed mice, glucose decreased by 8% at 30 min, and normalized at 1 h. Under both conditions, ZMP accumulated to approximately 2 μmol/g of liver at 1 h. It decreased progressively thereafter, although much more slowly in the fasted state. Inhibition of fructose-1,6-bisphosphatase was evidenced by time-wise linear accumulations of fructose-1,6-bisphosphate, from 0.006 to 3.9 μmol/g of liver at 3 h in fasted mice, and from 0.010 to 0.114 μmol/g of liver at 1 h in fed animals. AICAriboside did not significantly influence plasma insulin or glucose utilization by muscle. We conclude that in vivo as in isolated hepatocytes, AICAriboside, owing to its conversion into ZMP, inhibits fructose-1,6-bisphosphatase and consequently gluconeogenesis.     

Transplacental transfer of schistosomal circulating anodic antigens in cows

The present work investigated the transplacental passage of circulating anodic schistosome antigens (CAA) and the production of foetal antibodies in response to antigenic stimulation in Schistosoma mattheei infected cows. Three groups were available: six calves born to non-infected cows received colostrum from a pool from non-infected cows (group 1), six calves born to non-infected cows (group 2) and six calves born to infected cows (group 3) received colostrum from a pool from infected cows. Schistosoma-specific IgG1 antibody and CAA levels were measured in the colostrum pools, the sera collected from the cows, and the sera collected from the calves at birth, after intake of colostrum and at day 30. The specific IgG1 antibody levels were significantly higher in the sera from cows of group 3. In four cows of group 3 high CAA levels were detected. The specific IgG1 antibody levels were 0.646 and 0.176 OD for the infected and non-infected colostrum pool, respectively, and the CAA levels were 5667 and 2557 pg CAA/mL, respectively. At birth high levels of specific IgG1 antibody and CAA were detected in 4 calves of group 3; levels in the other two calves were negligible. After intake of colostrum, specific IgG1 antibody levels of group 1 increased slightly at day 1 to become again insignificant at day 30. In group 2 specific IgG1 antibody levels increased significantly between days 0 and 1, to decrease, although not significantly, at day 30. Finally, in group 3 the delta OD values increased at day 1 and remained high until day 30. After intake of colostrum the CAA level increased very slightly for groups 1 and 2 to become again undetectable at day 30. In group 3 a nonsignificant decrease in CAA levels was observed at day 1 followed by a further significant decrease to reach low levels at day 30. The suggested intrauterine antigenic stimulation may be important not only for generating immune responses to natural early infections, but also for enhancing the immunogenicity and efficacy of vaccines administered to newborns.     

Transplacental passage of protease inhibitors at delivery

OBJECTIVE: Although combinations of different antiretroviral drugs are increasingly used by pregnant HIV-1-infected women, few human data are available to evaluate in utero protease inhibitors (PI) exposure. The aim of this study was to assess the extent of transplacental passage of PI at delivery. METHODS: Pregnant women treated with antiretroviral drugs including PI and/or nevirapine were eligible for the study. Placental transfer was determined by comparison of drug concentrations in blood samples simultaneously collected from a peripheral maternal vein and the umbilical cord at delivery. Drug levels were determined by high-performance liquid chromatography. RESULTS: Thirteen maternal-cord blood sample pairs were evaluable for transplacental passage determination (nine nelfinavir, two ritonavir, one saquinavir, one lopinavir, two nevirapine). Median cord and maternal drug concentrations, respectively, were nelfinavir < 250 and 1110 ng/ml; ritonavir < 250 and 1113 ng/ml; saquinavir < 100 and 350 ng/ml; lopinavir < 250 and 3105 ng/ml and nevirapine 2072 and 2546 ng/ml. The cord-to-maternal blood ratio was extremely low for all PI. CONCLUSION: PI do not cross the placenta to an appreciable extent and consequently cannot be expected to exert a direct antiviral activity in utero during the whole dosing interval. Limited transfer may result from their high degree of plasma protein binding and their backwards transport through P-glycoprotein, largely expressed in the placenta. In contrast, nevirapine readily crosses the placental barrier. Such considerations may support treatment decisions in pregnant women.