Neonatal testosterone exposure protects adult male rats from stroke - PubMed (original) (raw)

Neonatal testosterone exposure protects adult male rats from stroke

Rebecca W Persky et al. Neuroendocrinology. 2013.

Abstract

Background: Men have a higher stroke incidence compared to women until advanced age. The contribution of hormones to these sex differences has been extensively debated. In experimental stroke, estradiol is neuroprotective, whereas androgens are detrimental. However, prior studies have only examined the effects of acute treatment paradigms; therefore, the timing and mechanism by which ischemic sexual dimorphism arises are unknown.

Methods: The effects of exogenous neonatal androgen exposure on subsequent injury induced by middle cerebral artery occlusion in adulthood in male rats were examined. Rats were administered vehicle (oil), testosterone propionate (TP) or the non-aromatizable androgen dihydrotestosterone (DHT) for 5 days after birth. At 3 months of age, a focal stroke was induced.

Results: Testosterone-treated rats (but not DHT-treated animals) had decreased infarct volumes (20 vs. 33%, p < 0.05) as well as increased estradiol levels (39.4 vs. 18.6 pg/ml, p < 0.0001) compared to oil-treated animals. TP-injected males had increased testicular aromatase (P450arom) levels (3.6 vs. 0.2 ng/ml, p < 0.0001) compared to oil-treated males. The level of X-linked inhibitor of apoptosis, the primary endogenous inhibitor of caspase-induced apoptosis, was increased in TP-treated rats compared with the oil-treated males.

Conclusions: Neonatal exposure to exogenous testosterone upregulates testicular aromatase expression in male rats and leads to adult neuroprotection secondary to changes in serum estradiol levels and cell death proteins. This study suggests that early exposure to gonadal hormones can have dramatic effects on the response to adult cerebrovascular injury.

Copyright © 2012 S. Karger AG, Basel.

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Figures

Figure 1

Figure 1

Stroke outcomes in adult rats exposed to neonatal TP or DHT treatment. (A) Cresyl violet stained coronal brain slices showing infarct (white) in TP or DHT treated rats. (B) Quantification of infarct in TP and oil injected rats (shown as a % of the contralateral structure) in the cortex, striatum, and hemisphere (n=15 for TP males, n=14 for oil males; *P<0.05 vs. oil group; **P<0.001 vs. oil group). (C) Quantification of infarct in DHT and placebo treated rats (shown as a % of the contralateral structure) in the cortex, striatum, and hemisphere; n=13 for placebo group, n=15 for DHT group. (D&E) Neurological deficit scores in TP (D) and DHT (E) treated groups. White and black boxes show the data within 25_–_50% and 50_–_75% respectively; error bars present the minimum or maximum value.

Figure 2

Figure 2

Serum testosterone and estradiol levels as well as gonadal weights were affected by neonatal testosterone and DHT injection in adult animals. (A) Serum testosterone levels were increased in Oil compared to TP-treated rats at time of sacrifice. (***P<0.0001vs. oil group, n=10/gp). (B) Serum estradiol levels were increased in TP compared with Oil-treated male rats at the time of stroke (***P<0.0001 vs. TP group, n=7/gp). Serum levels of testosterone (C) and estradiol (D) were not significantly different between DHT and placebo-pellet implanted rats at the time of sacrifice (DHT n=15, placebo n=13). (E) Gonadal weights were decreased in TP-injected males compared to oil controls (***P<0.0001 vs. oil group. n=15/TP group, n=14/oil group). (F) Adult gonad weights of DHT implanted male rats were decreased compared to placebo male rats (***P<0.0001 vs. placebo group, n=15/DHT group, n=13/placebo group) Relative gonad/body weights were decreased in (G) TP group compared to oil as well as (H) DHT group compared to placebo.

Figure 3

Figure 3

Increased testicular aromatase levels in TP injected rats at the time of stroke. (A) Aromatase levels measured by ELISA in gonads were dramatically increased in TP injected males compared to oil injected rats (***p<0.001 vs. TP group, n=6/gp). (B) No differences in aromatase (B) levels and (C) activity in the brain (cortex) between TP and oil treated rats at the time of stroke (n=4/gp).

Figure 4

Figure 4

Neonatal TP administration led to changes in serum hormone levels and gonadal aromatase levels in PND16 rats. TP males had significantly decreased gonad weights (A) as well as gonad/body weights (B) but no difference in testosterone levels (C) compared with vehicle treated animals. (D) TP treated males had decreased serum estradiol levels compared to oil controls at PND16. (E) Testicular aromatase levels in TP males were significantly decreased compared to oil treated males. (***P<0.001 vs. oil groups, n=11/gp).

Figure 5

Figure 5

XIAP levels were increased in adult males exposed to neonatal TP (A) Representative Western blots of XIAP protein in sham and stroke rats. B-tubulin served as loading control. (B) Quantification showed XIAP levels were increased in TP rats both with and without (sham) injury. The optical density was expressed as the ratio of XIAP bands to control bands (B-tubulin) (**P<0.05 vs. oil groups. Semi-quantitative analysis of densitometry was performed from four independent sets of data).

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