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.
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