* Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, S-752 36, Uppsala, Sweden; and
Department of Environmental Chemistry, Stockholm University, Stockholm, Sweden
Received August 22, 2001; accepted January 8, 2002
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: brain; brominated flame retardants; development; habituation; neurotoxicity; polybrominated diphenyl ethers; retention; spontaneous behavior.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
PBDEs are not fixed in the polymer product through chemical binding and can thus leak into the environment (Hutzinger et al., 1976; Hutzinger and Thoma, 1987
). Studies have shown that PBDEs are present in the global environment (de Boer et al., 1998
; Johnson and Olson, 2001
; Manchester-Neesvig et al., 2001
; Strandberg et al., 2001
) and that levels of PBDEs are increasing in the Swedish environment (Andersson and Blomkvist, 1981
; Nylund et al., 1992
; Sellström et al., 1993
). The most commonly found PBDEs in the environment are PBDE 47, PBDE 99, PBDE 100, and PBDE 153 (Darnerud et al., 2001
). A recent report has shown the presence of PBDEs in Swedish mother's milk and also an exponential increase in PBDEs since 1972, whereas PCBs are decreasing steadily (Meironyté et al., 1999
). The most commonly found PBDE congeners in human milk are 2,2`,4,4`-tetraBDE (PBDE 47) and 2,2`,4,4`,5-pentaBDE (PBDE 99) (Norén and Meironyté, 2000
). The concentrations of PBDEs are still lower than those for PCBs and DDT, about 80 times and 3 times, respectively (Meironyté et al., 1999
; Norén and Meironyté, 2000
). Samples of human blood have also been shown to contain PBDEs (Klasson-Wehler et al., 1997
), including from workers in the electrical dismantling industry that show serum levels of PBDEs (Sjödin et al., 1999
). This indicates that humans are exposed to PBDEs both as infants and as adults.
In a recent study, we have shown that neonatal exposure to PBDEs on day 10 can induce persistent dysfunction in adult mice, manifested as deranged spontaneous behavior (Eriksson et al., 2001b). Of three different flame retardants investigated, 2,2`,4,4`-tetraBDE (PBDE 47), 2,2`,4,4`,5-pentaBDE (PBDE 99), and tetrabromo-bis-phenol-A (TBBPA), both PBDE 47 and PBDE 99 caused developmental neurotoxic effects. The observed effects, i.e., altered spontaneous motor behavior and reduced habituation capabilities, were also seen to worsen with increasing age as they were more pronounced in 4-month-old mice compared to 2-month-old mice.
Exposure to low doses of persistent (nondegradable) and/or nonpersistent environmental agents during neonatal brain development in the mouse, has been shown to induce irreversible disruption in adult brain function (Eriksson, 1997). The persistent environmental agents, DDT and PCBs, have been shown to induce persistent effects in the mouse only when they are administered during a critical phase of neonatal brain development (Eriksson, 1998
; Eriksson et al., 1992
, 2001b
). These disturbances are induced during the period of rapid brain growth (brain growth spurt, BGS; Davison and Dobbing, 1968
). During the BGS, the brain undergoes several fundamental phases, such as dendritic and axonal outgrowth and the establishment of neural connections (Davison and Dobbing, 1968
; Kolb and Whishaw, 1989
). During this period, animals also acquire many new motor and sensory abilities (Bolles and Woods, 1964
) and their spontaneous behavior peaks (Campbell et al., 1969
). The BGS is associated with numerous biochemical changes that transform the feto-neonatal brain into that of the mature adult (Coyle and Yamamura, 1976
; Fiedler et al., 1987
). This is also a time during development when the synthesis of brain lipids reaches its maximum. A pronounced retention of lipophilic agents, such as DDT and PCBs (Eriksson, 1984
; Eriksson and Darnerud, 1985
), has been seen in the neonatal mouse brain during the BGS. In mammals, the timing of the BGS in terms of onset and duration varies from species to species. In the human, it begins during the third trimester of pregnancy and continues throughout the first 2 years of life, whereas in the guinea pig it takes place in utero. In rodents, however, the BGS is neonatal, spanning the first 34 weeks of life, and reaches its peak around postnatal day 10.
