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Differential expression of muscarinic subtype mRNAs after exposure to neurotoxic pesticides Article in Neurobiology of Aging · November 1998 DOI: 10.1016/S0197-4580(98)00095-5 · Source: PubMed
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Neurobiology of Aging, Vol. 19, No. 6, pp. 553–559, 1998 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/98 $–see front matter
PII:S0197-4580(98)00095-5
Differential Expression of Muscarinic Subtype mRNAs after Exposure to Neurotoxic Pesticides ULRIKA TALTS,* JAN F. TALTS,† AND PER ERIKSSON*1 *Department of Environmental Toxicology, Uppsala University, Norbyva¨gen 18A, S-752 36 Uppsala, and †Department of Animal Physiology, Uppsala University, Biomedical Center, Box 596, S-751 24 Uppsala, Sweden Received 12 January 1998; Revised 14 September 1998; Accepted 26 October 1998 TALTS, U., J. F. TALTS, AND P. ERIKSSON. Differential expression of muscarinic subtype mRNAs after exposure to neurotoxic pesticides. NEUROBIOL AGING 19(6) 553–559, 1998.—We have recently reported an increase in the density of muscarinic cholinergic receptors in mice neonatally exposed to a persistent environmental agent, dichlorodiphenyltrichloroethane (DDT), and a subsequent exposure as adults to nonpersistent toxicants, such as bioallethrin or paraoxon. Here we have examined the effects of an exposure like this on muscarinic receptor mRNA expression. Ten-day-old Naval Medical Research Institute mice received a single oral dose of DDT (0.5 mg/kg body weight). When aged 5 months, they received bioallethrin (0.7 mg/kg body weight per day for 7 days) or paraoxon (1.4 mg/kg body weight every second day for 7 days). mRNA expression of subtypes m1, m3, and m4 was studied in 7-month-old animals. Changes could only be discovered in the DDT-bioallethrin treated mice, where expression of subtype m4 was elevated in cortex and caudate putamen. Moreover, the expression pattern of the subtypes m1, m3, and m4 in mouse brains was found to be very similar to that seen in rats, except for slight differences in the pyramidal cell layer of the hippocampus, where the outermost part of the CA3 region did not show any m4 hybridization. The present study indicates that the earlier observed increase in muscarinic receptor density in mice exposed as neonates to DDT and as adults to bioallethrin can be attributed to changes in the expression of m4. © 1999 Elsevier Science Inc. Neurotoxicity
Pesticide
Muscarinic receptor
m4
mRNA expression
IN MANY SPECIES the suckling period coincides with a period of rapid brain growth known as the brain growth spurt (14). During this period the cholinergic transmitter system undergoes rapid development in the neonatal rodent (13,24) when gradually increasing numbers of muscarinic and nicotinic receptors are found (23,24,34,47). In previous studies, the developing cholinergic system has been found to be sensitive to low doses of different environmental toxicants such as dichlorodiphenyltrichloroethane (DDT), pyrethroids, polychlorinated biphenyls, diisopropylfluorophosphate (DFP), and nicotine (1,21,22,41), leading to persistent effects on cholinergic receptors and behavior (17,18,20). An exposure circumstance likely to occur in nature is the combination of early exposure (during suckling) to persistent environmental pollutants, such as DDT, and late (adult) exposure to pesticides commonly used now, such as pyrethroids and organophosphorus compounds (see (48)). We have also recently shown an increased susceptibility to both pyrethroid and organophosphate exposure in adult mice treated neonatally with the persistent pollutant DDT (19,30,31). The mechanism of action of DDT and the type I pyrethroids involves a specific interaction with the sodium channels in the nerve membrane, leading to an increased neuronal activity (37,39). Organophosphorus compounds affect the nervous system by inhibiting acetylcholinester-
