Camp. Biochem. Physiol. Vol. lGQC, No. l/2, pp. 269-270, 1991 Printed in Great Britain

0306~4492/91 $3.00 + 0.00 0 1991 Pergamon Press plc

DDT AND PYRETHROIDS-ECOTOXICOLOGICAL CONSIDERATIONS

PER ERKWN

Department of Zoophysiology, Uppsala University, Box 560, S-751 22 Uppsala, Sweden (Telephone: 46-18-182623; Telefax: 46-18-518843)

(Received 1 October 1990)

Abstract-l. DDT, and a DDT metabolite, DDOH, conjugated to palmitic acid, DDOH-PA, as well as bioallethrin and deltamethrin have all been shown to affect muscarinic choline@ receptors (MAChR) in the neonatal mouse brain after administration to lo-day-old mice during the period of rapid brain growth.

2. This early exposure has also been shown to lead to permanent changes in cholinergic and behavioural variables in the animals as adults.

INTRODUCTION

Environmental pollutants comprise a broad spectrum of substances. Many of the chlorinated hydrocarbons used in various industrial processes and pesticides such as PCB (polychlorinated biphenyls) and DDT are known to be persistent contaminants of the environment. Other potential hazards might be short- acting substances that do not become bioconcen- trated in biological systems but may nevertheless induce permanent disorder in the organism. Rela- tively little attention has been given to the possible toxic effects that persistent and non-persistent environmental hazards might exert on animals during their development, and the possible consequences in the adult animal. It is known that during the develop- ment of an animal there are periods which may be critical for its normal maturation, e.g. the period of rapid brain growth, the “brain growth spurt” (Davi- son and Dobbing, 1968), when the maturation of axonal and dendritic outgrowth and establishment of neural connections, synaptogenesis, and acquisition of new motor and sensory qualities takes place (Bolles and Woods, 1964; Davison and Dobbing, 1968). This stage of development is also associated with a large number of biochemical changes that will transform the foeto-neonatal brain into that of the mature adult. One of the transmitter systems that undergoes rapid development in the rodent during this period is the cholinergic system (Coyle and Yamamura, 1976; Falkeborn er al., 1983; Hiihmann and Ebner, 1985). In many mammalian species, such as mouse, rat, dog and man, the brain growth spurt coincides with the lactation period, when environ- mental hazards can be transferred from the mother to her offspring via the milk.

Earlier observations have shown that some of these environmental pollutants, such as DDT, PCB and chlorinated paraffins, are retained to a greater extent when administered to mice at the age of 10 days than when given at other ages (Eriksson, 1984; Eriksson and Darnerud, 1985). The retained sub- stances may be in either unmetabolized or metab- olized form. One possible mechanism by which

metabolized xenobiotics are retained in the body is via conjugation to fatty acids. This has been reported by Leighty and co-workers (1976, 1980, 1981) for cannabinoids, pentachlorphenol and a DDT metab- olite, DDOH, conjugated to palmitic acid, DDOH- PA. Pyrethroids are insecticides that have been applied widely in agricultural and in environmental health control, owing to their strongly insecticidal properties. These insecticides show similarities to DDT, with respect to both neurotoxic symptoms and neurotoxic action (Woolley, 1982; Narahashi, 1982) but have been found to be rapidly metabolized in mammals (Casida and Ruzo, 1980; Casida et al., 1983).

EFFECTS ON THE CHOLINERGIC SYSTEM

In an experiment on the neonatal mouse we ob- served that a single low oral dose of DDT (0.5 mg/kg bw) and DDOH-PA (0.7mg/kg bw), when given to the lo-day-old NMRI mouse affected the muscarinic cholinergic receptors (MAChR) in the cerebral cortex of the 17-day-old mouse (Eriksson and Nordberg, 1986). We also found that two different pyrethroids, bioallethrin (Type I) and deltamethrin (Type II), when given orally once daily (0.7 mg/kg bw) between the 10th and 16th postnatal day (in order to simulate the exposure time effective for DDT), affected the MAChR in the cerebral cortex of the 17-day-old mouse (Eriksson and Nordberg, 1990). This exposure caused an increase in the density of MAChR in the cerebral cortex as well as changes in the proportion of muscarinic receptor subtypes. DDT, DDOH-PA and bioallethrin all caused an increase in the pro- portion of low-affinity (LA) binding sites and a decrease in the proportion of high-affinity (HA) binding sites, whereas the reverse was observed after treatment with deltamethrin. Even in adult mice, at the age of 4 months, the cholinergic system was still affected (Eriksson et al., 1990b; Eriksson and Fredriksson, 1990). The change was found in the same brain region as in the 17-day-old mouse, namely the cerebral cortex. In DDT-exposed mice there was

269

210 PER ERIKSSON

an increased release of acetylcholine (ACh) and a tendency towards a decrease in the MAChR. In mice receiving bioallethrin and deltamethrin there was a decrease and a tendency towards a decrease in the MAChR, respectively, but no change in the pro- portions of HA- and LA- binding sites.

EFFECTS ON THE BEHAVIOUR

The neonatally exposed mice were also observed regarding behavioural deviations. The behavioural tests at the adult age of 4 months revealed disruption of a simple, non-associative learning process, i.e. habituation, in mice that had been treated with DDT, DDOH-PA, bioallethrin and deltamethrin (Eriksson et al., 1990a; Eriksson and Fredriksson, 1990). Thus, habituation, defined as a decrease in locomotion, rearing and total activity variables in response to the diminishing novelty of the test chambers, was demon- strated by the control mice and was considerably attenuated for mice treated with DDT, DDOH-PA, bioallethrin and deltamethrin.

