Cypermethrin is a widely used synthetic type II pyrethroid insecticide due to its high insect toxicity, low mammalian toxicity, and rapid metabolism (Crawford et al. 1981; Rhodes et al. 1984). Cypermethrin is primarily considered to be a sodium channel toxin. At high concentrations, pyrethroids induce a long-lasting depolarization and block nerve conduction. However, other secondary mechanisms of action are also involved in their toxicity, including antagonism of GABA inhibitory action, modulation of nicotinic cholinergic transmission, and enhanced noradrenaline and adrenaline release (reviewed in: Aldridge 1990; Ray 1991; Vijveberg and van den Bercken 1990). Gestational exposure to cypermethrin has been shown to cause severe and persistent alterations in the neural and physical development of rat offspring (Gomes et al. 1991; Malaviya et al. 1993; Biernacki et al. 1995).
Santoni et al. (1997) have shown that the prenatal exposure of rats to cyper-methrin results in increased numbers of peripheral blood lymphocytes and bone marrow cells but decreases in the number of lymphoid cells in the spleen and thymus. This study also demonstrated similar compartmental effects on NK cell number and function. Santoni et al. (1998) demonstrated that T cell number (thymocyte depletion, altered distribution of thymocyte subsets) and function (decreased mitogen proliferation and IL-2 production) were affected by gestational cypermethrin exposure from GD 7 to 16. Finally, Santoni et al. (1999) suggested that these immune changes may be due to the increased plasma levels of adrenaline (neuroendocrine) and noradrenaline (SNS) observed in gestationally cypermethrin-exposed offspring.
A number of other neuroteratogens. including additional drugs of abuse (heroin and other opiates, cocaine, and so on), pesticides, and other toxicants, act diffusely in the brain, affecting many regions through neural pathways and neurotransmitter systems, resulting in many behavioral effects and additional peripheral organ defects. In addition, some of these agents, particularly the opioids, can act directly on immune cells. A great deal of information is available on the effects of these drugs on the immune system of adults; however, their effects on the developing immune system are less well described than the examples provided above.
To help address the role that the extensive sympathetic innervation of primary and secondary lymphoid organs plays in modulating immune responses, Alaniz et al. (1999) analyzed the immune response in dopamine p-hydroxylase deficient mice. These mice cannot produce norepinephrine (NE) or epinephrine (E), but can produce the precursor dopamine. Compared to wild-type or heterozygous controls, these mice have been shown to have altered metabolism, thermoregulation, cardiovascular tone, and maternal behavior (Thomas et al. 1995; Thomas et al. 1997; Thomas et al. 1998). It was noticed that a third of these animals die during adolescence (Thomas et al. 1995); however, if housed under specific pathogen-free conditions (SPF), they were able to survive to adulthood. These results indicate that the development of the immune system was affected by the lack of norepinephrine or epinephrine.
Alaniz et al. (1999) performed additional studies to analyze in detail which aspects of the immune system were affected in these knockout mice. In these studies, mice kept under SPF conditions had no changes to the numbers of T- and B-
lymphocytes, granulocytes, and monocytes present in blood, thymus, or spleen compared to wild-type or heterozygous controls. However, they observed severe thymic involution in animals that were not maintained under SPF conditions. These results suggest that these mice did not have the capacity to respond to an immune challenge. This was confirmed with both a primary and secondary (re-challenge) infection model. When -/- vs. +/+ mice were infected with L. monocytogenes, the numbers of bacteria in the liver were higher and deaths occurred more frequently in the -/- animals. A similar result was found after a rechallenge. Alaniz et al. (1999) determined that this down-modulated immune response was due to depressed cytok-ine production by T-lymphocytes, particularly Th1 cytokine production. The antibody response that depended on Th1 cells (IgG2a) was reduced in these animals, but the antibody response that depended on Th2 cells (IgG1) was not affected.