With regard to our earlier observations of pronounced retention and developmental neurotoxic effects caused by DDT and PCBs, as well as the similarities between the PBDEs DDT, and PCBs in regard to chemical and physical properties, geographical distribution pattern, and occurrence in mother's milk, the present study was undertaken to ascertain whether there is a defined critical period during the BGS, in the neonatal mouse, when it is susceptible to the effects of 2,2`,4,4`,5-pentaBDE on the spontaneous motor behavior of the adult. In order to study whether the tissue distribution or a defined critical phase of brain development is the underlying cause for developmental effects, the uptake and retention of 2,2`,4,4`,5-pentaBDE in the neonatal mouse brain was conducted.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pregnant NMRI mice were obtained from B&K, Sollentuna, Sweden and were housed individually in plastic cages in a room with an ambient temperature of 22°C and a 12/12-h cycle of light and dark. The animals were supplied with standardized pellet food (Lactamin, Stockholm, Sweden) and tap water ad libitum. The pregnant NMRI mice were checked for births two times daily (0800 and 1800 h). The day of birth was assigned day 0, and pups born during the night were assigned day 0 when checked at 0800 h. The size of the litters was adjusted to 1012 mice, within the first 48 h after birth, by the killing of excess pups. The litters contained pups of both sexes, and no separation with regard to sex was made in the preweanling mice. At the age of 45 weeks, all females were sacrificed and the males were placed in groups of 47, in a room for male mice only, and raised under the same conditions as detailed above.
In the behavioral study, 3-, 10-, and 19-day-old mice of both sexes were given 8 mg of 2,2`,4,4`,5-pentaBDE/kg bw (14 µmol 2,2`,4,4`,5-pentaBDE/kg bw) via a metal gastric tube, as one single oral dose. Mice serving as controls received, in the same manner, 10 ml/kg bw of the 20% fat emulsion vehicle. The dose was selected in order to be comparable to earlier developmental neurotoxicity studies on PCBs (Eriksson, 1998), and also is a dose known to cause effects on adult spontaneous motor behavior when given to 10-day-old mice (Eriksson et al., 2001b
). Each of the different age categories contained three to five litters.
In the retention study, five male offspring in each litter were given 1.5 M Bq 2,2`,4,4`,5-penta[14C]BDE/kg body weight (40.5 µCi/kg bw), as one single oral dose, via a metal gastric tube, at the age of 3, 10, or 19 days. A sixth male in each litter, which did not receive 14C-labeled PBDE 99, was used as a background control. Each age category contained two litters.
Spontaneous behavior test.
Spontaneous behavior was tested in the male mice at the age of 4 months, as described by Eriksson et al. (1992). The animals were tested between 0800 and 1200 h under the same ambient light and temperature as their housing conditions. A total of 10 mice were randomly picked from the three to five different litters in each treatment group. Motor activity was measured for a 60-min period, divided into three 20-min time intervals, in an automated device consisting of cages (40 x 25 x 15 cm) placed within two series of infrared beams (low and high level) (Rat-O-Matic, ADEA Elektronik AB, Uppsala, Sweden) (Fredriksson, 1994). The cages were placed in individual soundproofed boxes with separate ventilation. Twelve devices were run simultaneously, allowing a balance between treatments:
Radioactivity of 2,2`,4,4`,5-penta[14C]BDE measured in the neonatal mouse brain.
Each of the two litters from the three different age categories was sacrificed by decapitation 24 h or 7 days, respectively, after administration. The skull was opened and the brain sectioned just behind the cerebellum. The brain samples were placed in preweighed vials and weighed and individually solubilized in 1.5 ml Biolute tissue solubilizer (Zinsser Analythic, UK) at 48°C for 24 h. After solubilization, 18.5 ml scintillation liquid (Aquasafe 300+, Zinsser, UK) was added to each vial. The samples were adapted overnight before being counted in a scintillation analyzer (Packard Tri-Carb 1900 CA). Counting efficiency was approximately 90% and quench correction was made by the external standard method. Counts/min values not exceeding background + 3background were excluded.
