Invited review article »Cooperation of sex chromosomal genes and endocrine influences for hypothalamic sexual differentiation," outlines findings that alter our concept/understanding of sexual differentiation of the brain. This paper presents the results of our own ongoing research work and findings of other research groups in the field; it illustrates the brain sexual differentiation from hormonal and sex chromosome perspective and discusses the influence of such differences on animal and human behavior. There have been occasional lively debates about the actual number of sexes that can be defined. However, there is little debate that mammalian sexual differentiation starts from the perspective of two primary sexes that correspond to differential sex chromosomes (X versus Y) that lead to individuals with sex typical characteristics, ranging from breast development and function, facial hair, different reproductive organs in humans, to larger body sizes in many mammals, presence or absence of antlers in ungulates, and differential plumage in birds. Beside obvious external differences, sex differences exist in many other organs or organ systems such as liver, immune system and brain. While sex chromosomes are usually credited as the key trigger for generating sex differences, most sex differences (at least in mammals) are thought to arise due to differential exposure to sex steroid hormones secreted by the gonads during development. In male mammals, the formation of the testis is triggered by the expression of the Sry gene on the Y chromosome. Sry gene induces a genetic cascade that leads gonadal primordia to develop into testes. Subsequently, testes secrete different hormones, key among them being the steroid hormone testosterone and the peptide anti-mullerian hormone, which are responsible for development of the male phenotype. While dogma states that ovaries develop in the absence of Sry gene, newer data indicate a critical genetic cascade for ovarian development. Although sex steroid hormones account for most aspects of brain sexual differentiation, a growing literature has raised important questions about the direct role of genes on sex chromosomes separate from sex steroid actions. Sex chromosomes obviously differ by sex, but it has been controversial as to what extent the genes on these chromosomes might affect brain development directly and differentially to cause differences in the brain between males and females.
COBISS.SI-ID: 3318906
APS12-2 is one of many synthetic analogues of the polymeric alkylpyridinium salts isolated from marine Mediterranean sponge Reniera sarai. Since it is a potential candidate for treating non small cell lung cancer, we wanted to assess its possible lethal and toxic effects on rats and mice in vivo. For this purpose we determined the median lethal dose (LD50) in mice and monitored dose dependent effects of APS12-2 on the electrical cardiac activity (ECG), respiratory activity, arterial blood pressure, muscle function, some plasma electrolytes and on histopathological changes in heart and lungs in rats under general anaesthesia, which were untreated, artificially respirated or pharmacologically vagotomised. In one group of animals, in vivo effects of APS12-2 on nerve evoked muscle contraction were also studied. We discovered that LD50 in mice was relatively high (11.5 mg/kg). APS12-2 at high doses used (8 mg/kg) in rats caused progressive reduction in arterial blood pressure to mid-circulatory value, bradycardia, myocardial ischemia, ventricular extrasystoles, atrio-ventricular block of second degree and death of experimental animals just few minutes after APS12-2 application. Similar changes in ECG and arterial blood pressure with APS12-2 at a dose of 8 mg/kg were observed in animals pretreated with atropine and in artificially ventilated animals. This indicates that cholinergic effects and hypoxia do not play a crucial role in APS12-2´s toxicity. At sublethal doses of APS12-2 (4 and 5.5 mg/kg) we did not observed drastic changes in measured parameters. Since it was shown that APS12-2 causes lysis of rat erythrocytes in vitro, we therefore expected to see the same effect in vivo. Indeed hyperkalemia was observed in the blood samples of experimental animals and it probably played important role in APS12-2 cardiotoxicity since no evident changes in histopathology of the heart were found. However, we found acute lesions in pulmonary vessels of rats injected with APS12-2 at lethal dose. In conclusion, our results show that APS12-2 has some adverse toxic effects, but only at very high doses that will never be achieved in potential treatment of non small lung cancer.
COBISS.SI-ID: 3364218
Original scientific article describes altered position of different cells in the ventromedial hypothalamic nucleus in SF-1 KO mice. Using immunocytochemistry, golgi staining and neuronal tracing methods we have described altered position of cells, involved in body weight regulation. Results of this study provide an insight into the possible causes for late onset obesity in SF-1 KO mice. The ventromedial nucleus of the hypothalamus (VMH) is a key cell group in the medial-basal hypothalamus that participates in the regulation of energy balance. Previous studies have shown that the cellular organization of the VMH is altered in mice with a disruption of the steroidogenic factor-1 (NR5a1) gene (SF-1 KO mice). The present study examined orexigenic/anorexigenic peptides (neuropeptide Y (NPY), agouti-related peptide (AgRP) and cocaine- and amphetamine-regulated transcript (CART)) and neural connections to and from the VMH in SF1 KO mice. NeuroVue tracing and Golgi staining were used to evaluate connections between the preoptic area (POA) and VMH and the orientation of dendrites in the VMH, respectively. Results of this study reveal changes in the cytoarchitecture of the region of the VMH with respect to the distribution of immunoreactive NPY, AgRP and CART. In wild type mice projections from the POA normally surround the VMH while in SF-1 KO mice, projections from the POA stream through the region that would otherwise be VMH. Golgi impregnation of the region revealed fewer dendrites with ventrolateral orientations and in general, more variable dendritic orientations in SF-1 KO mice providing additional evidence that the connectivity of cells in the region is likely altered due to the cellular rearrangements consequent to disruption of the NR5a1 gene. In conclusion, this report greatly extends the data showing that the morphology of the regions containing the VMH is disrupted in SF-1 KO mice and suggests that changes in the location of cells or fibers containing NPY, AgRP and CART may, in part, account for changes in body weight homeostasis in these mice.
COBISS.SI-ID: 3397242