ase. As a result, acetylcholine accumulates in the synaptic clefts, leading to excessive postsynaptic stimulation (2,26,38). The organophosphorus compounds have also been suggested to interact directly with cholinergic receptors (16,29,32). In the earlier studies, adult mice exposed neonatally to DDT and as adults to bioallethrin (a type I pyrethroid) or paraoxon (an organophosphate) had permanent behavioral disturbances and an increased density of muscarinic receptors measured with the tritiated quinuclidinylbenzilate (QNB) binding technique. QNB is an antagonist that does not distinguish between different subtypes of muscarinic receptors. Presently, five different muscarinic receptor genes have been identified by molecular cloning (8,9,33). The nature of the receptor changes, i.e., whether or not they are on a transcriptional or translational level or if one or several of the muscarinic receptor subtypes are responsible for the changes seen in receptor density, is therefore of concern. The aim of the present work was to study whether the receptor changes seen after neonatal exposure to DDT and subsequent adult exposure to bioallethrin or paraoxon were due to changes on the mRNA level, and in the case that they were, to reveal which of the muscarinic subtypes had been affected. In the present study animals were exposed to DDT on Day 10 after birth and to bioallethrin or paraoxon at 5 months of age. The muscarinic
1 Address correspondence to: Per Eriksson, Department of Environmental Toxicology, Uppsala University, Norbyva¨gen 18A, S-752 36, Uppsala, Sweden. E-mail:
[email protected]
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receptor expression was studied in the brains of 7-month-old animals by Northern blotting and RNase protection assay to determine mRNA levels. Furthermore, in situ hybridization studies were applied to localize the changes. METHODS
Animals and Chemicals Pregnant Naval Medical Research Institute (NMRI) mice were obtained from B&K, Sollentuna, Sweden. Subsequently, each litter, adjusted within 48 h to 8 –12 pups, was kept together with its respective dam in a plastic cage in a room maintained at 22°C and a 12/12-h light/dark cycle. At the age of 4 weeks, pups were weaned, and males were placed and raised in groups of 4 –7 in a room for male mice only. Animals were supplied with standardized pellet food and tap water ad libitum. DDT (1,1,1trichloro-2,2-bis(p-chlorphenyl)-ethane; Puriss, Fluka, Switzerland), bioallethrin (2-allyl-4-hydroxy-3-methyl-2-cyclopenten-1one-(1R,3R,4S)-2,2-dimethyl-cyclopropane carboxylate; Roussel Uclaf, France), or paraoxon (diethyl p-nitrophenyl phosphate; Sigma) was dissolved in a mixture of egg lecithin (Merck) and peanut oil (Oleum arachidis) (1:10 w/w) and was sonicated together with water to yield a 20% fat emulsion vehicle containing DDT, bioallethrin, or paraoxon at the concentrations of 0.05, 0.180, and 0.350 mg/mL, respectively. Ten-day-old mice received a single dose of 0.5 mg (1.4 mmol) DDT/kg body weight orally via a polyvinyl chloride (PVC) tube (diameter 1.0 mm). Mice serving as controls received 10 mL/kg body weight of the 20% fat emulsion vehicle in the same manner. At the age of 5 months, bioallethrin or paraoxon was administered by gavage. Bioallethrin was given as one single dose, daily, for 7 days (0.7 mg (2.4 mmol)/kg body weight). Paraoxon was given as one single dose every second day for 7 days (1.4 mg (5.0 mmol)/kg body weight), a dose known to cause about 45% inhibition of acetylcholinesterase (31). Mice serving as controls received again 10 mL/kg body weight of the 20% fat emulsion vehicle. For in situ hybridization, one mouse was randomly picked from each treatment group. For RNase protection assays, the cerebral cortex from two mice, randomly picked from each treatment group, were pooled. For Northern blots, six mice were randomly selected from each treatment group, and the cerebral cortex from two animals were pooled. Statistical analysis for Northern blots were submitted to Kruskal–Wallis with pair-wise testing