Statistical analysis.
Body weight data from each age category was subjected to the Student's t-test, comparing controls vs. treated animals. Spontaneous behavior data were subjected to a split-plot ANOVA (analysis of variance), and pairwise testing between treated groups and their corresponding control groups was performed using a Tukey HSD (honestly significant difference) test (Kirk, 1968). The amount of radioactivity of 2,2`,4,4`,5-penta[14C]BDE in neonatal brain at 24 h after administration, as per mille (
) of that administered, was compared with that found 7 days after administration in the same age category, using Student's t-test.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects on spontaneous behavior in adult mice.
The results from the spontaneous behavioral variables, locomotion, rearing, and total activity in 4-month-old male mice after exposure to a single oral dose of 8.0 mg 2,2`,4,4`,5-pentaBDE/kg bw at the age of 3, 10, or 19 days are shown in Figure 1.
|
Mice receiving the vehicle at the age of either 3, 10, or 19 days showed a decrease in activity over time in response to the diminished novelty of the test chambers. This behavioral pattern in control animals is in agreement with earlier reports (Ahlbom et al., 1995; Eriksson et al., 1992
, 1998
, 2000
).
Pairwise testing between 2,2`,4,4`,5-pentaBDE-treated mice and the control mice revealed a significant difference in behavior (Fig. 1). Mice neonatally exposed to 2,2`,4,4`,5-pentaBDE on day 3 showed significantly altered behavior in the three variables, locomotion, rearing, and total activity, compared with the controls. The locomotion variable was significantly increased (p
0.01) during the last 20-min period (time 4060 min). The rearing variable was significantly decreased (p
0.01) during the first 20-min period (time 020 min) and a significant increase (p
0.01) in the rearing variable was seen in the 2,2`,4,4`,5-pentaBDE-treated mice, as compared with the control animals, during the last 20-min period (time 4060 min). For the third variable, total activity, a significantly increased activity (p
0.01) was evident during the last 20-min period (time 4060 min) in mice exposed to 2,2`,4,4`,5-pentaBDE at 3 days of age.
Mice neonatally exposed to 2,2`,4,4`,5-pentaBDE on day 10 exhibited significantly decreased activity (p 0.01) for all three behavioral variables, locomotion, rearing, and total activity, compared with the control group, during the first 20-min interval of the 60-min period (time 020 min). During the last 20-min period (time 4060 min), a significantly increased activity (p
0.01), compared with the control group, was seen for all three behavioral variables.
In mice neonatally exposed to 2,2`,4,4`,5-pentaBDE on day 19 there were no changes concerning the three behavioral variables compared with controls, i.e. a decrease in activity in all variables was evident over the 60-min period observation.
Retention of 2,2`,4,4`,5-penta[14C]BDE in mouse brain after 24 h and 7 days following an oral exposure on day 3, 10, or 19.
