Estrogen Induces Thymic Atrophy by Eliminating Early Thymic Progenitors and Inhibiting Proliferation of β-Selected Thymocytes

Abstract

Although it has been established that high levels of estrogen can induce thymic involution, the mechanism by which this happens is not known. We have found that daily i.p. injections of the synthetic estrogen 17-β-estradiol reduce thymus cellularity by 80% over a period of 4–6 days. Although the atrophy is most strikingly observed in the CD4/CD8 double-positive (DP) thymic subset, the loss of thymocytes is not accompanied by a significant increase in thymocyte apoptosis, suggesting that direct killing of cells may not be the dominant means by which estrogens induce thymic atrophy. Instead, we find that estradiol drastically reduces the lineage-negative, Flt3+Sca-1+c-Kit+ population in the bone marrow, a population that contains thymic homing progenitors. Within the thymus, we observe that estradiol treatment results in a preferential depletion of early thymic progenitors. In addition, we find that estradiol leads to a significant reduction in the proliferation of thymocytes responding to pre-TCR signals. Reduced proliferation of DN3 and DN4 cell subsets is likely the major contributor to the reduction in DP thymocytes that is observed. The reduction in early thymic progenitors is also likely to contribute to thymic atrophy, as we show that estradiol treatment can reduce the size of Rag1-deficient thymuses, which lack pre-TCR signals and DP thymocytes.

17β-Estradiol's salutary effects on splenic dendritic cell functions following trauma–hemorrhage are mediated via estrogen receptor-α

“…Previous studies have also demonstrated that E2 suppresses lymphocytes (Jimenez Del Rio and Velez-Pardo, 2000) and B cells apoptosis (Grimaldi et al, 2002;Peeva et al, 2005). Nonetheless, there are some reports which showed E2 induces apoptosis of thymocytes (Hoffman-Goetz et al, 2001;Zoller and Kersh, 2006). The reason for E2-induced thymocytes apoptosis as well as the precise mechanism by which E2 decreases splenic DCs apoptosis remains unknown.…”

Perinatal TCDD exposure and the adult onset of autoimmune disease

“…Interestingly, females but not males showed significantly altered thymus to body weight ratios and thymocyte phenotypes (Table 1). This gender bias in the females could be a result of a hormonal additive effect such as estrogen, as a number of investigators have shown estrogens to also induce thymic atrophy and affect thymoctye differentiation (Rijsinghani et al, 1996;Zoller and Kersh, 2006). This increased sensitivity of the female thymus to developmental TCDD is different from a T-cell function endpoint previously described in rats.…”

The hematopoietic stem cell niche in homeostasis and disease

“…For example, administration of 17b-estradiol to male mice leads to an increase of committed B-cell progenitors at the expense of HSPCs. 87 Other studies have shown that 88 In contrast, a direct effect of E2 on HSCs was only recently explored by Nakada et al This group demonstrated expression of E2 receptors in HSCs, and found that E2 in pregnant females promotes HSPC self-renewal. They reported an increase in cycling HSPCs in female compared with male mice, a phenomenon that decreased with ovariectomy (OVX).…”