To determine which component of this reduced immune response might be due to effects on the HPA axis, as opposed to the SNS-induced effects, corticosterone and prolactin concentrations were measured in these mice. Corticosterone can inhibit an immune response and prolacton, which is induced by dopamine, can enhance T cell function. Alaniz et al. (1999) found that corticosterone was elevated during a primary infection but not during a secondary infection, indicating that corticosterone may be only partly responsible for the observed T cell suppression. In addition, prolactin concentrations were similar in both groups. These findings provide direct evidence that the SNS has a dramatic influence on the development of Th1 cell responsiveness. Interestingly, leptin-deficient knockout mice with reduced sympathetic outflow, show similar T cell deficiencies (Lord et al. 1998). These mice may also offer a potential explanation for why malnourished animals have suboptimal immune responses. In fact, morphometric studies have shown links between certain parameters of birth size and depressed immune function in offspring (Leadbitter et al. 1999; McDade et al. 2001).
Conversely, nerve growth factor transgenic mice, displaying a developmentally early hyperinnervation of immune organs, are also characterized by an immune system down-regulation (Carlson et al. 1995; Carlson et al. 1998). Similarly, a naturally occurring mutant, the Spontaneous Hypertensive Rat, which also has a hyperactivation of lymphoid organ adrenergic neurons, also manifests immune deficits (Purcell and Gattone 1992; Purcell et al. 1993). These rats have reduced numbers of immature T cells, decreased proliferative responses to T cell mitogens, decreased delayed-type hypersensitivity, allograft rejection, and altered antibody formation (Strausser 1983; Sauro and Hadden 1992; Purcell et al. 1993).
The studies discussed demonstrate that inappropriate (either too much or too little) sympathetic stimulation of immune organs during development can result in depressed immune responses. The exact mechanisms responsible for these alterations after either hyper- or hypoadrenergic stimulation remain to be determined.
This review has concentrated on the potential non-neuroendocrine routes by which the developing brain can modulate offspring immune responses. The infor mation reviewed illustrates that this is a complex issue in that different insults affect different brain regions, and the specific effects can vary depending on the timing, duration, and dose of the insult. For these reasons, it is clear that additional studies are necessary to more exactly define how changes (injuries) to different parts of the developing brain may cause downstream effects on immune system development. The studies performed with nicotine have presented considerable evidence that hyperactivation of cholinergic input leads to long-term immune alterations. Studies are still needed, however, to determine the exact process that causes the immune misprogramming. Remaining questions include which brain regions are involved, what changes occur in these regions, what specific neural pathways (sympathetic, parasympathetic, or neuropeptides) are involved, and what signaling mechanisms in immune organs have been altered that mediate the adverse developmental out-come(s). Although the answers to these questions have yet to be defined, clues from the developmental exposures and genetic manipulation research described indicate that long-term changes to SNS and other neuropeptides' systems input into immune organs, as well as how immune cells respond to this input (i.e., changes to common second messenger systems), are likely involved. In fact, it is entirely possible that both common and specific alterations occur in the "setting of immune tone" after different developmental insults.
The author would like to thank my collaborator Dr. Hernan A. Navarro for providing invaluable suggestions and comments, and to Drs. Sherry Parker and Jeremy Taylor for their expert editing.
Ackerman KD, Madden KS, Linmat S, Felton SY, and Felton DL. 1991. Neonatal sympathetic denervation alters the development of in vitro spleen cell proliferation and differentiation. Brain Behav Immun 5: 235-261. Alaniz RC, Thomas SA, Perez-Melgosa M, Mueller K, Farr AG, Palmiter RD, and Wilson CB. 1999. Dopamine b-hydroxylase deficiency impairs cellular immunity. Proc Natl Acad Sc USA96: 2274-2278. Aldridge WN. 1990. An assessment of the toxicological properties of pyrethroids and their neurotoxicity. CRC Crit Rev Toxicol 21:89-104. Balduni W and Costa LG. 1989. Effect of ethanol on muscarinic receptor-stimulated phos-phoinositide metabolism during brain development. J Pharmacol Exp Ther 250: 541-547.
Basham KB, Whitmore SP, Adcock AF, and Basta PV. 1998. Chronic and acute prenatal and postnatal ethanol exposure on lymphocyte subsets from offspring thymic, splenic and intestinal intraepithelial sources. Alcohol Clin Exp Res22: 1501-1508. Basta PV, Basham KB, Ross WP, Brust ME, and Navarro HN. 2000. Gestational nicotine exposure alone or in combination with ethanol down-modulates offspring immune function. Int J Immunopharmacol 22: 159-169.
Besedovsky H and Sorkin E. 1977. Network of immune-neuroendocrine interactions. Clin Exp Immunol 27(1): 1-12.
