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An evaluation of Ciprofloxacin toxicity in the neonatal minipig
Abstracts / Toxicology Letters 172S (2007) S1–S240
D02 Developmental neurotoxicity of propylthiouracil in rats Marta Axelstad 1, , Pernille Hansen 1 , Sofie Christiansen 1 , Christine Nellemann 1 , Karin Sørig Hougaard 2 , Søren Peter Lund 2 , Ulla Hass 1 1 Department
of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Copenhagen, Denmark; 2 National Research Centre for the Working Environment, Copenhagen, Denmark It has been known for a long time that markedly lowered thyroid hormone levels during development can have severe consequences for the intellectual, behavioural and auditory development of the child. However, recent studies indicate that even small changes in the mother’s thyroid hormone status early in pregnancy may cause adverse effects on the offspring. This has led to increased concern about thyroid hormone disrupting chemicals (TDCs) in our environment. We have studied how developmental exposure to the known antithyroid agent propylthiouracil (PTU) affects the development of rat pups. The overall aim was to provide detailed knowledge on the relationship between effects on thyroid hormone levels and long-lasting developmental neurotoxicity effects. Groups of 16–18 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/(kg day)) from gestation day 7 to postnatal day (PND) 16 and the development and behaviour of the offspring was assessed. Measurements of thyroid hormone levels during the dosing period showed that both dams and pups in the higher dose groups had markedly lowered T4 levels, but these levels normalized shortly after dosing had stopped. The tested endpoints all showed statistically significant changes in the high dose group. Pup motor activity levels were lowered on PND 14, while they were elevated on PND 23 and in adulthood, and auditory function in adult animals was impaired. Generally the results showed that PTU exposure and the resulting hypothyroxinemia influenced behaviour and hearing function. This supports that exposure to TDC’s in general may cause long-lasting developmental neurotoxicity. doi:10.1016/j.toxlet.2007.05.451
S177
D03 Effects of maternal 4-tert-octylphenol exposure on hematology and histopathology of the liver, kidney and spleen of adult female rats M¨ufide Aydogan, Nurhayat Barlas Department of Biology, Faculty of Science, University of Hacettepe, Ankara, Turkey Over the past two decades, many chemicals in the environment have been identified as environmental estrogens. 4-tert-Octylphenol (OP) is an estrogenic compound. In the present study, we investigated the effects of fetal octylphenol (OP) exposure on the liver, kidney, spleen and hematological parameters at adulthood. Female rats were treated with OP in uteri at doses of 0, 0 (vehicle), 100 or 250 mg/kg bw/day. After birth, female rats were allowed to grow until adulthood and then liver, kidney and spleen were investigated histopathologically. The blood samples were collected from hearts and analysed for hematological parameters. The absolute kidney weight, the absolute and relative spleen weights in OP treatment group was decreased compared with the control group. There were no significant differences in relative liver weight and body weight among groups. The hemosiderin deposition was increased in 250 mg/kg bw/day OP treatment group. The red blood cells and platelets were decreased in 250 mg/kg bw/day OP treatment group compared with the control group. Mean corpuscular hemoglobin of was increased in 250 mg/kg bw/day OP treatment group. Our findings of this study indicate that exposure of OP at doses of 100 and 250 mg/kg bw/day subcutaneously during fetal life may cause adverse effects on some hematological parameters, and also histopathological damages in the liver, kidney and spleen of rats. doi:10.1016/j.toxlet.2007.05.452 D04 An evaluation of Ciprofloxacin toxicity in the neonatal minipig Paul Barrow, Fanny Bellebeau, C´eline Perrocheau, Marie-Agn`es Simonin MDS Pharma Services, St Germain sur L’Arbresle, France The fluroquinolone antibiotics cause chondrotoxicity in growing animals and are contraindicated for use in paediatric patients, even though the pertinence of the effect has never been clearly demonstrated in the human.