using Duncan’s test. In Situ Hybridization To detect muscarinic receptor mRNAs for the subtypes m1, m3, and m4, synthetic 48-mer oligonucleotides were used. Probes complementary to nucleotides 894 –941 in the i3 region of mouse m1 (46); 59-TCT TTC CAG CTG TAG GCC TGC AGA AGT CTG GGA GCC CGG CAA CAG GGA-39, nucleotides 75–122 in the i3 region of mouse m3 (3); 59-TTC ATC AGA AGA AGC AGA GTT TTC CAG GGA GGC AGC AGC ATC GTT GTT-39, and nucleotides 1100 –1147 in the i3 region of mouse m4 (50); and 59-GTG GTG GAC AGC TCT GTG GGT GGT CGT TCC TTG GTG TTC TGG GTG GCA-39 were used. The oligonucleotides were selected with oligo 228 4.0 software (National Biosciences Inc., Plymouth, MN). The in situ hybridization was performed as described by Durbeej et al. (15). Fourteen mm cryosections of the mouse brains were fixed in 4% paraformaldehyde in a 0.2 M phosphate buffer (pH 7.0). The sections were dehydrated in increasing concentrations of ethanol, defatted in chloroform, and slightly rehydrated in ethanol. Sections were hybridized overnight at 42°C in 100 mL of hybridization buffer containing 43 SSC, 13 Denhardts solution, 50% formamide, 10% dextransulfate, 250
mg/mL yeast RNA, 500 mg/mL salmon sperm DNA, 0.1 M DTT, and 1 3 106 c.p.m. 35S-labeled probe. Sections were washed 2 3 15 min in 13 SSC at 60°C, 1 3 15 min in 13 SSC and 0.05% N-lauryl sarcosine at 60°C, 1 3 15 min in 13 SSC at 60°C and 2 3 1 min in cold water. Sections were rapidly dehydrated, air dried, and exposed to KODAK NTB2 autoradiography emulsion for 4 –7 weeks. Control sections, hybridized with the same amount of labeled probe plus unlabeled probe in excess, did not show any hybridization. RNase Protection Assay Total RNA was isolated as described by Chirgwin et al. (11). RNase protection assays were performed with an RPA II™ kit (Ambion, Austin, TX) according to the manufacturers instructions. Briefly, single stranded riboprobes were generated from linearized muscarinic receptor cDNA clones using SP6 RNA polymerase and 32 P-UTP (Amersham). Samples of total brain cortex RNA (10 mg) were hybridized at 42°C overnight with the labeled antisense transcript. Hybridization to b-actin was used as an internal standard in all samples. Hybrids were digested for 30 min at 37°C with RNase A and T1. Protected fragments were separated on 5% polyacrylamide/8 M urea gels and analyzed by autoradiography. Signals were quantified by densitometric scanning using a BioRad GS 670 Imaging densitometer and the profile analysis program of the Macintosh/Molecular analyst 1.1 software (BioRad, Hercules, CA). The values were normalized to mouse b-actin signal intensities in the same lane. Yeast RNA (10 mg) was used as a negative control. The DNA templates used for RNase protection assays were fragments corresponding to nucleotides in the i3 region of rat m1 or m4 (8). Northern Blotting Total RNA was isolated as described by Chomczynski and Sacchi (12) and fractionated by agarose gel electrophoresis. The fractionated RNA was transferred to Zeta-Probe GT membranes and hybridized to 32P-oligolabeled cDNA clones in a 0.25 M sodium-phosphate solution containing 7% SDS at 65°C. The filters were subsequently washed in 0.02 M sodium-phosphate solutions containing 5 and 1% SDS for 4 3 1 h before autoradiography. The following previously described cDNA clones were used: a 0.39-kb m1 clone (8), a 0.52-kb m4 clone (8), and a 1.1-kb human G3PDH clone (Clontech). Signals were quantified by densitometric scanning using a Bio-Rad GS 670 Imaging densitometer and the profile analysis program of the Macintosh/Molecular analyst 1.1 software. The values were normalized to G3PDH signal intensities of the same lanes. RESULTS
