Thymic atrophy

Miller Scott (1985) reported marked reduction in thymus weight in rats fed dioctyltin dichloride for 8 or 12 weeks at a level of 75 mg/kg diet. Numbers of lymphocytes together with T cell subpopulations were reduced in treated rats, but no difference was seen in antibody response to sheep red blood cells in vivo. No evidence was foimd of in vitro cytocidal effects of dioctyltin dichloride on blood lymphocytes. Evans et al. (1986) dosed pregnant and non-pregnant rats for 3 weeks at 75 mg/kg diet and reported severe thymic atrophy and extensive vacuolation of reticuloendothelial cells in pregnant animals only. 

Rat DOTC 3 weeks at 75 mg/kg diet = 3.75 mg/kg body weight Severe thymic atrophy extensive vacuolation of the reticuloepithellal cells in pregnant animals only Effects reported at 3.75 Evans et al. (1986)... 

Monobutyltin Rat MBTC Gestation days 7-17at0, 50, 100, 200, and 400 mg/kg body weight Maternal toxicity thymic atrophy dose-dependent developmental toxicity fetuses with visceral or skeletal abnormalities NOAEL >400 Noda etal. (1992)... 

Rat DBTC Gestation days 6-15 atO, 1,2.5, 5, and 10 mg/kg body weight Slightly increased incidence of maternal thymic atrophy LOAEL = 2.5 NOAEL =1 ORTEPA(1994)... 

Subchronic studies that measure Ah receptor-mediated responses, such as thymic atrophy, loss in body weight, and immunotoxicity... 

PCBs (105, 114, 118, 123, 126, 156, 157, 169) produced a linear correlation between the EC50 response (in vitro) of AHH induction against the ED50 (in vivo) of body weight loss, thymic atrophy, hepatic AHH, and EROD induction (Safe 1987b). The planar mono- and di-orf/zo-derivatives (PCBs 105, 118, 156, 189, 128, 138, 153, 170, 180) are referred to as mixed inducers because they elicit effects similar to coadministration of phenobarbital plus methylcholanthrene (Hansen 1987). 

Laiosa, M., et. al., Cell proliferation arrest within intrathymic lymphocyte progenitor cells causes thymic atrophy mediated by the aryl hydrocarbon receptor, J. Immunol., 171,4582, 2003. 

Staples, J., et. al., Overexpression of the anti-apoptotic oncogene bcl-2 in the thymus does not prevent thymic atrophy induced by estradiol or 2,3,7,8-tetrachlorodibenzo-p-dioxin, Toxicol. Appl. Pharmacol., 151, 200, 1998. 

Mercuric chloride in the BN rat gives a lymphoproliferation in spleen and lymph nodes, including B and T helper cells, an increase in the number of Ig containing cells resulting in a rise in all serum Ig isotypes and an early thymic atrophy [196]. The kinetics of the increase in the serum level of various Ig isotypes were similar to that observed for IgE, suggesting spontaneous autoregulation, which could involve suppressor T cells [ 197, 198] and/or auto-anti-idiotypic antibodies [ 199]. 

At this time there are still two rodent naturally occurring osteopetroses without defined gene the one termed ostepetrotic or op/op that is distinct from the mouse op/op, associated with premature thymic atrophy and curable by bone marrow transplantation (Milhaud et al, 1977) and the one produced by mutation of incisor-absent gene also curable by bone marrow transplantation (Marks, 1976). The latter was, however, was recently mapped to chromosome 10q32.1 (VanWesenbeeck et al, 2004), which should help its identification. On... 

Reproductive toxicity to 2,3,7,8-TCDD has been demonstrated in animals. "" The effects include pre- and postimplantation losses in females, morphologic and functional changes in male and female reproductive organs, and hormonal imbalance in both sexes. A number of developmental effects have been observed in animals acutely exposed to 2,3,7,8-TCDD by the oral route. Effects observed in offspring of animals include cleft palate, kidney anomalies, immune system damage (thymic atrophy and immunosuppression), impaired development of the reproductive system, decreased growth, and fetal/newborn mortality. 

Exon JH, Mather GG, Bussiere JL, et al Effects of subchronic exposure of rats to 2-methoxyethanol or 2-butoxyethanol thymic atrophy and immunotoxicity. Fundam Appl Toxicol 16 830-840, 1991... 

For halogenated aromatic hydrocarbons like polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) the binding to the aryl hydrocarbon (Ah) receptor regulates their toxicity [89]. The Ah receptor controls the induction of one of the cytochrome P450 enzymes in the liver. Toxic responses such as thymic atrophy, iveight loss, immu-notoxicity and acute lethality are associated ivith the relative affinity of PCBs, PCDFs and PCDDs for the Ah receptor [89]. The quantitative structure-activity relationship (QSAR) models predicting the affinity of the halogenated aromatic hydrocarbons ivith the Ah receptor describe the electron acceptor capability as well as the hydrophobicity and polarizability of the chemicals [89[. 

In laboratory animals, TCDD administered in suitable doses has produced a wide variety of toxic effects, including a wasting syndrome (severe weight loss accompanied by reduction of muscle mass and adipose tissue), thymic atrophy, epidermal changes, hepatotoxicity, immunotoxicity, effects on reproduction and development, teratogenicity, and carcinogenicity. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, discrete chloracne may be the only manifestation. 

TCDD binds to the AhR and initiates a number of responses as well as induction of CYP1A1, including induction of UDP-glucuronosyl transferases, GSH transferases, and stimulation of apoptosis in thymocytes, resulting in thymic atrophy. 

The anticancer effect of curcumin in murine thymoma cells was found to be due to the blocking of IL-1 signaling by the inhibition of the recruitment of the IL-1 receptor-associated kinase (IRAK) [Jurrmann et al., 2005]. A recent study showed that curcumin could prevent tumor-induced thymic atrophy in thymic T cells, leading to the neutralization of tumor-induced oxidative stress and the restoration of NF-kB activity and the re-education of the TNF-a signaling pathway, resulting in thymic protection [Bhattacharyya et al., 2007]. 

Ah receptor (AHR) A protein coded for by a gene of the Ah locus. The initial location of the Ah receptor is believed to be in the cytosol and, after binding to a ligand such as TCDD, is transported to the nucleus. Binding of aromatic hydrocarbons to the Ah receptor of mice is a prerequisite for the induction of many xenobiotic metabolizing enzymes, as well as for two responses to TCDD epidermal hyperplasia and thymic atrophy. Ah-responsive mice have a high-affinity receptor, whereas the Ah-nonresponsive mice have a low-affinity receptor. 

Rat (Wistar) once (GO) 25 M (reversible thymic atrophy starting on day 13) De Heer et al. 1994b... 

Hamster (Golden Syrian) once (GO) 48 (ED for thymic atrophy) Hanberg et al. 1989... 

Rat (Han/Wistar) Gd 8 1 x/d (GO) 1 10 (hydronephrosis, thymic atrophy, gastrointestinal hemorrhage, decreased number of live fetuses) Huuskonen et al. 1994... 

---