The amounts of radioactivity found in the brain 24 h and 7 days after administration are shown in Fig. 2. The amount of radioactivity, given as
of total amount administered, was between 3.7 and 5.1
in the three different age categories, 24 h after administration. Seven days after administration, radioactivity was still present in the brain, but the amount of radioactivity had significantly declined to between 1.3 and 2.8
of the administered dose.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The spontaneous motor behavior data showed a disruption of habituation in adult mice neonatally exposed to 2,2`,4,4`,5-pentaBDE on day 3 or 10. Normal habituation, defined here as a decrease in the variables locomotion, rearing, and total activity, in response to the diminished novelty of the test chamber over a 60-minute test period, divided into three 20-min periods, was seen in the control mice, treated on neonatal day 3, 10, or 19 with the 20% fat emulsion vehicle. The mice treated neonatally with 2,2`,4,4`,5-pentaBDE on day 3 or 10 showed a deviation from the normal habituation. The most pronounced effect was seen in mice exposed to 2,2`,4,4`,5-pentaBDE on neonatal day 10. At the age of 4 months these mice displayed a significantly hypoactive behavior during the first 20 min of the 60-min period for all three spontaneous behavior variables, locomotion, rearing and total activity. They also showed hyperactive behavior for all three spontaneous behavior variables during the last 20 min of the 60-min period. This supports the earlier findings by Eriksson et al. (2001b) concerning developmental toxicity of brominated flame retardants. In that study, male mice (NMRI) exposed neonatally on day 10 to 0.8 or 12 mg 2,2`,4,4`,5-pentaBDE/kg body weight, as one single oral dose, showed differences in spontaneous behavior at 4 months of age. It is of particular interest to note that the dose used in the present study (8 mg 2,2`,4,4`,5-pentaBDE/kg body weight) caused a derangement in spontaneous behavior in 4-month-old mice that falls in between the disturbances earlier seen for the two doses, 0.8 and 12 mg 2,2`,4,4`,5-pentaBDE/kg body weight (Eriksson et al., 2001b), when comparing the ratio between the activity of the last 20-min period (time 4060 min) and the activity of the first 20-min period (time 020 min) for the total activity variable, where the ratio for 2,2`,4,4`,5-pentaBDE 0.8 mg = 0.60; 8.0 mg = 1.07; and 12 mg = 1.38. Taken together, the present findings and the earlier observed effects on spontaneous motor behavior in mice neonatally exposed to 2,2`,4,4`,5-pentaBDE (Eriksson et al., 2001b
) indicate a dose-dependent mode of action by 2,2`,4,4`,5-pentaBDE. These changes in spontaneous behavior are very similar to the changes seen after neonatal exposure to certain PCBs. Neonatal exposure in mice on day 10 to some ortho-substituted PCBs, such as 2,4,4`-trichlorobiphenyl (PCB 28), 2,2`,5,5`-tetrachlorobiphenyl (PCB 52), 2,2`,4,4`,5,5`-hexachlorobiphenyl (PCB 153), and some coplanar PCBs, 3,3`,4,4`-tetrachlorobiphenyl (PCB 77), 3,3`,4,4`,5-pentachlorobiphenyl (PCB 126), and 3,3`,4,4`,5,5`-hexachlorobiphenyl, has been shown to cause a hypoactive condition in spontaneous behavior during the first 20-min period, while toward the end of the 60-min period the mice became hyperactive (see Eriksson, 1998
). These effects were shown to be related to both dose response and time response. These dose- and time-related similarities in effects of PBDEs and PCBs indicate that PBDEs can constitute a new class of environmental agents that might be involved in the induction of a brain dysfunctional process induced at a time of rapid brain development in the neonatal mouse.
In the mice exposed to 2,2`,4,4`,5-pentaBDE on neonatal day 3, the spontaneous behavior was also altered, although the effects were not as pronounced as in the animals exposed on neonatal day 10. Significantly hypoactive behavior during the first 20 min was only seen for the rearing variable. However, significantly hyperactive behavior was observed during the last 20 min for all three variables (locomotion, rearing, and total activity). This behavioral response also shows striking similarities to the changes in spontaneous behavior seen after neonatal exposure to PCB 52 on day 3. The effect from exposure on day 3 has been explained by the pronounced retention of PCB 52 in the neonatal mouse brain (see Eriksson, 1998). In mice given 14C-labeled PCB 52 on day 3, the amount of PCB 52 present on day 10 was calculated to be sufficient to induce behavioral disturbances.