Expression of Muscarinic Receptors in Normal Mouse Brain In situ hybridizations were performed on brains from 7-monthold mice. It was found that m1 was highly expressed in the hippocampus in the CA1, CA2, and CA3 regions and also in the dentate gyrus. Expression of m1 mRNA was also high throughout the cortex, with most of the expression in the more superficial and deeper layers (Fig. 1A). The m3 subtype was expressed in the CA1, CA2, and CA3 regions of the hippocampus, but not in the dentate gyrus. Some expression of m3 mRNA was also seen in the cortex (Fig. 1B). The m4 muscarinic receptor mRNA was expressed in the hippocampus throughout the CA1 and CA2 regions, but not in the outermost part of the CA3 region or in the dentate gyrus. It was also found in the superficial and deeper layers of the cerebral cortex (Fig. 1C). These results are in agreement with earlier published work on the muscarinic receptors of the rat brain
PESTICIDES AND MUSCARINIC SUBTYPE mRNAs
555 FIG. 1. In situ hybridizations of muscarinic receptors m1, m3, and m4 in 7-month-old mouse brains. (A) m1 is expressed in high levels in CA1, CA2, and CA3 regions of the hippocampus and in the dentate gyrus (DG). It is also expressed throughout the cortex with most of the expression in the uppermost and lower layers and in the piriform cortex (Pir). (B) m3 is expressed in the CA1, CA2, and CA3 regions of hippocampus, but not in the dentate gyrus. Some expression of m3 mRNA can also be seen in the cortex. (C) m4 is expressed in the superficial and deeper layers of cerebral cortex and throughout the CA1 and CA2 regions in the hippocampus, but not in the outer part of the CA3 region (denoted by white arrow) or in the dentate gyrus. Bar 5 1 mm.
(10), except for the absence of m4 transcripts in a part of the CA3 region of hippocampus. This discrepancy may be attributable to slight differences in the expression pattern of muscarinic receptors in mice compared to that of rats.
FIG. 2. Densitometric analysis of RNase protection assay showing muscarinic receptor m1 (A) and muscarinic receptor m4 (B) mRNA levels in 7-month-old mouse cerebral cortex. Signals were normalized to b-actin signal intensities for each lane and then expressed as % of vehicle-vehicle treated animals (VV), which was designated as 100%. The treatment groups are designated: VV, Vehicle-Vehicle; VB, Vehicle-Bioallethrin; VP, Vehicle-Paraoxon; DV, DDT-Vehicle; DB, DDT-Bioallethrin; DP, DDT-Paraoxon.
556
TALTS ET AL. Effect of Neonatal Exposure to DDT and Subsequent Adult Exposure to Bioallethrin or Paraoxon on m4 Localization To localize the changes in m4 mRNA expression seen in RNase protection assays and by Northern blot, in situ hybridizations were performed. The latter was also performed with probes reacting with m1 and m3 mRNAs for further elucidation of expression of the muscarinic cholinergic subtypes in areas other than the cortex. The in situ hybridization revealed both changes in the expression level and in the pattern of m4 expression (Fig. 6). Thus, m4 mRNA was elevated in the caudate putamen after neonatal exposure to DDT and subsequent adult exposure to bioallethrin (Fig. 6D). No obvious increase of m4 expression in the cerebral cortex was seen in this treatment group. Nor were any changes in the expression of m4 mRNA seen after neonatal exposure to DDT and subsequent adult exposure to paraoxon as adults (Fig. 6F). The expression pattern of m1 and m3 were about the same in all treatment groups. DISCUSSION
The present study has indicated that the earlier observed increases in the cortical density of specific [3H]QNB binding sites in animals exposed as neonates to DDT and as adults to bioallethrin (19,30) could be attributed to changes in the expression of muscarinic receptor m4 mRNA. Furthermore, the in situ
FIG. 3. Northern blot of muscarinic m1 receptor mRNA expression in 7-month-old mouse brain cortex. Total RNA (15 mg) was loaded in each lane, run on a 1% agarose gel, transferred to a nylon filter, and hybridized to a 32P-labeled rat m1 cDNA clone. As a control of loading, each lane was also hybridized to human G3PDH. In the upper panel the sizes of 28S and 18S rRNA are indicated to the left. The treatment groups are designated: VV, Vehicle-Vehicle; VB, Vehicle-Bioallethrin; DV, DDT-Vehicle; DB, DDT-Bioallethrin.
