| 1. |
- Johansson, Niclas, 1976-
(författare)
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Neonatal Exposure to Highly Brominated Diphenyl Ethers and Perfluorinated Compounds : Developmental Dependent Toxicity and Interaction
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigated the developmental neurotoxic effects of neonatal exposure to highly brominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs), alone or in combinations, during a critical period of the brains’ rapid growth and development, in mice. The compounds investigated were the decaBDE (PBDE 209), nonaBDE (PBDE 206), octaBDE (PBDE 203), heptaBDE (PBDE 183), and three PFCs, PFOS, PFOA, and PFDA. PBDEs and PFCs have been identified as emerging classes of persistent environmental compounds, present in wildlife as well as humans, and present at higher levels in infants/children, compared to older persons. Individuals can be exposed to these compounds throughout her/his lifetime and newborn/children can be exposed to toxicants both via the mothers’ milk and directly via ingestion and inhalation. The brain growth spurt (BGS) is defined by rapid growth and developmental of the brain. For rodents (mice and rats), the BGS is postnatal spanning the first 3-4 weeks after birth. In humans this period begins during the third trimester of pregnancy and continues throughout the first two years of life. It has been shown that several environmental toxicants can induce permanent disorders in brain function when administered to the neonatal mouse, during the BGS. This thesis shows that highly brominated PBDEs, including PBDE 209, PBDE 206, and PBDE 203 can cause developmental neurotoxic effects, when given directly to the neonatal mouse. Of the investigated PFCs, PFOS and PFOA were shown to cause similar effects as the PBDEs. Furthermore, PBDE 209 and PFOA can at low doses interact and enhance the neurotoxic effects in mice. Effects in the adult animal included; deranged spontaneous behavior, reduced or lack of habituation, decreased learning and memory abilities, and increased susceptibility of the cholinergic system. Both classes of compounds were shown to affect proteins (CaMKII, GAP-43, synaptophysin, and tau) important for neuronal growth and synaptogenesis in the neonatal mouse brain.
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| 2. |
- Lilienthal, Hellmuth, et al.
(författare)
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Auditory effects of developmental exposure to purity-controlled Polychlorinated Biphenyls (PCB52 and PCB180) in rats
- 2011
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Ingår i: Toxicological Sciences. - : Oxford Journals. - 1096-6080 .- 1096-0929. ; 122:1, s. 100-111
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Tidskriftsartikel (refereegranskat)abstract
- Polychlorinated biphenyls (PCBs) are still present in the environment, with ongoing exposure in humans, including babies nursed by their mothers. Whereas toxicity of dioxin-like PCBs is well described, less systematic knowledge is available for non-dioxin-like PCBs (NDL-PCBs) which do not act via the Ah receptor. This study compared effects of developmental exposure to two ultrapure NDL-PCB congeners (PCB52 and PCB180) on auditory function in rats, using the brainstem auditory evoked potential (BAEP). Pregnant rats received repeated oral doses of PCB52 (total dose - 0, 30, 100, 300, 1000, or 3000 mg/kg body weight) or of PCB180 (total dose - 0, 10, 30, 100, 300, or 1000 mg/kg). BAEPs were recorded in adult male and female offspring after stimulation with clicks or pure tones in the frequency range from 0.5 kHz to 16 kHz. Significant elevation of BAEP thresholds were detected in the low-frequency range after developmental exposure to PCB52. Calculation of benchmark doses revealed lowest values in the frequency range of 0.5 - 2 kHz. Effects were more pronounced in male compared to female offspring. Latencies of waves II and IV were prolonged in exposed males, while only wave IV was affected in females. PCB180 increased thresholds only at few conditions and only in female offspring. These results confirm that developmental exposure to ultrapure NDL-PCBs affects auditory function, but different congeners exhibit differences in potencies.
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| 3. |
- Lilienthal, Hellmuth, et al.
(författare)
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Developmental exposure to purity-controlled polychlorinated biphenyl congeners (PCB74 and PCB95) in rats : Effects on brainstem auditory evoked potentials and catalepsy
- 2015
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 327, s. 22-31
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Tidskriftsartikel (refereegranskat)abstract
- Whereas the effects of dioxin-like polychlorinated biphenyls (DL-PCBs) are well described, less is known about non-dioxin-like PCBs (NDL-PCBs), including influences on the nervous system and related behavioral effects after developmental exposure. Following the examination of the highly purified NDL congeners PCB52 and PCB180, we report here the results of experiments with PCB74 and PCB95. Rat dams were orally exposed to equimolar doses of either congener (40 mu mol/kg bw - 11.68 mg PCB74/kg bw or 13.06 mg PCB95/kg bw) from gestational day (GD) 10 to postnatal day (PND) 7. Control dams were given the vehicle. Adult offspring were tested for cataleptic behavior after induction with haloperidol, a classical neuroleptic drug, and brainstem auditory evoked potentials (BAEPs), using clicks and tone pips of different frequencies for stimulation. Results revealed slight effects on latencies to movement onset in female offspring exposed to PCB74, whereas PCB74 males and offspring exposed to PCB95 were not affected. Pronounced changes were observed in BAEPs at low frequencies in PCB74 offspring, with elevated thresholds in both sexes. PCB95 increased thresholds in males, but not females. Small effects were detected on latency of the late wave IV in both sexes after developmental exposure to PCB74 or PCB95. Compared with the other NDL-PCB congeners tested, PCB74 caused the most pronounced effects on BAEPs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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| 4. |
- Lilienthal, Hellmuth, et al.