The amount of toxic agent present in the brain at different neonatal ages may vary. Previous studies have shown a pronounced retention of lipophilic chlorinated hydrocarbons or their metabolites (e.g. DDT, PCB 52, PCB 153, and chlorinated paraffins) in the brain when administered on neonatal day 10 (Eriksson, 1984, 1998
; Eriksson and Darnerud, 1985
). The amount of 2,2`,4,4`,5-pentaBDE or its metabolites, seen after neonatal exposure in the three different age categories, is in the same range as seen for the PCBs and DDT, i.e. 35
of the administered dose (Eriksson, 1984
, 1998
; Eriksson and Darnerud, 1985
). Differences in the amounts of 2,2`,4,4`,5-pentaBDE present in the neonatal brain at the different neonatal ages do not appear to explain the different behavioral effects seen in adult mice exposed on day 3, 10, or 19. The amount of radioactivity was not higher in the brains of animals exposed on day 3 or 10, yet a disturbance is seen in the spontaneous behavior of animals exposed to 2,2`,4,4`,5-BDE on postnatal day 3 or 10 but not in animals exposed on postnatal day 19. The disturbances seen after exposure on day 3 may be attributable to the fact that the amount was enough to induce behavioral disturbances. The calculated amount present on day 10 was approximately 10.7 pmol/g brain. The corresponding calculation for mice exposed to 0.8 mg 2,2`,4,4`,5-pentaBDE/kg body weight on postnatal day 10 in the previous study by Eriksson and coworkers (2001b) revealed an amount of 7.2 pmol/g brain, which was enough to induce behavioral disturbances in adult mice. The similarities between 2,2`,4,4`,5-pentaBDE and PCBs regarding uptake and neurobehavioral effects are of special concern, not only for PBDE as a single agent, but also because of the possibility of additative or interactive effects between these persistent environmental agents and PCB. Human epidemiological studies suggest that perinatal exposure to PCBs may have developmental neurotoxic effects (Fein et al., 1984
; Jacobson and Jacobson, 1996
; Rogan et al., 1988
), and experimental studies in animals (mice, rats, monkeys) support findings that exposure to PCBs during development can cause long-term neurobehavioral alterations (Tilson et al., 1990
; Tilson and Harry, 1994
; Seegal, 1996
).
In conclusion, the present investigation has shown that exposure in the mouse to 2,2`,4,4`,5-pentaBDE during a defined critical phase of brain development can give rise to irreversible changes in adult brain function. It was also shown that 2,2`,4,4`,5-pentaBDE can be taken up and retained in the neonatal mouse brain. The amount of 2,2`,4,4`,5-pentaBDE administered is comparable, on a molar level, to the dose at which some PCBs are known to cause developmental behavioral effects (for ref. see Eriksson, 1998; Eriksson et al., 2001b
). Susceptibility to developing such irreversible disturbances during a limited phase of the BGS has earlier been reported for PCBs (Eriksson, 1998
), DDT (Eriksson et al., 1992
), nicotine (Eriksson et al., 2000
), and OPs (Ahlbom et al., 1995
). It is worth noting that these agents also affected the cholinergic transmitter system, which is one of the major transmitter systems that correlate closely with cognitive function (Drachman, 1977
; Fibiger, 1992
). This calls for further investigations of PBDEs as developmental neurotoxic agents, since levels in breast milk (Meironyté et al., 1999
; Norén and Meironyté, 2000
) and in the environment are increasing (Strandberg et al., 2001
).
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Andersson, Ö., and Blomkvist, G. (1981). Polybrominated aromatic pollutants found in fish in Sweden. Chemosphere 10, 10511060.[ISI]
Bolles, R. G., and Woods, P. J. (1964). The ontogeny of behavior in the albino rat. Anim. Behav. 12, 427441.[ISI]
Campbell, B. A., Lytle, L. D., and Fibiger, H. C. (1969). Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat. Science 166, 635637.[ISI][Medline]
Coyle, J. T., and Yamamura, H. I. (1976). Neurochemical aspects of the ontogenesis of cholinergic neurons in the rat brain. Brain Res. 118, 429440.[ISI][Medline]
Darnerud, P. O., Eriksen, G. S., Johannesson, T., Larsen, P. B., and Viluksela, M. (2001). Polybrominated diphenyl ethers: Occurrence, dietary exposure, and toxicology. Environ. Health Perspect. 109(Suppl. 1), 4968.[ISI][Medline]
Davison, A. N., and Dobbing, J. (1968). Applied Neurochemistry. Oxford, Blackwell.