Effect of Neonatal Exposure to DDT and Subsequent Adult Exposure to Bioallethrin or Paraoxon on Muscarinic Receptor Expression To further study the effect of neonatal exposure to DDT and subsequent adult exposure to bioallethrin or paraoxon, muscarinic receptor mRNA expression was investigated. RNase protection assays were performed on total RNA from the cerebral cortex of 7-month-old mice exposed to these toxicants. The probes used were against the muscarinic subtypes m1 and m4. Subtype m3 was excluded because its expression was to low to measure differences with sufficient accuracy. The analyses showed a 25% increase in m4 mRNA expression in animals treated neonatally with DDT and with bioallethrin as adults compared to control (Fig. 2B), whereas no alterations in the levels of m1 mRNA could be seen in any of the treatment groups (Fig. 2A). No other exposure situation tested led to any changes in m4 expression. The increase seen in m4 mRNA expression by RNase protection assay could also be seen with the technique of Northern blotting (Fig. 4). Three individual Northern blots showed a significant increase (p , 0.05), 45%, of m4 mRNA expression (Fig. 5B). No changes in m1 expression could be detected with Northern blotting (Figs. 3 and 5A).
FIG. 4. Northern blot of muscarinic m4 receptor mRNA expression in 7-month-old mouse brain cortex. Total RNA (15 mg) was loaded in each lane, run on a 1% agarose gel, transferred to a nylon filter, and hybridized to a 32P-labeled rat m4 cDNA clone. As a control of loading, each lane was also hybridized to human G3PDH. In the upper panel, the sizes of 28S and 18S rRNA are indicated to the left. The treatment groups are designated: VV, Vehicle-Vehicle; VB, Vehicle-Bioallethrin; DV, DDT-Vehicle; DB, DDT-Bioallethrin.
PESTICIDES AND MUSCARINIC SUBTYPE mRNAs
557 It is indicated that the muscarinic receptor m4 is expressed in the cortex and in the hippocampus throughout the CA1 and CA2 regions, but not in the outermost part of the CA3 region or in the dentate gyrus. This differs from the expression of muscarinic receptor m4 in rats because all CA-regions of the hippocampus in the rat are positive for m4. This discrepancy may be attributable to slight differences in the expression pattern of muscarinic receptors in mice compared to rats. The effects of the neurotoxic insecticides on the expression of muscarinic receptor subtypes indicated that the earlier observed increase in the cortical density of specific [3H]QNB binding sites in animals exposed as neonates to DDT and as adults to bioallethrin (19,30) could be attributed to changes in expression of
FIG. 5. Densitometric analysis of Northern blots from three separate experiments showing muscarinic receptor m1 (A) and muscarinic receptor m4 (B) mRNA levels in 7-month-old mouse brain cortex. Signals were normalized to G3PDH signal intensities for each lane and then expressed as % of vehicle-vehicle treated animals (VV), which was designated as 100%. The treatment groups are designated VV, Vehicle-Vehicle; VB, Vehicle-Bioallethrin; DV, DDT-Vehicle; DB, DDT-Bioallethrin.
hybridization study reports new information regarding the expression pattern of the muscarinic receptor subtypes in the mouse brain. With the use of in situ hybridization (10,51) and subtypeselective antibodies (35,36,52,53,55), the five muscarinic receptor mRNAs and proteins have been localized in the rat brain. The receptor subtype m1 mRNA and protein are found in high levels in the pyramidal cell layer (CA1, CA2, and CA3) and the dentate gyrus of the hippocampus and in several layers of the cerebral cortex. Both the m3 mRNA and protein are present in the pyramidal cell layer, but not dentate gyrus of the hippocampus. Both the m3 mRNA and protein are also present in the cerebral cortex. The m4 transcript is expressed in the pyramidal layer of the hippocampus and also in the cerebral cortex and caudate putamen. The m4 protein is found in the same areas. However, there is a lack of reports regarding the expression pattern of the muscarinic receptor subtypes in the mouse. We have demonstrated here with in situ hybridization that the muscarinic receptors m1 and m3 are expressed in the cerebral cortex and in hippocampus in a pattern consistent with that reported earlier for these receptors in rats (10).