The effect of neonatal exposure to DDT on the cholinergic system and on behaviour in the adult mouse could not be correlated to the concentration of DDT or its metabolites in the adult mouse brain since, one month after the administration of [ 14C]DDT to the lo-day-old mouse, no radioactivity was present in the brain (Eriksson et al., 1990b). This also seems to be the case with neonatal exposure to pyrethroids as they are rapidly metabolized in mam- mals (Casida and Ruzo, 1980; Casida et al., 1983).

CONCLUSION

Our studies showed that early exposure to short- acting pesticides such as pyrethroids can have the same effects as DDT and its fatty acid conjugate. The amount of DDT given in our studies was of physio- logical significance and toxicological relevance, since it is of the same order of magnitude as that to which animals and humans can be exposed during the lactation period (Bevenue, 1976; WHO, 1979; Slorach and Vaz, 1983). Therefore, a current area of concern must be whether the input of short-acting pesticides to an environment already contaminated with persist- ent environmental pollutants can lead to unexpected ecotoxicological effects. Short-acting pesticides might also be of ecotoxicological significance, since they can cause the same effects as long-lasting chemicals.

Acknowledgements-Grants have been received from The Bank of Sweden Tercentenary Foundation and the Swedish Environmental Protection Board.

REFERENCES

Bevenue A. (1976) The “bioconcentration” aspects of DDT in the environment. Resid. Rev. 61, 37-112.

Bolles R. G. and Woods P. J. (1964) The ontogeny of behaviour in the albino rat. Anim. Behau. 12, 42741.

Casida J. E. and Ruzo L. 0. (1980) Metabolic chemistry of pyrethroid insecticides. Pesric. Sci. 11, 257-269.

Casida J. E., Gammon D. W., Glickman A. H. and Lawrence L. J. (1983) Mechanisms of selective action of pyrethroid insecticides. A. Reo. Pharmac. Toxicol. 23, 413-38.

Coyle J. T. and Yamamura H. I. (1976) Neurochemical aspects of the ontogenesis of cholinergic neurons in the rat brain. Brain Res. 118, 429440.

Davison A. N. and Dobbing J. (1968) Applied Neurochem- isfrv. DD. 178-221. 253-316. Blackwell. Oxford. , --

Eriksson P. (1984) Age-dependent retention of [ ‘%Z]DDT in the brain of the postnatal mouse. Toxicol. LAX 22, 323-328.

Eriksson P., Archer T. and Fredriksson A. (1990a) Altered behaviour in adult mice exposed to a single low oral dose of DDT and its fatty acid conjugate as neonates. Brain Res. 514, 141-142.

Eriksson P. and Darnerud P. 0. (1985) Distribution and retention of some chlorinated hydrocarbons and a phtha- late in the mouse brain during the pre-weaning period. Toxicology 31, 185-203.

Eriksson P. and Fredriksson A. (1990) Neurotoxic effects of two different pyrethroids, deltamethrin and bioallethrin, on immature and adult mice: changes in behavioural and muscarinic receptor variables (submitted).

Eriksson P., Nilsson-Hakansson L., Nordberg A., Aspberg A. and Fredriksson A. (1990b) Neonatal exposure to DDT and its fatty acid conjugate-Effects on cholinergic and behavioural variables in the adult mouse. Neurotoxicology 11, 345-354.

Eriksson P. and Nordberg A. (1986) The effects of DDT, DDOH-palmitic acid, and a chlorinated paraffin on muscarinic receptors and the sodium-dependent choline uptake in the central nervous system of immature mice. Toxicol. appl. Pharmac. 85, 121-127.

Eriksson P. and Nordberg A. (1990) Effects of two pyrethroids, bioallethrin and deltamethrin, on subpopu- l&ions of muscarinic and nicotinic receptors in the neo- natal mouse brain. Toxicol. aopl. Pharmac. 102.456463.

Falkeborn Y., Larsson C., Nbrdberg A. and Slanina P. (1983) A comparison of regional ontogenesis of nicotine- and muscarine- like binding sites in mouse brain. Inf. J. Dev. Neurochem. 1, 187-190.

Hdhmann C. C. and Ebner F. F. (1985) Development of cholinergic markers in mouse forebrain. I. Choline acetyl- transferase enzyme activity and acetylcholineesterase his- tochemistry. Devl Brain Res. 23, 225-241.

Leighty E. G. and Fentiman A. F., Jr. (1981) Liver micro- somal conjugation of pentachlorophenyl to fatty acids. Fedn Proc. Fedn Am. Sots exp. Biol. 40, 677.

Leighty E. G., Fentiman A. F., Jr and Foltz R. L. (1976) Long-retained metabolities of A9-and Aa-tetrahydrocan- nabinols identified as novel fatty acid conjugates. Res. Commun. Path. Pharmac. 14, 13-28.

Leighty E. G., Fentiman A. F., Jr and Thompson R. M. (1980) Conjugation of fatty acids to DDT in the rat: possible mechanism for retention. Toxicology 15, 77-82.

Narahashi T. (1982) Cellular and molecular mechanisms of action of insecticides: neurophysiological approach. Neurobehav. Toxicol. Teratol. 4, 753-758.

Slorach S. A. and Vaz R. (1983) Assessment of human exposure to selected organochlorine compounds through biological monitoring. Swedish Natn Food Admin. pp. 134. Uppsala.

WHO (1979) DDT and its derivatives. Environ. Health Crif. 9, 5687.

Woolley D. E. (1982) Neurotoxicity of DDT and possible mechanism of action. In Mechanism of Action of Neuro- toxic Substances (Edited by Prasad K. N. and Vernadakis A.), pp. 95-141. Raven Press, New York.