DEVELOPMENTAL EXPOSURE TO POPs ALTERS THE SUSCEPTIBILITY OF THE CHOLINERGIC SYSTEM – IMPLICATIONS FOR NEURODEVELOPMENTAL DISORDERS AND DISEASES
Eriksson P, Viberg H, Johansson N, Luo F and Fredriksson A
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, 75236, Uppsala, Sweden
Abstract
Foetuses and neonates are known to be high-risk groups for exposure to toxicants, and several epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development in childhood. We have reported that low-dose exposure of neonatal mice, during the rapid brain growth (BGS), to environmental toxic agents (e.g. PCBs, BFRs, PFCs) and known neurotoxic agents (nicotine, organophosphorous compounds (OP)) can lead to disruption of the adult brain and to increased susceptibility to toxic agents at adult age. Several of these toxicants can also interact and enhance developmental neurotoxic effects. These neurobehavioural changes and changes in the cholinergic system are induced during a defined critical period of the BGS in neonatal mice when also proteins that are important for normal neuronal development can be affected. Present study indicates that agents known to affect the cholinergic system in neonates and adults can cause increased levels of the protein tau, a diagnostic marker for Alzheimer’s diseases.
Taken together this indicate that differences in adult susceptibility to environmental pollutants are not
necessarily an inherited condition, instead be acquired by low dose exposure to toxic agents during early life and which can have implications for the development of neurological disorder and/or diseases.
Introduction
Several epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development in childhood (1,2). Perinatal developmental neurotoxicity in humans has been demonstrated by the adverse effects of lead in children, by the fetal alcohol syndrome, by methylmercury poisoning and by drug abuse during pregnancy (1,2,3). Epidemiological studies also indicate that smoking during late gestation in humans can cause ADHD in children (4). An early exposure to toxicants may also be involved in the slow, implacable induction of neurodegenerative disorders and /or interfere with the normal aging process.
Foetuses and neonates are known to be high-risk groups for exposure to toxicants. It is known that newborns, toddlers, and children can be exposed to persistent organic pollutants (POPs) via mothers’ milk or directly via ingestion and inhalation. Direct exposure to chemicals by inhalation and dust ingestion might constitute an important non-dietary exposure route for humans. In many mammalian species the perinatal/neonatal period is characterized by a rapid development of the brain - `the brain growth spurt´ (BGS) (5). In the human, the BGS begins during the third trimester (the last three months) of pregnancy and continues throughout the first 2 years of life. However, in mouse and rat this BGS is neonatal, spanning the first 3-4 weeks of life. During this period the brain undergoes several fundamental developmental phases, viz. maturation of axonal and dendritic outgrowth, establishment of neural connections, and the acquirement of many new motor and sensory faculties.
This period in the development of the mammalian brain is associated with numerous biochemical changes that transform the feto-neonatal brain into that of the mature adult. One of the major neurotransmitters in the CNS is acetylcholine (ACh), which acts as the transmitter in the cholinergic pathways. The cholinergic system is associated with many physiological processes and consciousness, such as memory, learning, audition and vision (6,7,8,9) where the cholinergic receptors in the cerebral cortex and hippocampus play a central role. Interfering with the cholinergic signalling during development may disrupt the final architectural assembly of brain regions containing cholinergic zones (10). The basal forebrain complex plays a special role in learning and memory functions (9) and the interest in the basal forebrain complex led to the discovery that these cells are among the first cells to die during the course of Alzheimer’s disease, which is characterised by a progressive and profound loss of cognitive functions. Several other diseases in the CNS are associated with deficits of the cholinergic system such as Parkinson´s disease, Tourett´s syndrome, epilepsy and schizophrenia (11,12). The origin to different diseases can be multiple factorials. Neurological diseases and disorders are rarely unidimensional or unifactorial. Even those whose etiologies seem closely linked to genetic predispositions tend to be the product of multiple and interwinded risk factors, of which chemical exposure is an important component
Results and Discussion
Vol. 71, 2009 / Organohalogen Compounds page 001990
By using the mouse as an animal model we can study the effect of a single toxicant administered directly to animals during different stages of the BGS. This animal model allows us to isolate the effects of certain
toxicants/combination of toxicants and also to specify certain issues that can be difficult to solve in traditional developmental toxicity tests and also in epidemiological studies.