S178
Abstracts / Toxicology Letters 172S (2007) S1–S240
Arthropathy has been observed in young animals of several species, including the rat, mouse, dog and guinea pig. The juvenile pig, however, appears less sensitive to this toxicity, possibly due to a more advanced state of skeletal development at the time of birth. This experiment was performed to investigate whether the sensitive window to the developmental effects of Ciprofloxacin occurs before weaning in the minipig. Four litters of G¨ottingen minipigs were treated by oral gavage from post-natal day 7 up to 4 weeks of age (weaning). Half of the piglets of each sex in each litter were given 30 mg/(kg day) of Ciprofloxacin, the other half were given 5 mL/(kg day) of water and acted as controls. Ophthalmology and cardiovascular examinations were performed from the first week. Blood samples were taken at intervals from the first week for clinical laboratory determinations. Physical development was monitored by recording body weight, standing shoulder height and tibia length. Selected tissues, including articular cartilage from the femoral head-cap and the Achilles tendon, were submitted to histopathological examination. Ciprofloxacin did not obviously affect the physical development of the piglets and did not induce any lesions of the cartilage or tendon. Further investigation will be necessary to uncover the reasons for this lack of sensitivity of the minipig to the developmental effects of Ciprofloxacin.
used to establish a TDI for dioxins in the UK.7 We have previously found that a single dose of TCDD causes no decrease in F1 sperm levels (Bell et al., 2005), and we have now undertaken a study to determine if chronic dosing of TCDD affects the developing rat. CRL:WI(Han) rats were chronically exposed to TCDD, then mated, and offspring killed at PND 70 and 120. There was significant lethality in the high dose F1, males showed a TCDD-dependant delay in balanopreputial separation (BPS), and the high dose group were slightly less active in motor activity trials. There were no adverse effects of maternal treatment on seminology data at PND 70 or 120, nor any effect on the fertility of the animals. Our data from both an acute and a chronic dosing study show that developmental exposure to TCDD does not decrease sperm counts of F1 animals. However, our chronic dosing data reveal BPS to be an extremely sensitive response to maternal TCDD exposure, and that the dosing regime is a key determinant of response. This work was supported by the UK Food Standards Agency.
doi:10.1016/j.toxlet.2007.05.453
doi:10.1016/j.toxlet.2007.05.454
D05 TCDD is a potent developmental toxin, but fails to affect spermatogenesis in offspring of chronically treated CRL:WI(Han) rats
D06 The relationship between cadmium and lead with selenium, copper and zinc in normal and intrauterine growth restriction pregnancy
David Bell 1 , Sally Clode 2 , MingQi Fan 1 , Alwyn Fernandes 3 , Paul Foster 4 , Tao Jiang 1 , George Loizou 5 , Alan MacNicoll 3 , Brian Miller 6 , Martin Rose 3 , Lang Tran 6 , Shaun White 3
Suzana Cavar 1 , Tomislav Klapec 2 , Zoran Kasac 3 , Silvija Rucevic 4 , Ana Popinjac 2 , Marina Valek 1 , Nikola Kraljik 1
1 University
of Nottingham, Nottingham, United Kingdom; 2 Covance, Harrogate, United Kingdom; 3 Central Science Laboratory, York, United Kingdom; 4 NIEHS, NC, United States; 5 HSL, Buxton, United Kingdom; 6 IOM, Edinburgh, United Kingdom 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is reported to affect the developing male reproductive system, after dosing the pregnant mother to as little as 64 ng/kg (Mably et al., 1992). This endpoint has been
Reference Bell, et al., 2005. Toxicologist Abstract 681. Mably, et al., 1992. Toxicol. Appl. Pharm. 114, 118–126.
1 Institute
of Public Health for Osijek-Baranya County, Osijek, Croatia; 2 Faculty of Food Technology, Osijek, Croatia; 3 Clinical Hospital, Department of Obstetrics and Gynaecology, Osijek, Croatia; 4 Faculty of Philosophy, Osijek, Croatia Elemental status of the mother and newborn has been connected to pregnancy outcome and this study investigated placental Pb, Cd, Se, Cu and Zn concentrations in a group of pregnancies with birth weight appropriate for gestational age and in a group of intrauterine growth restriction cases. Collection of placenta samples 7
http://www.food.gov.uk/multimedia/pdfs/cot-diox-full.
