Hormonal pathways regulating intermale and interfemale aggression.
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Aggression↗
Biomedical subjects
Shan Hu
Publications and source records attributed to Shan Hu.
ERbeta protein expression in female cynomolgus monkey and CF-1 mouse brain: Western analysis.
In humans and rodents, multiple ERbeta variants with sizes ranging from 477-549 amino acids (aa) have been described. The identification of these variants in target tissues has important implications for estrogen signaling and cellular responsiveness. Western blot analysis using two anti-ERbeta antibodies specific for mammalian ERbeta sequences (PA1-310B and PA1-311) was employed to examine ERbeta protein expression in neural tissues from ovariectomized (OVX) cynomolgus macaques and CF-1 mice as well as to assess potential regulatory effects of acute and extended estradiol (E(2)) treatment. In hypothalamic extracts from both species, a single ERbeta immunoreactive (ERbeta-ir) band was detected at approximately 54 kDa, corresponding to the expected molecular weight for ERbeta477 and/or 485. In cynomolgus females, oral E(2) administration for 16 weeks had no apparent effect on hypothalamic ERbeta protein expression. In mouse, a single injection of E(2) did not change hypothalamic ERbeta protein levels 1.5, 4, 8, 16, or 24 h after injection. Extending the hormonal treatment to 4 or 21 days in OVX female mice also had no effect on the level of hypothalamic ERbeta protein. Additional regional analyses in female mouse brain with PA1-310B antibody showed that a second, 59 kDa ERbeta-ir band was present in cortex, striatum, hippocampus, and amygdala that could represent one or both of the larger ERbeta variants (530 and 549aa). The expression level of the second ERbeta isoform exhibited regional variation, with the strongest immunoreactivity detected in cortex and amygdala. Elucidating the functions of these ERbeta isoforms in the CNS will facilitate our understanding of the tissue- and promoter-specific actions of estrogen.
Animals↗
DHEA and DHEA sulfate differentially regulate neural androgen receptor and its transcriptional activity.
The mechanism of action of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), two interconvertable neurosteroids, has not been fully characterized in the central nervous system (CNS). Previous studies demonstrated that DHEA was intrinsically androgenic, suggesting that it may act through a genomic pathway. However, it is not known whether DHEA-S also produces androgenic effects, an important question given that the concentration of DHEA-S in brain is some 7-12 times that of DHEA. The current study compared the potential androgenic effects of DHEA-S with DHEA by examining their capacity to induce two characteristic effects of an androgenic compound. These included the ability to (1) up-regulate neural androgen receptor (AR) protein level in mouse brain and immortalized GT1-7 hypothalamic cells and (2) assess their effect on reporter gene expression through AR in CV-1 cells cotransfected with pSG5-AR and pMMTV-ARE-CAT reporter. Semi-quantitative Western blot analysis showed that DHEA treatment significantly augmented AR in mouse brain and GT1-7 cells in a dose-dependent manner and that these effects were not blocked by trilostane (TRIL), a known 3beta-hydroxysteroid dehydrogenase inhibitor. DHEA also promoted AR-mediated reporter gene expression as a function of dose and the effect was comparable with or without the addition of TRIL. In contrast, DHEA-S treatment failed to increase AR level in the mouse brain or GT1-7 cells and modestly induced AR-mediated reporter gene expression only at substantially elevated concentrations compared to DHEA. The findings demonstrate that DHEA is capable of exerting androgenic effects through AR while the androgenicity of DHEA-S is negligible. The implications of the results for models of the mechanism of action of DHEA and its sulfate ester, DHEA-S, in the brain are considered.
Adipates↗
Increased aggressive behavior and decreased affiliative behavior in adult male monkeys after long-term consumption of diets rich in soy protein and isoflavones.
Estrogen produced by aromatization of gonadal androgen has an important facilitative role in male-typical aggressive behavior that is mediated through its interaction with estrogen receptors (ER) in the brain. Isoflavones found in soybeans and soy-based dietary supplements bind ER and have dose- and tissue-dependent effects on estrogen-mediated responses. Yet, effects of isoflavone-rich diets on social and aggressive behavior have not been studied. We studied the effects of long-term (15 months) consumption of diets rich in soy isoflavones on spontaneous social behavior among adult male cynomolgus macaques (Macaca fascicularis) (n = 44) living in nine stable social groups. There were three experimental conditions which differed only by the source of dietary protein: casein and lactalbumin (no isoflavones), soy protein isolate containing 0.94 mg isoflavones/g protein, and soy protein isolate containing 1.88 mg isoflavones/g protein. In the monkeys fed the higher amount of isoflavones, frequencies of intense aggressive (67% higher) and submissive (203% higher) behavior were elevated relative to monkeys fed the control diet (P's < 0.05). In addition, the proportion of time spent by these monkeys in physical contact with other monkeys was reduced by 68%, time spent in proximity to other monkeys was reduced 50%, and time spent alone was increased 30% (P's < 0.02). There were no effects of treatment on serum testosterone or estradiol concentrations or the response of plasma testosterone to exogenous gonadotropin-releasing hormone (GnRH). The results indicate that long-term consumption of a diet rich in soy isoflavones can have marked influences on patterns of aggressive and social behavior.
Aggression↗
Dehydroepiandrosterone upregulates neural androgen receptor level and transcriptional activity.
The mechanism of action of dehydroepiandrosterone (DHEA), a neuroactive neurosteroid synthesized in the brains of humans and other mammals, has not been fully characterized in the adult brain. Although well known for modulatory effects on GABA(A), NMDA, and sigma(1) receptors, studies in both CNS and peripheral target cells suggest that DHEA also may exert genomic effects via the androgen receptor (AR). The current study tested the hypothesis that DHEA was capable of producing androgenic effects in the CNS by assaying its ability to induce three characteristic effects of an androgenic compound. These included the ability to upregulate neural AR protein level in mouse brain and immortalized GT1-7 hypothalamic cells, the capacity to induce transcriptional activity through AR in CV-1 cells transfected with an MMTV-ARE-CAT reporter, and competition for recombinant AR binding in a radioligand binding assay. The results showed that DHEA treatment significantly augmented AR both in vivo and in vitro, and that this effect was not blocked by trilostane (TRIL), a known 3beta-hydroxysteroid dehydrogenase (3beta-HSD) inhibitor. DHEA also promoted AR-mediated CAT reporter expression and competed with dihydrotestosterone (DHT) for binding to recombinant AR in a cell-free system. These data indicate that DHEA possesses intrinsic androgenic activity that is potentially independent of metabolic conversion to other androgens, and that it can affect gene function through the AR. In combination with its modulation of neurotransmitter receptors at the cell membrane level, the findings suggest that the mechanism of action of DHEA in the brain can involve a "crosstalk" cellular signaling system that involves both nongenomic and genomic components.
Animals↗