FIG. 6. In situ hybridizations demonstrating muscarinic receptor m4 expression in 7-month-old mouse brains. (A) Vehicle-Vehicle; (B) DDTVehicle; (C) Vehicle-Bioallethrin; (D) DDT-Bioallethrin; (E) VehicleParaoxon; (F) DDT-Paraoxon. Note the elevated expression of m4 in the caudate putamen (CPu) in the DDT-bioallethrin group (D). Bar 5 1 mm.
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muscarinic receptor m4 mRNA. This could be shown by both RNase protection assay and by Northern blot. An earlier study has also shown that neonatal exposure to DDT and subsequent exposure to paraoxon may cause a similar increase in the density of specific [3H]QNB binding sites (31). However, there were no changes in m4 expression after neonatal exposure to DDT and adult exposure to paraoxon. A possible explanation for the observed differences might be that DDT-paraoxon treated animals have slight increases in the production of mRNA of more than one muscarinic receptor subtype, and therefore these changes may be undetectable in our assays. Another possibility is that the increase seen in the density of specific [3H]QNB binding sites (31) of DDT-paraoxon treated animals is on the level of protein expression and not reflected in mRNA production. The localization of changes in expression of m4 mRNA were analyzed with in situ hybridization. Although no obvious increase of m4 mRNA expression were found in the cerebral cortex, the study revealed an induction of m4 mRNA expression in the caudate putamen after neonatal exposure to DDT and adult exposure to bioallethrin. The differences in m4 mRNA expression between DDTbioallethrin and DDT-paraoxon treated animals are interesting in light of results from previous studies (30,31). In these studies, animals exposed to DDT as neonates and to bioallethrin as adults had an impaired learning capacity in a swim maze, whereas animals exposed to DDT as neonates and paraoxon as adults showed no significant differences in that learning situation. Although both treatment groups had the same increase in specific [3H]QNB binding sites, it appears that only in the DDTbioallethrin group is this increase due to an increase in the gene expression of m4. The coupling of learning deficits to changes in the expression of the muscarinic subtype m4 is therefore of special interest to explore further. Neurodegenerative disorders such as Alzheimer’s disease (AD) are characterized by impairments in memory and cognitive functions. The cholinergic system in particular plays an important role in aging and memory deficit disorders. Dysfunctions in the
cholinergic system have been shown to cause learning and memory impairments (6,42). Although AD is a disorder involving multiple neurotransmitter systems, the cholinergic system is severely and consistently affected (for review, see (40,54)). There are contradictory reports concerning muscarinic receptors in AD because receptor binding capacity is reported to decrease, remain unchanged, or increase (for review, see (27)). Conflicting reports have also been presented regarding which of the muscarinic receptor subtypes that are involved in AD. Several reports on decreases of the pharmacologically defined M2 subtype have been published (4,7), but significant increases in M2 binding density were observed in various cortical areas of aged, cognitively impaired versus unimpaired (based on their performance in the Morris swim maze task) rats (5,43). An increse in M2 has also been found in the striatum of AD brains (45) and there have been reports on increased m1 mRNA levels (28) and increases in immunoprecipitated m4 receptor proteins (25) in cortical areas of AD brains. One study reports increased M2-binding in the cerebral cortex of patients with Parkinson’s disease (44), which may be relevant in view of the known overlap of AD and Parkinsonian (49). The results obtained in that study support a possible role for the muscarinic subtype m4 when memory and learning are impaired. In this regard, the present results may tentatively implicate a possible role of environmental toxicants in the etiology of neurodegenerative disorders. In conclusion, we have shown that muscarinic receptor m4 mRNA expression can be altered by a combination of neonatal and adult exposure to low doses of neurotoxic pesticides and that these alterations can be site-specific. We have also shown that the expression pattern of the muscarinic receptor subtypes in mice is very similar to the expression pattern seen in rats, except for slight differences in m4 expression in the hippocampus. ACKNOWLEDGEMENTS
This work was financially supported by grants from the Bank of Sweden Tercentenary Foundation, the Swedish Work Environmental Fund, and the Swedish Environmental Protection Board.
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