Besedovsky HO, del Rey A, Sorkin E, Da Prada M, and Keller HH. 1979. Immunoregulation mediated by the sympathetic nervous system. Cell Immunol 48(2): 346-55.
Besedovsky HO, del Rey AE, and Sorkin E. 1985. Immune-neuroendocrine interactions. J Immunol 135: 750s-754s.
Biernacki B, Wlodarczyk B, Minta M, and Juszkiewicz T. 1995. The influence of cypermethrin on the pregnant and prenatal development of rabbits. Med Weter 51:31-35.
Carlson SL, Albers KM, Beiting DJ, Parish M, Conner JM, and Davis BM. 1995. NGF modulates sympathetic innervation of lymphoid tissues. J Neurosci 15:5892-5899.
Carlson SL, Johnson S, Parrish ME, Cass WA. 1998. Development of immune hyperinner-vation in NGF-transgenic mice. Exp Neurol 149: 209-220.
Chambers DA, Cohen RL, and Perlman RL. 1993. Neuroimmune modulation: signal transduction and catecholamines. Neurochem Int 22(2): 95-110.
Chang MP, Yamaguchi DT, Yeh M, Taylor AN, and Norman DC. 1994. Mechanism of the impaired T-cell proliferation in adult rats exposed to alcohol in utero. Int J Immu-nopharmacol 16(4): 345-357.
Chiapelli F and Taylor AN. 1995. The fetal alcohol syndrome and fetal alcohol effects on immune competence. Alcohol Alcohol30: 259-263.
Chrousos GC. 1998. Stressors, stress, and neuroendocrine integration of the adaptive response: The 1997 Hans Selye memorial lecture. Ann NY Acad Sci851: 311-335.
Chrousos GC. 2000. The stress response and immune function: Clinical implication: The 1999 Novera H. Spector Lecture. Ann NY Acad Sci917: 38-67.
Coe CL and Lubach GR. 2000 Prenatal influences on Neuroimmune Set Points in Infancy. Ann NY Acad Sci917: 468-477.
Costa LG and Guizzetti M. 1999. Muscarinic cholinergic receptor signal transduction as a potential target for the development of neurotoxicity of ethanol. Biochem Pharm 57: 721-726.
Crawford MJ, Croucher A, and Hutson DH. 1981. Metabolism of cis- and trans-cypermethrin in rats: Balance and tissue retention study. J Agric Food Chem 29: 130-135.
Crumpton TL, Seidler FJ, and Slotkin TA. 2000. Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation. Brain Research, 857: 87-98.
Elenkov IJ, Wilder RL, Chrousos GP, and Vizi ES. 2000. The sympathetic nerve—an inte-grative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4): 595-638.
Ewald SJ. 1989. T lymphocyte populations in fetal alcohol syndrome. Alcohol Clin Exp Res 13: 485-489.
Ewald SJ and Walden SM. 1988. Flow cyrometric and histological analysis of mouse thymus in fetal alcohol syndrome. J Leukoc Bio. 44: 434-440.
Felten DL, Felten SY, Bellinger DL, Carlson SI, Ackerman KD, Madden KS, Olschowska JA, Livnat S. 1987. Noradrenergic sympathetic neural interactions with the immune system: structure and function. Immunol Rev 100: 225-260.
Felten SY, Felten DL, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, Olschowka JA, and Livnat S. 1988 Noradrenergic sympathetic innervation of lymphoid organs. Prog Allergy 43: 14-36.
Felten SY, Madden KS, Bellinger DL, Kruszewska B, Moynihan JA, and Felten DL. 1998. The role of the sympathetic nervous system in the modulation of immune responses. Adv Pharmacol 42: 583-587.
Geng Y, Savage SM, Johnson LJ, Seagrave JC, and Sopori ML. 1995. Effects of nicotine on the immune response. I. Chronic exposure to nicotine impairs antigen receptor-mediated signal transduction in lymphocytes. Toxicol Appl Pharmacol 135: 268-278.
Geng Y, Savage SM, Razani-Boroujerdi S, and Sopori ML. 1996. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy. J Immunol 156: 2384-2390.
Goodlett CR and Horn KH. 2001. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res Health 25: 175-184.
