Testosterone-induced susceptibility to Plasmodium chabaudi malaria: persistence after withdrawal of testosterone

Abstract

Testosterone induces susceptibility to Plasmodium chabaudi malaria by imposing restrictions on those mechanisms which mediate resistance controlled by genes of the H-2 complex and the non-H-2 background in mice. This study investigated whether these restrictions are abolished after withdrawal of testosterone. Female mice of the inbred strain C57BL/10 were treated with 0.9 mg testosterone twice a week for 3 weeks and testosterone was then withdrawn for 12 weeks. The treatment raised plasma testosterone levels from 0.18 ng/ml to 3.79 ng/ml. After the testosterone treatment, these levels progressively dropped and reached 0.21 ng/ml by week 12 after testosterone withdrawal. Surprisingly, however, the testosterone-induced susceptibility still persisted. When mice were challenged on week 12 after testosterone withdrawal, P. chabaudi infections were still fatal in testosterone-treated mice, in contrast to self-healing infections in resistant, i.e. untreated, control mice. In addition, testosterone caused a persistent decrease in the levels of total IgG antibodies, especially IgG1 and IgG2b isotypes. In contrast, testosterone-induced changes in spleen cells, such as the reduction in number by 50%, the relative increase in CD8+ cells and the decrease in Ig+ cells, as well as the acquisition of the susceptible phenotype, were completely reversed on week 10 after testosterone withdrawal at the latest. Testosterone did not affect the production of the TH1-signalling cytokine interferon-gamma and the TH2-signalling cytokines interleukin (IL)-4 and IL-10 in response to P. chabaudi malaria. Together, our data indicated that the gene-controlled host resistance to P. chabaudi malaria is subject to superior hormonal imprinting: when once induced by testosterone, mechanisms which suppress resistance thus causing susceptibility persist independently of testosterone.

Testosterone-induced permanent changes of hepatic gene expression in female mice sustained during Plasmodium chabaudi malaria infection

“…the persistent downregulation of Igk-C by testosterone indicates that testosterone ultimately leads to a partially reduced production of antibodies. Indeed, this confirms previous studies that testosterone lowers the production of antibodies (Fujii et al 1975, Hirota et al 1980, Morton et al 1981, Kincade et al 1994, Benten et al 1997). More complicated is the situation with Ifng which is upregulated by the end of the testosterone withdrawal period, but the subsequent malaria infection induces expression of Ifng in both the vehicle-and the testosterone-pretreated mice, however, at a higher extent in control than in testosterone-pretreated mice.…”

“…9 mg testosterone (TestosteroneDepot-50, Schering, Berlin, Germany) twice a week for 3 weeks (Wunderlich et al 1988, Benten et al 1997.…”

“…79 to 0 . 21 ng/ml, by the end of the 12-week period of testosterone withdrawal, the mice still succumb to malaria (Benten et al 1997). Livers were aseptically removed from three animals at each of the four time points on days 0 and 8 p.i., i.e.…”

“…it persists for rather a long time. Thus, when mice are pretreated with testosterone for 3 weeks, and then testosterone treatment is discontinued for 12 weeks, thereafter the mice are still susceptible to P. chabaudi infections (Benten et al 1997). Obviously, this testosterone-induced susceptibility persists, even though the circulating testosterone levels have declined to those levels characteristic for female mice after withdrawal for 12 weeks (Benten et al 1997).…”

Effect of Sex Steroids on Babesia microti Infection in Mice

“…14,15 Testosterone appears to increase this susceptibility of male animals to P. berghei, 7 P. chabaudi, [16][17][18] L. major, 19 and T. cruzi. 13 Female animals are more susceptible than males to Toxoplasma gondii infection, and estrogen causes this effect.…”