In our earlier studies we have shown that low-dose exposure of neonatal mice during the BGS to environmental toxic agents (e.g. PCBs, PBDEs, PFOA, DDT, BFRs, PFCs) as well as known neurotoxic agents (nicotine, organophosphorous compounds, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can lead to disruption of the adult brain functioning and to increased susceptibility to toxic agents at adult age (14-23).
Neurobehavioural changes and changes in the cholinergic system are induced during a defined critical period of the BGS in mice, namely around postnatal day 10 (14,16,24-26). Recently, we have observed that neonatal exposure to PBDEs and the PFCs can affect proteins, such as CaMKII, GAP-43, synaptophysin and tau, which are important for neuronal growth and synaptogenesis, in the neonatal mouse brain (27-31).
In earlier studies we have noticed that neonatal exposure to environmental neurotoxic agents such as DDT and PCB can lead to increased susceptibility in adults to short-acting insecticides such as bioallethrin and paraoxon (15) and PCB (16). Among the effects observed were behavioural disturbances, including learning and memory deficits, and changes in cholinergic receptors. These behavioural aberrations were also found to develop over time, indicating a time-response/time-dependent effect. Furthermore, the dose used for adult exposure had no significant effect on neonatally untreated animals.
The vulnerability of the developing cholinergic system and altered susceptibility at adult age has been further explored by using cholinergic agents such as nicotine and acetylcholinesterase inhibitors (the
organophosphorous compound, paraoxon) (31,32). In a study10-day-old mice were exposed twice daily for five days to 33 or 66 g nicotine base/kg b.wt. s.c. At adult age the animals were exposed to paraoxon once every second day for 7 days. The paraoxon doses (0.17 and 0.25 mg/kg b.wt.) caused an inhibition of acetylcholine esterase of about 30 to 40 %. Two months after the adult exposure to paraoxon, the animals were observed for spontaneous behaviour. Animals that were only exposed to paraoxon as adults did not show any difference in behaviour compared to animals that had received saline both neonatally and as adults. All of these animals habituated equally well. However, animals neonatally exposed to nicotine and exposed to paraoxon as adults, showed deranged spontaneous behaviour with loss of habituation to a novel home environment and hyperactive condition. Clearly, the neonatal nicotine exposure has left these animals more susceptible to the adult paraoxon exposure and probably affected the ability to recover from the adult paraoxon exposure since the aberrations worsened with age. This early exposure to nicotine has also been shown to increase the adult susceptibility to PBDEs, PBDE 99, causing defect spontaneous behaviour, an effect that also worsened with age (32). We have now seen that this early exposure to nicotine and later adult exposure to paraoxon, accompanied with changes in spontaneous behaviour, also caused increased levels of the protein tau.
Spontaneous behaviour reflects a function dependent on the integration of a sensoric input into a motoric output, thus revealing animals’ ability to habituate to a novel home environment and integrate new with previously attained information, and thereby constitute a measure of cognitive function. The neurodegenerative disease, Alzheimer’s disease (AD), is characterized by a progressive and profound loss of cognitive functions and the cholinergic neurons are severely affected in the brain (34). In AD, the neuropathological hallmarks are senile plaques and neurofibrillary tangles. The pathogenic peptide -amyloid42 has been shown to induce
hyperphosphorylation of tau and that this may impair the function and plasticity of the synapse. This malfunction is thought to be one of many possible abnormalities linked to AD (35). Increased levels of tau in CSF is also used as a diagnostic marker for AD (36,37).
Taken together, these data indicate that differences in adult susceptibility to environmental pollutants are not necessarily an inherited condition. Rather they might well be acquired by low dose exposure to different toxic agents during early life. This might also have implications for the development of neurological disorder and/or diseases.