Gomes M, Bernardi MM, and de Souza Spinosa H 1991. Pyrethorid insecticides and pregnancy: effect on physical and behavioral development of rats. Vet Hum Toxicol 33: 315-317.
Gottesfeld Z, Christie R, Felten DL, and Legrue SJ. 1990. Prenatal ethanol exposure alters immune capacity and noradrenergic synaptic transmission in lymphoid organs of the adult mouse. Neuroscience 35: 185-194.
Gottesfeld Z and Abel E. 1991. Maternal and paternal alcohol use: Effects on the immune system of the offspring. Life Sci 48:1-8.
Gottesfeld Z and Ullrich SE. 1995. Prenatal alcohol exposure selectively suppresses cellmediated but not humoral immune responsiveness. Int J Immunopharmacol 17(3): 247-54.
Guerri C. 1998 Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure. Alcohol Clin Exp Res 22: 304-312.
Haas HS and Schauenstein K. 1997. Neuroimmunomodulation via limbic structures—the neuroanatomy of psychoimmunology. Prog Neurobiol 51(2): 195-222.
Hofer MA. 1983. The mother-infant interaction as a regulator of infant physiology and behavior. In: Sosenblum LA and Moltz H (Eds.), Symbiosis in Parent-Offspring Interactions, pp. 61-76. Plenum; New York.
Janson AM, Fuxe K, Agnati LF, Kitayama L, Harfstrand A, Andersson K, and Goldstein M. 1988. Chronic nicotine treatment counteracts the disappearance of tyrosine-hydrox-ylase-immunoreactive nerve cell bodies, dendrites and terminals in the mesostriatal dopamine system of the male rat after hemitransection. Brain Res 455: 332-345.
Jerrells TR. 1991. Immunodeficiency associated with ethanol abuse. Adv Exp Med Biol .288: 229-236.
Johnson S, Knight R, Marmer, DJ, and Steele R. 1981. Immune deficiency in fetal alcohol syndrome. Pediatr Res 15: 908-911.
Kohm AP and Sanders VM. 2000. Norepinephrine: a messenger from the brain to the immune system. Trends Immunol Today 21(11): 539-542.
Lauder JM, Liu J, Devaud L, and Morrow AL. 1998. GABA as a trophic factor for developing monoamine neurons. Perspect Dev Neurobiol 5: 247-259.
Leadbitter P, Pearce N, Cheng S, Sears MR, Holdaway MD, Flannery EM, Herbison GP, and Beasley R. 1999. Relationship between fetal growth and the development of asthma and atopy. Thorax 54: 905-910.
Lindstrom J. 1997. Nicotinic acetylcholine receptors in health and disease. Mol Neurobiol. 15: 193-222.
Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, and Lechler RI. 1998. Leptin modulates the T-cell immune response and reverses starvation-induced immunosup-pression. Nature (London) 394: 897-901.
Madden KS, Felten SY, Felten DL, and Bellinger DL. 1995. Sympathetic nervous system— immune system interactions in young and old Fischer 344 rats. Ann N Y Acad Sci 771: 523-534
Maestroni GJ. 2000. Neurohormones and catecholamines as functional components of the bone marrow microenvironment. Ann NY Acad Sci917:29-37.
Malaviya M, Husain, Seth PK, and Husain R. 1993. Perinatal effects of two pyrethoid insecticides on brain neurotransmitter function in the neonatal rat. Vet Hum Toxicol 35: 119-122.
McDade TW, Beck MA, Kuzawa C, and Adair LS. 2001. Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence. Am J Clin Nut 74: 543-548.
Miller MW and Robertson S. 1993. Prenatal exposure to ethanol alters the postnatal development and transformation of radial glia to astrocytes in the cortex. J Comp Neurol 337: 253-266.
Monjan AA and Mandell W. 1980. Fetal alcohol and immunity: Depression of mitogen-induced lymphocyte blastogenesis. Neurobehav Toxicol 2: 213-215.
Morale MC, Gallo F, Tirolo C, Testa N, Caniglia S, Marletta N, Spina-Purrello V, Avola R, Caucci F, Tomasi P, Delitala G, Barden N, and Marchettie B. 2001. Neuroendocrine-immune (NEI) circuitry from neuron-glial interaction to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system. Immunol Cell Biol 79(4): 400-417.
