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  • 1. Abela, D
    et al.
    Ritchie, H
    Ababneh, D
    Gavin, C
    Nilsson, Mats F
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Niazi, M Khalid Khan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Centrum för bildanalys.
    Carlsson, K
    Webster, WS
    The effect of drugs with ion channel-blocking activity on the early embryonic rat heart2010Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 89, nr 5, s. 429-440Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the IKr/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or IKr/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

  • 2. Beyer, Bruce K.
    et al.
    Chernoff, Neil
    Danielsson, Bengt R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Davis-Bruno, Karen
    Harrouk, Wafa
    Hood, Ronald D.
    Janer, Gemma
    Liminga, Ulla Wändel
    Kim, James H.
    Rocca, Meredith
    Rogers, John
    Scialli, Anthony R.
    ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation2011Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 92, nr 1, s. 36-51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures.

  • 3.
    Nilsson, Mats F
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Helen, Ritchie
    University of Sydney.
    Webster, William S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. University of Sydney.
    The effect on rat embryonic heart rate of Na+-, K+ and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age2013Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 98, nr 5, s. 416-427Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To determine the changes in dependence on ion channels during rat cardiac development we compared the effects of four ion channel blockers on rat embryonic heart function during the organogenic period from gestational day (GD) 10-15. Rat embryos in culture were exposed to either the hERG potassium channel blocker dofetilide (400 nM), the sodium channel blocker lidocaine (250 μM) the L-type calcium channel blocker nifedipine (1.8 μM), or the multi-channel blocker phenytoin (200 μM). Lidocaine slowed the heart rate (HR) with the effect becoming more severe with increasing GD. Dofetilide slowed the embryonic HR and caused arrhythmias with the most severe effect on GD 11-13. Nifedipine primarily caused a negative inotropic effect except on GD 10 when it stopped the heart in most embryos. Phenytoin stopped the heart of most GD 10-12 embryos while on GD 13-15 phenytoin it slowed the heart. The results demonstrate that as the rat heart develops during the organogenic period its functional dependence on ion channels changes markedly. These changes are important for understanding drug effects on the embryo during pregnancy and the methodology used provides a simple procedure for assessing drug effects on the developing heart.

  • 4.
    Nilsson, Mats F.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Webster, William S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro2014Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 101, nr 2, s. 189-198Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-a-go-go-related (hERG)/I-Kr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 mu M), clarithromycin (25-500 mu M), or azithromycin (100 mu M to 1mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1mM. Additional studies were performed with the embryos cultured at 40 degrees C instead of 38 degrees C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human

  • 5. Samsioe, Annika
    et al.
    Feinstein, Ricardo
    Saade, George
    Sjöholm, Åke
    Hörnfeldt, Birger
    Fundele, Reinald
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Klitz, William
    Niklasson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Intrauterine death, fetal malformation, and delayed pregnancy in Ljungan virus-infected mice2006Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 77, nr 4, s. 251-256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: A picornavirus (Ljunganvirus [LV]) has recently been associated with disease during pregnancy in its natural rodent reservoir and in humans. A study of laboratory mice infected under controlled conditions was therefore undertaken. METHODS: CD-1 female mice were infected gestational day two and subjected to varying regimes of stress. RESULTS: LV infection in combination with stress resulted in uterine resorptions, malformations, and neonatal death. A short delay in time to first pregnancy and births was observed in pairs infected in utero. CONCLUSIONS: LV is found in different species of native animals in both Europe and the United States and human epidemiological evidence connects LV and human reproduction, while the observations here indicate that LV is responsible for reproductive problems in a laboratory mouse model. The current findings suggest that the hypothesis that LV also causes disease in pregnant women and their offspring deserves further study.

  • 6. Samsioe, Annika
    et al.
    Sjoholm, Ake
    Niklasson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Klitz, William
    Fetal Death Persists Through Recurrent Pregnancies in Mice Following Ljungan Virus Infection2008Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 83, nr 5, s. 507-510Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: Laboratory mice infected with Ljungan virus (LV) early in pregnancy suffer from perinatal death. Here we investigate the persistence of that effect through the outcome of consecutive pregnancies in LV-infected mice. STUDY DESIGN: CD-1 mice were infected while pregnant and their adult female offspring were followed in parallel with uninfected control mice during repeated pregnancies. Three mating attempts resulted in two or three pregnancies per dam. The outcome of the last pregnancy was carefully monitored. RESULTS: Both the dams infected as adults and their adult female offspring suffered perinatal deaths during the last pregnancy which occurred approximately 6 months after the original LV exposure and acute infection. The non-infected control animals experienced no perinatal death. CONCLUSIONS: Perinatal death persists across recurrent pregnancies in this mouse model of LV infection, both in animals infected as adults and in females exposed to the virus in utero. This implies that LV persists in mice long after intial infection, and is maintained in a quiescent state but can remain pathogenic in later pregnancies. Birth Defects Res (Part B) 83:507-510, 2008.

  • 7.
    Wentzel, Parri
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Altered Gene Expression in Rat Cranial Neural Crest Cells Exposed to a Teratogenic Glucose Concentration In Vitro: Paradoxical Downregulation of Antioxidative Defense Genes2011Ingår i: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 92, nr 5, s. 487-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Diabetic pregnancy is associated with increased risk of malformation in the infant. Diabetes-induced anomalies of the face and heart are strongly correlated with neural crest cell (NCC) maldevelopment. We aimed to study glucose-induced alterations of mRNA levels in cranial and trunk NCCs isolated from rat embryos with increased risk of developing mandibular and cardiac malformations in diabetic pregnancy.

    METHODS: Inbred Sprague-Dawley rat embryos were used for NCC isolation from neural tube explants. The migrating cells were exposed to 5.5 or 30mmol/l glucose concentration for 48 hr, harvested, and prepared for gene expression measurement by RT-PCR or immunostaining with either distal-less (Dlx) or AP-2-alpha antibodies.

    RESULTS: Evaluation of the immunostained slides showed that approximately 75% of the cells were of NCC origin. Exposure to 30 mM glucose decreased mRNA levels of Copper-Zinc superoxide dismutase, manganese superoxide dismutase, extracellular superoxide dismutase, Catalase, Gpx-1, Nrf2, poly-ADP ribose polymerase, B-cell leukemia/lymphoma protein 2, and beta-Catenin genes in cranial neural crest explant cultures. In addition, Pax-3, Pax-6, Wnt3a, and Apc mRNA levels were decreased by high glucose exposure in both cranial and trunk neural crest explant cultures.

    CONCLUSION: Cranial NCCs diminish their mRNA levels of antioxidative enzymes and the Nrf2 response factor, as well as the antiapoptotic B-cell leukemia/lymphoma protein 2 gene, in response to increased ambient glucose concentration. Furthermore, both cranial and trunk NCC decrease the mRNA levels of the transcription factors Pax-3 and Pax-6, as well as key components of the Wnt pathway. These patterns of glucose-altered gene expression in a developmentally important cell population may be of etiological importance for NCC-associated malformations in diabetic pregnancy.

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