(författare)
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Dopamine-dependent behavior in adult rats after perinatal exposure to purity-controlled polychlorinated biphenyl congeners (PCB52 and PCB180)
- 2014
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Ingår i: Toxicology Letters. - : Elsevier. - 0378-4274 .- 1879-3169. ; 224:1, s. 32-39
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Tidskriftsartikel (refereegranskat)abstract
- Since knowledge about toxic effects of non-dioxinlike (NDL) PCBs is fragmentary, regulatory panels have concluded that risk assessment of these congeners is hampered or impossible. As the dopaminergic system is one of the main targets in PCB-related neurotoxic effects after developmental exposure, we selected catalepsy induced by the dopamine receptor blocker haloperidol to characterize effects of the NDL congeners PCB52 and PCB180 in adult offspring from exposed rat dams. Rat dams were treated with PCB congeners by gavage using six dose levels (total doses: PCB52 - 0, 30, 100, 300, 1000 or 3000 mg/kg body wt.; PCB180 - 0, 10, 30, 100, 300, or 1000 mg/kg body wt.) to allow benchmark dose analysis of the results. Testing of adult offspring (starting at 180 days of age) for catalepsy induced by injection with haloperidol revealed slightly prolonged latencies to movement onset in female offspring exposed to PCB52. Exposure to PCB180 resulted in more pronounced effects, with generally reduced latencies in male offspring. These results indicate reduced dopaminergic activity after PCB52 exposure, whereas the outcome for PCB180 may be related to increased extracellular dopamine as reported in the literature. Benchmark dose analyses revealed that both PCB congeners exerted effects mainly at moderate exposure levels. Together, these results underline the importance of effects on the dopaminergic system as indicated by studies in human females after occupational PCB exposure.
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| 5. |
- Lilienthal, Hellmuth, et al.
(författare)
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Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats
- 2013
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Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 311:1-2, s. 52-60
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Tidskriftsartikel (refereegranskat)abstract
- Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000mg/kg body wt) or PCB180 (6 dose groups, total dose of 0-1000mg/kg body wt). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760μMol/kg body wt, corresponding to 229mg/kg or 248mg/kg body wt of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs.
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| 6. |
- Lundgren, Magnus, et al.
(författare)
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Coxsackievirus B3 infection and PBDE exposure causes organ-specific effects on CYP-gene expression in the mouse
- 2007
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 242:1-3, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- Common viral infections have been shown to change the tissue distribution of xenobiotics, including polybrominated diphenyl ethers (PBDEs). In previous studies, it has been shown that CYP2B gene expression is induced after PBDE exposure whereas coxsackievirus B3 (CBV3) infection suppresses the expression of CYP-gene expression in the liver. In the present study, CVB3 adapted to Balb/c mice was used to study the combined effects of infection and exposure to pure BDE-99 or the commercial mixture Bromkal on CYP1A1 and CYP2B expression in the lungs and pancreas on day 3 of the infection. The quantitative gene expression of virus, CYP1A1 and CYP2B was measured by real-time polymerase chain reaction (RT-PCR). PBDE exposure in the non-infected mice tended to increase CYP2B expression in the lungs but not in the pancreas. Infection in both non-exposed and PBDE-exposed mice increased CYP2B expression in the lungs but was non-detectable in the pancreas. In the non-infected mice PBDE exposure left the CYP1A1 expression unaltered in both the lungs and pancreas. Infection in both non-exposed and PBDE-exposed mice tended to decrease the gene expression of CYP1A1 in the lungs but to induce it in the pancreas. A correlation between the amount of virus and the gene expression of CYP2B was found in the lungs. However, no effects of PBDE on virus replication were observed in any organ. In conclusion, viral infection affects CYP-gene expression differently in the pancreas and lungs whereas PBDE-induced effects were not obvious. The organ-specific change in gene expression could explain a changed tissue distribution of xenobiotics during infection.
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| 7. |
- Lundgren, Magnus, et al.
(författare)
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Viral infection and PBDE exposure interact on CYP gene expression and enzyme activities in the mouse liver
- 2007
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 242:1-3, s. 100-108
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Tidskriftsartikel (refereegranskat)abstract
- In the present study coxsackievirus B3 (CVB3) adapted to Balb/c mice was used to examine whether infection affects xenobiotic-metabolising CYP1A1 and CYP2B gene expression (measured by RT-PCR) and the corresponding enzyme activities of ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-depentylase (PROD), as observed on day 3 of infection. To study the simultaneous effects of xenobiotic exposure, mice were administered the polybrominated diphenyl ether (PBDE) compounds BDE-99 (single congener) and Bromkal 70-5 DE (commercial mixture). Serum thyroxine levels were also measured. High numbers of CVB3 were found in the livers of infected mice but no significant effects of PBDE on virus replication were observed. In infected mice gene expression and CYP activities were decreased in comparison with non-infected mice, especially for CYP2B. PBDE exposure in the non-infected mice was characterised by an increase in both CYP2B and PROD levels/activities, whereas CYP1A levels increased and EROD activity decreased. In general, PBDE exposure in the infected mice did not increase EROD and PROD activities to the same extent as in the non-infected exposed mice. Infected mice exposed to BDE-99 showed significantly higher CYP2B and PROD levels than both the infected non-exposed and Bromkal-exposed groups. T(4) levels were greatly decreased by infection and a tendency of reduced T(4) levels after PBDE exposure could be observed in non-infected mice. In conclusion, infection reduced the detoxifying capacity of the liver and the serum T(4) levels. PBDE exposure can modify these effects. Notably, in the infected mice differences between BDE-99 and Bromkal were observed on CYP2B gene expression and PROD activity.
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| 8. |
- Viluksela, Matti, et al.
(författare)
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Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104639-
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Tidskriftsartikel (refereegranskat)abstract
- PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.
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