Navarro, H.A., Mills E, Seidler FJ, Baker FE, Lappi SE, Tayyeb MI, Spencer JR, and Slotkin TA. 1990. Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding. Brain Res Bull 25: 233-237.
Navarro HN, Basta PV, Seidler FJ, and Slotkin TA. 2001a. Adolescent nicotine: deficits in immune function. Dev Brain Res 130: 253-256.
Navarro HN, Basta PV, Seidler FJ, and Slotkin TA. 2001b. Neonatal chlorpyrifos administration elicits deficits in immune function in adulthood: a neural effect? Dev Brain Res 130: 249-252.
Navarro HN, Basta PV, Seidler FJ, and Slotkin TA. 2003. Short-term adolescent nicotine exposure in rats elicits immediate and delayed deficits in T-lymphocyte Function: Critical periods, patterns of exposure, dose thresholds. Submitted to Nicotine and Tobacco Research 5: 859-868.
Ng PC. 2000. The fetal and neonatal hypothalamic-pituitary-adrenal axis. Arch Dis Child 82: F250-F254.
Niijima A. 1995. An electrophysiological study on the vagal innervation of the thymus in the rat. Brain Res Bull 38: 319-323.
Norman DC, Chang MP, Castle SC, Van Zuylen JE, and Taylor AN. 1989. Diminished proliferative response of con A-blast cells to interleukin 2 in adult rats exposed to ethanol in utero. Alcohol Clin Exp Res 13(1): 69-72.
Olney JW, Wozniak DF, Jevtovic-Todorovic V, and Ikonomidou C. 2001. Glutamate signaling and the fetal alcohol syndrome. MRDD Res Reviews7: 267-275.
Owman C, Fuxe K, Janson AM, and Kahrstrom J. 1989. Chronic nicotine treatment eliminates asymmetry in striatal glucise utilization following unilateral transection of the mesos-tiatal dopamine pathway in rats. Neurosci Lett 102:279-283.
Purcell ES and Gattone VH. 2nd, 1992. Immune system of the spontaneously hypertensive rat. I. Sympathetic innervation. Exp Neurol 117: 44-50.
Purcell ES, Wood GW, and Gattone VH. 2nd 1993. Immune system of the spontaneously hypertensive rat: II. Morphology and function. Anat Rec. 237(2): 236-242.
Ray ED. 1991. Pesticides derived from plants and other organisms. In: Hayes WY Jr and Laws ER Jr (Eds.), Handbook of Pesticide Toxicology. Academic Press, San Diego, CA, pp. 585-636.
Redei E, Clark WR, and McGivern RF. 1989. Alcohol exposure in utero results in diminished T-cell function and alterations in brain corticotropin-releasing factor and ACTH content. Alcohol Clin Exp Res 13(3): 439-443.
Rhodes C, Jones BK, and Croucher A. 1984. The bioaccumulation and biotransformation of cis, trans-cypermethrin in the rat. Pest Sci 15: 471-480.
Roy TS, Seidler FJ, and Slotkin TA. 2002. Prenatal nicotine exposure evokes alteration of cell structure in the hippocampus and somatosensory cortex. J Pharmacol Exp Ther 300: 124-133.
Salzet M, Vieau D, and Day R. 2000. Crosstalk between nervous and immune systems through the animal kingdom: focus on opioids. TINS 23(11): 550-555.
Sanders VM and Straub RH. 2002. Norepinephrine, the beta-Adrenergic Receptor, and Immunity. Brain Behav Immun 16(4): 290-332.
Santoni G, Cantalamessa F, Mazzucca L, Romagnoli S, and Piccoli M. 1997. Prenatal exposure to cypermethrin modulates rat NK cell cytotoxic functions. Toxicol 120: 231-242.
Santoni G, Cantalamessa F, Cavagna R, Romagnoli S, Spreghini E, and Piccoli M. 1998. Cypermethrin-induced alteration of thymocyte distribution and functions in prena-tally-exposed rats. Toxicol 125: 7-78.
Santoni G, Cantalamessa F, Spreghini E, Sagretti O, Staffolani M, and Piccoli M. 1999. Alteration of T cell distribution and functions in prenatally cypermethrin-exposed rats: possible involvement of catecholamines. Toxicol 138: 175-187.