de Boer, J., Wester, P. G., Klamer, H. J., Lewis, W. E., and Boon, J. P. (1998). Do flame retardants threaten ocean life? Nature 394, 2829.[ISI][Medline]
Drachman, D. A. (1977). Cognitive function in man: Does the cholinergic system have a special role? Neurology 27, 783790.[Abstract]
Eriksson, P. (1984). Age-dependent retention of [14C]DDT in the brain of the postnatal mouse. Toxicol. Lett. 22, 323328.[ISI][Medline]
Eriksson, P. (1997). Developmental neurotoxicity of environmental agents in the neonate. Neurotoxicology 18, 719726.[ISI][Medline]
Eriksson, P. (1998). Perinatal Developmental Neurotoxicity of PCBs. Swedish Environmental Protection Agency, report 4897.
Eriksson, P., Ahlbom, J., and Fredriksson, A. (1992). Exposure to DDT during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behavior in adult mice. Brain Res. 582, 277281.[ISI][Medline]
Eriksson, P., Ankarberg, E., and Fredriksson, A. (2000). Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behavior of adult mice. Brain Res. 853, 4148.[ISI][Medline]
Eriksson, P., Ankarberg, E., Viberg, H., and Fredriksson, A. (2001a). The developing cholinergic system as target for environmental toxicants, nicotine, and polybrominated biphenyls (PCBs): Implications for neurotoxicological processes in mice. Neurotoxicity Res. 3, 3751.
Eriksson, P., Jakobsson, E., and Fredriksson, A. (2001b). Brominated flame retardants: A novel class of developmental neurotoxicants in our environment? Environ. Health Perspect. 109, 903908.[ISI][Medline]
Eriksson, P., and Darnerud, P. O. (1985). Distribution and retention of some chlorinated hydrocarbons and a phthalate in the mouse brain during the pre-weaning period. Toxicology 37, 189203.[ISI][Medline]
Fein, G. G., Jacobson, J. L., Jacobson, S. W., Schwartz, P. M., and Dowler, J. K. (1984). Prenatal exposure to polychlorinated biphenyls: Effects on birth size and gestational age. J. Pediatr. 105, 315320.[ISI][Medline]
Fibiger, H. C. (1992). The organization and some projections of the cholinergic neurons in the mammalian forebrain. Brain Res. Rev. 4, 327388.
Fiedler, E. P., Marks, M. J., and Collins, A. C. (1987). Postnatal development of cholinergic enzymes and receptors in mouse brain. J. Neurochem. 49, 983990.[ISI][Medline]
Fredriksson, A. (1994). MPTP-induced behavioral deficits in mice: Validity and utility of a model of parkinsonism. Acta Universitatis Uppsaliensis, Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine.
Hutzinger, O., Sundström, G., and Safe, S. (1976). Environmental chemistry of flame retardants: I. Introduction and principles. Chemosphere 1, 310.
Hutzinger, O., and Thoma, H. (1987). Polybrominated dibenzo-p-dioxins and dibenzofurans: The flame retardant issue. Chemosphere 16, 18771880.[ISI]
IPCS (1993) International Programme on Chemical Safety. Polychlorinated biphenyls and terphenyls. In Environmental Health Criteria, 2nd ed., vol 140. World Health Organization, Geneva.
IPCS (1994) International Programme on Chemical Safety. Brominated diphenyl ethers. In Environmental Health Criteria, vol. 162. World Health Organization, Geneva.
Jacobson, J. L. and Jacobson, S. W. (1996). Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N. Engl. J. Med. 335, 783789.
Johnson, A., and Olson, N. (2001). Analysis and occurrence of polybrominated diphenyl ethers in Washington state freshwater fish. Arch. Environ. Contam. Toxicol. 41, 399344.
Keller, W. C., and Yeary, R. A. (1980). A comparison of the effects of mineral oil, vegetable oil, and sodium sulfate on the intestinal absorption of DDT in rodents. Clin. Toxicol. 16, 223231.[ISI][Medline]
Kirk, R. E. (1968). Procedures for the Behavioral Sciences. Brooks/Cole, Belmont, CA.
