A growing literature base indicates that laboratory animals exposed in utero (during immune system development) to immunotoxic chemicals may result in severe effects on the immune system that last into adult life. For example, mice exposed to the organochlorine insecticide chlordane in utero have been found to display reduced numbers of granulocyte-macrophage colony-forming units (GM-CFU) and colony-forming units/spleen (CFU-S) as early as gestational day (GD) 18 and the suppression extended to 200 days of age (Barnett et al. 1990). Previous studies with in utero chlordane exposure demonstrated long-term depression of the contact hypersensitivity response to oxazolone in mice at 101 days of age (Spyher-Cranmer et al. 1982). It is noteworthy that these immune effects are either reduced or not observed in adult mice exposed to chlordane at dose levels equal to those given to the pregnant mice (Johnson et al. 1986). Similar results have been reported in mice with in utero exposure to benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH). Offspring of pregnant mice treated with B[a]P have been found to display depressed antibody, graft-vs.-host, and mixed lymphocyte responses at 18 months of age (Urso and Gengozian 1984). These mice further exhibited an 8-to10-fold higher tumor incidence than control mice who did not experience in utero B[a]P exposure.
Low-level prenatal exposure to some of the halogenated aromatic hydrocarbons (HAH), notably dioxins, also results in severe, long-lasting immunologic incompetence in rodents (Ball et al. 1969; Faith and Moore 1977; Poland et al. 1982; Dencker et al. 1985; Corrier and Ziprin 1987; Fine et al. 1989). Collectively, these reports demonstrate that prenatal exposure to certain immunotoxic compounds may alter fetal development of immunity in mice, causing severe and sustained postnatal immunosuppression in the absence of overt toxicity. Additional agents producing developmental immunotoxicity in rodents are diverse and include: PAH other than B[a]P (e.g., 7,12-dimethylbenzanthracene; 3-methylcholanthrene); pesticides other than chlordane (e.g., hexachlorocyclohexane; DDT); polycyclic halogenated hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); heavy metals (cadmium; mercury); hormonal substances (diethylstilbestrol [DES], testosterone, cortisone); mycotoxins (most notably T2 toxin); and therapeutic agents (acyclovir, cyclophosphamide) (reviewed in: Holladay and Luster 1994). A target of several of these agents is the fetal thymus, inducing thymic atrophy as well as altered differentiation of fetal thymocytes. Exposure of fetal thymocytes to such chemicals during the maturation process could alter or modulate critical periods of "self-learning," resulting in potentially detrimental consequences on immune function in postnatal life, including possible expression of autoimmunity (Silverstone et al. 1998).
Most available data suggesting a link between induction of autoimmune reactivity and prenatal chemical exposure concerns estrogenic chemicals such as DES, which produce altered prenatal hormonal environment and which directly target developing immune cells, and HAH such as TCDD. Cyclosporin A (CsA), a widely used therapeutic immunosuppressant, has been shown to produce a T cell-mediated autoimmunity in rodents by effects on T cell development similar to those caused by TCDD, and will also be discussed.
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