D02 Developmental neurotoxicity of propylthiouracil in rats Marta Axelstad 1, , Pernille Hansen 1 , Sofie Christiansen 1 , Christine Nellemann 1 , Karin Sørig Hougaard 2 , Søren Peter Lund 2 , Ulla Hass 1 1 Department
of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Copenhagen, Denmark; 2 National Research Centre for the Working Environment, Copenhagen, Denmark It has been known for a long time that markedly lowered thyroid hormone levels during development can have severe consequences for the intellectual, behavioural and auditory development of the child. However, recent studies indicate that even small changes in the mother’s thyroid hormone status early in pregnancy may cause adverse effects on the offspring. This has led to increased concern about thyroid hormone disrupting chemicals (TDCs) in our environment. We have studied how developmental exposure to the known antithyroid agent propylthiouracil (PTU) affects the development of rat pups. The overall aim was to provide detailed knowledge on the relationship between effects on thyroid hormone levels and long-lasting developmental neurotoxicity effects. Groups of 16–18 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/(kg day)) from gestation day 7 to postnatal day (PND) 16 and the development and behaviour of the offspring was assessed. Measurements of thyroid hormone levels during the dosing period showed that both dams and pups in the higher dose groups had markedly lowered T4 levels, but these levels normalized shortly after dosing had stopped. The tested endpoints all showed statistically significant changes in the high dose group. Pup motor activity levels were lowered on PND 14, while they were elevated on PND 23 and in adulthood, and auditory function in adult animals was impaired. Generally the results showed that PTU exposure and the resulting hypothyroxinemia influenced behaviour and hearing function. This supports that exposure to TDC’s in general may cause long-lasting developmental neurotoxicity. doi:10.1016/j.toxlet.2007.05.451
S177
D03 Effects of maternal 4-tert-octylphenol exposure on hematology and histopathology of the liver, kidney and spleen of adult female rats M¨ufide Aydogan, Nurhayat Barlas Department of Biology, Faculty of Science, University of Hacettepe, Ankara, Turkey Over the past two decades, many chemicals in the environment have been identified as environmental estrogens. 4-tert-Octylphenol (OP) is an estrogenic compound. In the present study, we investigated the effects of fetal octylphenol (OP) exposure on the liver, kidney, spleen and hematological parameters at adulthood. Female rats were treated with OP in uteri at doses of 0, 0 (vehicle), 100 or 250 mg/kg bw/day. After birth, female rats were allowed to grow until adulthood and then liver, kidney and spleen were investigated histopathologically. The blood samples were collected from hearts and analysed for hematological parameters. The absolute kidney weight, the absolute and relative spleen weights in OP treatment group was decreased compared with the control group. There were no significant differences in relative liver weight and body weight among groups. The hemosiderin deposition was increased in 250 mg/kg bw/day OP treatment group. The red blood cells and platelets were decreased in 250 mg/kg bw/day OP treatment group compared with the control group. Mean corpuscular hemoglobin of was increased in 250 mg/kg bw/day OP treatment group. Our findings of this study indicate that exposure of OP at doses of 100 and 250 mg/kg bw/day subcutaneously during fetal life may cause adverse effects on some hematological parameters, and also histopathological damages in the liver, kidney and spleen of rats. doi:10.1016/j.toxlet.2007.05.452 D04 An evaluation of Ciprofloxacin toxicity in the neonatal minipig Paul Barrow, Fanny Bellebeau, C´eline Perrocheau, Marie-Agn`es Simonin MDS Pharma Services, St Germain sur L’Arbresle, France The fluroquinolone antibiotics cause chondrotoxicity in growing animals and are contraindicated for use in paediatric patients, even though the pertinence of the effect has never been clearly demonstrated in the human.