Klasson-Wehler, E., Hovander, L., and Bergman, Å. (1997). New organohalogens in human plasma: Identification and quantification. 17th Symposium on Halogenated Environmental Organic Pollutants, Indianapolis, IN.
Kolb, B., and Whishaw, I. Q. (1989). Plasticity in the neocortex: Mechanisms underlying recovery from early brain damage. Prog. Neurobiol. 32, 235276.[ISI][Medline]
Manchester-Neesvig, J. B., Valters, K., and Sonzogni, W. C. (2001). Comparison of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in Lake Michigan salmonids. Environ. Sci. Technol. 35, 10721077.[ISI][Medline]
Marsh, G., Hu, J., Jakobsson, E., Rahm, S., and Bergman, Å. (1999). Synthesis and characterization of thirty-two polybrominated diphenyl ethers (PBDEs). Environ. Sci. Technol. 33, 30333037.[ISI]
Meironyté, D., Norén, K., and Bergman, A. (1999). Analysis of polybrominated diphenyl ethers in Swedish human milk: A time-related trend study, 19721997. J. Toxicol. Environ. Health A 58, 329341.[ISI][Medline]
Norén, K., and Meironyte, D. (2000). Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 2030 years. Chemosphere 40, 11111123.[ISI][Medline]
Nylund, K., Asplund, L., Jansson, B., and Jonsson, P. (1992). Analysis of some polyhalogenated organic pollutants in sediment and sewage sludge. Chemosphere 24, 17211730.[ISI]
Örn, U., Eriksson, L., Jakobson, E., and Bergman, Å. (1996). Synthesis and characterization of polybrominated diphenyl ethersunlabeled and radiolabeled tetra-, penta-, and hexa-bromodiphenyl ethers. Acta Chem. Scand. 50, 802807.[ISI]
Palin, K. J., Wilson, C. G., Davis, S. S., and Phillips, A. J. (1982). The effects of oil on the lymphatic absorption of DDT. J. Pharm. Pharmacol. 34, 707710.[ISI][Medline]
Rogan, W. J., Gladen, B. C., Hung, K. L., Koong, S. L., Shih, L. Y., Taylor, J. S., Wu, Y. C., Yang, D., Ragan, N. B., and Hsu, C. C. (1988). Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241, 334336.[ISI][Medline]
Seegal, R. F. (1996). Epidemiological and laboratory evidence of PCB-induced neurotoxicity. Crit. Rev. Toxicol. 26, 70937.[ISI][Medline]
Sellström, U., Jansson, B., Kierkegaard, A., and de Wit, C. (1993). Polybrominated diphenyl ethers (PBDE) in biological samples from the Swedish environment. Chemosphere 26, 17031718.[ISI]
Sjödin, A., Hagmar, L., Klasson-Wehler, E., Kronholm-Diab, K., Jakobsson, E., and Bergman, Å. (1999). Flame-retardant exposure: Polybrominated diphenyl ethers in blood from Swedish workers. Environ. Health Perspect. 107, 643648.[ISI][Medline]
Strandberg, B., Dodder, N. G., Basu, I., and Hites, R. A. (2001). Concentrations and spatial variations of polybrominated diphenyl ethers and other organohalogen compounds in Great Lakes air. Environ. Sci. Technol. 35, 10781083.[ISI][Medline]
Tilson, H. A., and Harry, G. J. (1994). Developmental neurotoxicology of polychlorinated biphenyls and related compounds. In: The Vulnerable Brain and Environmental Risks (R. L. Isaacson and K. F. Jensen, Eds.), pp. 267279. New York, Plenum Press.
Tilson, H. A., Jacobson, J. L., and Rogan, W. J. (1990). Polychlorinated biphenyls and the developing nervous system: Cross-species comparisons. Neurotoxicol. Teratol. 12, 239248.[ISI][Medline]