References
1. Schettler T. Environ Health Perspect 2001: 109; 813.
2. Grandjean P and Landrigan PJ. Lancet 2006: 368; 2167 3. Court mfl
4. Thapar A, Fowler T, Scourfield J, van den Bree M, Hollie T, Harold G, and Hay D. Am J Psychiatry 2003;
160:1985
5. Davison AN and Dobbing J. Applied Neurochemistry. Blackwell, Oxford, UK, 1968.
Vol. 71, 2009 / Organohalogen Compounds page 001991
6. Karczmar, A. G. Cholinergic influences on behaviour, in: Cholinergic Mechanisms. (P. G. Waser, ed.) Raven Press, New York, 501-529 (1975).
7. Nabeshima, T. Prog Brain Res 98, (1993) 405-411.
8. Perry, E., Walker, M., Grace, J., and Perry, R. Trends Neurosci 22, (1999) 273-280.
9. Fibiger, H.C., Brain Res. Rev., 4 (1991) 327-388.
10. Hohmann, C.F., and Berger-Sweeney, J., Perspect. Dev. Neurobiol., 5 (1998) 401-425.
12. Lipton, S.A., and Kater, S.B., TINS, 12 (1989) 265-270.
13. McGehee, D.S., and Role, L.W. Annu. Rev. Physiol., 57 (1995) 521-546.
14. Eriksson P. Neurotoxicology 1977; 18:719.
15. Eriksson P, Talts U. Neurotoxicology 2000;21:37.
16. Eriksson, P. In PCBs: Human and Environmental Disposition and Toxicology (L. G. Hansen, and L. W.
Robertson, Eds.). University of Illinois Press, Urbana and Chicago 2008; 172-182.
17. Eriksson P, Jakobsson E, Fredriksson A. Environ Health Perspec 2001;109:903.
18. Viberg H, Johansson N, Fredriksson A, eriksson J, Marsh G and Eriksson P. Toxicol Sci 2006: 76; 112.
19. Eriksson P, Ankarberg E, Viberg H, Fredriksson A. Neurotoxicity. Res 2001;3:37.
20. Viberg H, Fredriksson A, Eriksson P. Toxicol. Sci 2004;81:344.
21. Viberg H, Fredriksson A and Eriksson P. Toxicol. Appl. Pharmacol. 2003: 192; 95.
22. Johansson N, Viberg H, Fredriksson A and Eriksson P. Neurotoxicology 2009: 29; 911.
23. JohanssonN, Fredriksson A and Eriksson P. Neurotoxicology 2008: 29; 160.
24. Eriksson P, Ahlbom J and Fredriksson A. Brain res 1992 : 582 ; 277.
25. Eriksson P, Ankarberg E and Fredriksson A. Brain Res 2000 : 853 ; 41.
26. Viberg H, Fredriksson A, Jakobsson E, Örn U, Eriksson P. Toxicol Sci 2003;76:112-20.
27. Viberg H, Mundy W, Eriksson P. Neurotoxicology 2008; 29:152-59.
28. Johansson N, Eriksson P and Viberg H. Toxicol Sci 2009 : 108; 412.
30. Viberg, H. (2009). The neonatal ontogeny and neurotoxic effect of decabrominated diphenyl ether (PBDE 209) on levels of synaptophysin and tau. Dev Neurosci 2009: in press
31. Viberg, H. (2009). Exposure to PBDE 203 and 206 during the neonatal brain growth spurt affects proteins important for normal neurodevelopment in mice. Toxicol Sci 2009: doi:10.1093/toxsci/kfp074.
32. E. Ankarberg, A. Fredriksson and P. Eriksson. Toxicol Sci, 2004:82; 555.
33.Emma Ankarberg, 2003. Acta Univ. Ups., Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 907. 48 pp. Uppsala. ISBN 91-554-5800-9.
34. Paterson D and Nordberg A. Prog Neurobiol 2000 : 61 ; 75
35. Mutane G, Dalfo E, Martinez A and Ferrer I. Neuroscience 2008: 152; 913.
36. Andreasen N, Minthon L, Davidson P, Vanmechelen E, Vanderstichele H, Winblad B and Blennow K. Arch Neurol 2001: 58; 373.
37. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K and Minthon L. Lancet Neurol, 2006: 5; 228.
Vol. 71, 2009 / Organohalogen Compounds page 001992