S178
Abstracts / Toxicology Letters 172S (2007) S1–S240
Arthropathy has been observed in young animals of several species, including the rat, mouse, dog and guinea pig. The juvenile pig, however, appears less sensitive to this toxicity, possibly due to a more advanced state of skeletal development at the time of birth. This experiment was performed to investigate whether the sensitive window to the developmental effects of Ciprofloxacin occurs before weaning in the minipig. Four litters of G¨ottingen minipigs were treated by oral gavage from post-natal day 7 up to 4 weeks of age (weaning). Half of the piglets of each sex in each litter were given 30 mg/(kg day) of Ciprofloxacin, the other half were given 5 mL/(kg day) of water and acted as controls. Ophthalmology and cardiovascular examinations were performed from the first week. Blood samples were taken at intervals from the first week for clinical laboratory determinations. Physical development was monitored by recording body weight, standing shoulder height and tibia length. Selected tissues, including articular cartilage from the femoral head-cap and the Achilles tendon, were submitted to histopathological examination. Ciprofloxacin did not obviously affect the physical development of the piglets and did not induce any lesions of the cartilage or tendon. Further investigation will be necessary to uncover the reasons for this lack of sensitivity of the minipig to the developmental effects of Ciprofloxacin.
used to establish a TDI for dioxins in the UK.7 We have previously found that a single dose of TCDD causes no decrease in F1 sperm levels (Bell et al., 2005), and we have now undertaken a study to determine if chronic dosing of TCDD affects the developing rat. CRL:WI(Han) rats were chronically exposed to TCDD, then mated, and offspring killed at PND 70 and 120. There was significant lethality in the high dose F1, males showed a TCDD-dependant delay in balanopreputial separation (BPS), and the high dose group were slightly less active in motor activity trials. There were no adverse effects of maternal treatment on seminology data at PND 70 or 120, nor any effect on the fertility of the animals. Our data from both an acute and a chronic dosing study show that developmental exposure to TCDD does not decrease sperm counts of F1 animals. However, our chronic dosing data reveal BPS to be an extremely sensitive response to maternal TCDD exposure, and that the dosing regime is a key determinant of response. This work was supported by the UK Food Standards Agency.
doi:10.1016/j.toxlet.2007.05.453
doi:10.1016/j.toxlet.2007.05.454
D05 TCDD is a potent developmental toxin, but fails to affect spermatogenesis in offspring of chronically treated CRL:WI(Han) rats
D06 The relationship between cadmium and lead with selenium, copper and zinc in normal and intrauterine growth restriction pregnancy
David Bell 1 , Sally Clode 2 , MingQi Fan 1 , Alwyn Fernandes 3 , Paul Foster 4 , Tao Jiang 1 , George Loizou 5 , Alan MacNicoll 3 , Brian Miller 6 , Martin Rose 3 , Lang Tran 6 , Shaun White 3
Suzana Cavar 1 , Tomislav Klapec 2 , Zoran Kasac 3 , Silvija Rucevic 4 , Ana Popinjac 2 , Marina Valek 1 , Nikola Kraljik 1
1 University
of Nottingham, Nottingham, United Kingdom; 2 Covance, Harrogate, United Kingdom; 3 Central Science Laboratory, York, United Kingdom; 4 NIEHS, NC, United States; 5 HSL, Buxton, United Kingdom; 6 IOM, Edinburgh, United Kingdom 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is reported to affect the developing male reproductive system, after dosing the pregnant mother to as little as 64 ng/kg (Mably et al., 1992). This endpoint has been
Reference Bell, et al., 2005. Toxicologist Abstract 681. Mably, et al., 1992. Toxicol. Appl. Pharm. 114, 118–126.
1 Institute
of Public Health for Osijek-Baranya County, Osijek, Croatia; 2 Faculty of Food Technology, Osijek, Croatia; 3 Clinical Hospital, Department of Obstetrics and Gynaecology, Osijek, Croatia; 4 Faculty of Philosophy, Osijek, Croatia Elemental status of the mother and newborn has been connected to pregnancy outcome and this study investigated placental Pb, Cd, Se, Cu and Zn concentrations in a group of pregnancies with birth weight appropriate for gestational age and in a group of intrauterine growth restriction cases. Collection of placenta samples 7
http://www.food.gov.uk/multimedia/pdfs/cot-diox-full.