Sauro MD and Hadden JW. 1992. Gamma-interferon corrects aberrant protein kinase C levels and immunosuppression in the spontaneously hypertensive rat. Int J Immunophar-macol. 14: 1421-1427.
Seelig LL Jr, Steven WM, and Stewart GL. 1996. Effects of maternal ethanol consumption on the subsequent development of immunity to Trichinella spiralis in rat neonates. Alcohol Clin Exp Res 20(3): 514-522.
Seidler FJ, Levin ED, Lappi SE, and Slotkin TA. 1992. Fetal nicotine exposure ablates the ability of postnatal nicotine challenge to release norepinephrine from rat brain regions. Dev Brain Res 69: 288-291.
Shanks N and Lightman SL. 2001. The maternal-neonatal neuro-immune interface: Are there long-term implications for inflammatory or stress-related disease? J Clin Invest 108 (11): 1567-1573.
Slotkin TA, Cho H, and Whitmore WL. 1987. Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways. Brain Res Bull 18: 601-611
Slotkin TA, McCook EC, Lappi SE, and Seidler FJ. 1992. Altered development of basal and forskolin-stimulated adenylate cyclase activity in brain regions of rats exposed to nicotine prenatally. Brain Res Dev Brain Res 68(2): 233-239.
Slotkin TA. 1998. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther 285: 931-945.
Slotkin TA. 1999. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect 107 Suppl 1: 71-80.
Slotkin TA. 2002. Nicotine and the adolescent brain. Insights from an animal model. Neuro-toxicol Teratol 24(3): 369-384.
Song X, Seidler FJ, Saleh JL, Zhang J, Padilla S, and Slotkin TA. 1997. Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade. Toxicol Appl Pharmacol 145(1): 158-174.
Song DK, Im YB, Jung JS, Suh HW, Huh SO, Song JH, and Kim YH. 1999. Central injection of nicotine increases hepatic and splenic interleukin 6 (IL-6) mRNA expression and plasma IL-6 levels in mice: involvement of the peripheral sympathetic nervous system. FASEB J 13:1259-1267.
Stevens-Felten SY and Bellinger DL. 1997. Noradrenergic and peptidergic innervation of lymphoid organs. Chem Immunol 69: 99-131.
Straub RH, Cutolo M, Zeitz B, and Scholmerich J. 2001. The process of aging changes the interplay of the immune, endocrine, and nervous systems. Mech Ageing Dev 122 (14): 1591-1611.
Strausser HR. 1983. Immune response modulation in the spontaneously hypertensive rat. Thymus 5: 19-33.
Tewari S, Diano M, Bera R, Nguyen Q, and Parekh H. 1992. Alterations in brain polyribosomal RNA translation and lymphocyte proliferation in prenatal ethanol-exposed rats. Alcohol Clin Exp Res 16(3): 436-442.
Thomas SA, Matsumoto AM, and Palmiter RD. 1995. Noradrenaline is essential for mouse fetal development. Nature (London) 374: 643-646.
Thomas SA and Palmiter RD. 1997. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature (London) 387: 94-97.
Thomas SA, Marck BT, Palmiter RD, and Matsumoto AM. 1998. Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase. J Neu-rochem 70: 2468-76.
Vijveberg HP and van den Bercken J. 1990. Neurotoxicological effects and mode of action of pyrethroid insecticides. Crit Rev Toxicol 21: 105-126.
Webster JI, Tonelli L, and Sternberg EM. 2002. Neuroendocrine regulation of Immunity. Annu Rev Immunol 20: 125-163.
Weinberg J and Jerrells TR. 1991. Suppression of immune responsiveness: sex differences in prenatal ethanol effects. Alcohol Clin Exp Res 15(3): 525-31.
Whitney KD, Seidler FJ, and Slotkin TA. 1995. Developmental neurotoxicity of chlorpyrifos: cellular mechanisms. Toxicol Appl Pharmacol 134(1): 53-62.
Zagon IS and McLaughlin PJ. 1984. Duration of opiate receptor blockade determines tum-origenic response in mice with neuroblastoma: a role for endogenous opioid systems in cancer. Life Sci 35(4): 409-416.
Zhou FC, Sari Y, Zhang JK, Goodlett CR, Li T-K. 2001. Prenatal alcohol exposure retards the migration and development of serotonin neurons in fetal C57BL mice. Dev Brain Res 126: 147-155.
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.