Neuronal and endocrine cells' susceptibility to physiologic and toxic stimuli : a study on the effects of steroid hormones

The propensity of a cell to die can be influenced by a number of factors, including hormones, which affect the intracellular and extracellular milieu. The aim of this thesis was to investigate the effects of hormones on cell fate in the nervous system and in the pituitary, with special reference to glucocorticoid and gonadal hormones. An interdisciplinary approach was taken combining in vitro and in vivo experimental models, and applying methods stretching from single cell to behavioral analysis.

To test the effects of the selected hormones on neuronal cell susceptibility, cerebellar granule cells were used as an experimental model. Cells were challenged with toxicants inducing cell death via different mechanisms. A toxic stimuli used triggered apoptotic cell death, as shown by the typical morphological alterations and DNA fragmentation patterns. However, only the microtubule disrupting agent colchicine activated caspases, a family of proteases that plays a crucial role in apoptosis.

The neuroprotective properties of gonadal hormones and synthetic estrogen-like compounds, such as J811, were tested on neuronal cells exposed to the apoptosis-inducing agents. Both androgens and the estrogen-like compound J811 protected from oxidative stress. While the protective effects of androgens were receptor-mediated and involved an upregulation of antioxidant enzyme-activity, the estrogen-like compound exerted its protective action via the phenolic A-ring, which confers part of the radical scavenging properties.

The effects of prenatal exposure to high levels of glucocorticoids on the vulnerability of neuronal cells to stimuli inducing cell death were also investigated. The results indicated that prenatal exposure to high levels of glucocorticoids in utero induces long lasting changes in neurons, including altered mitochondrial function and decreased antioxidant enzyme activity, that render cells more sensitive to oxidative stress. Since oxidative stress is known to be involved in a variety of neuropathological conditions including aging-related disorders, prenatal exposure to excess of glucocorticoids may be a risk factor that increases cell vulnerability to insults occurring later in life.

Using an in vivo model, possible sex-related differences in the susceptibility to prenatal exposure to the neurotoxic metal methylmercury were investigated. The results show that prenatal exposure to methylmercury changes dopamine-modulated motor activity in male but not in female rats. Several mechanisms may be behind the observed gender-related difference, including a sexual dimorphism in the expression of cellular defense systems.

The pituitary remodeling which occurs after cessation of lactation was investigated, since it can provide greater insight into pituitary tumor formation. The results showed that apoptosis is the type of death responsible for lactotroph cell-deletion as was further confirmed by the induction of the pro-apoptotic gene Bax with a concomitant decrease in Bcl-2.

Altogether, the results suggest that by elucidating beneficial and detrimental hormonal effects on cell survival preventive and therapeutic strategies may be developed.

List of scientific papers

I. Gorman AM, Daré E, Ahlbom E, Götz M, Momoi T, Ceccatelli S (2000). "Activation of different cell death pathways is associated with apoptotic morphology in cerebellar granule cells" Neurotox Res (Submitted)

II. Götz ME, Ahlbom E, Zhivotovsky B, Blum-Degen D, Oettel M, Römer W, Riederer P, Orrenius S, Ceccatelli S (1999). "Radical scavenging compound J 811 inhibits hydrogen peroxide-induced death of cerebellar granule cells" J Neurosci Res 56(4): 420-426
https://pubmed.ncbi.nlm.nih.gov/99270574

III. Ahlbom E, Grandison L, Bonfoco E, Zhivotovsky B, Ceccatelli S (1999). "Androgen treatment of neonatal rats decreases susceptibility of cerebellar granule neurons to oxidative stress in vitro" Eur J Neurosci 11(4): 1285-1291
https://pubmed.ncbi.nlm.nih.gov/99203356

IV. Ahlbom E, Prins G, Ceccatellli S (2000). "Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism" Brain Res (Submitted)

V. Ahlbom E, Gogvadze V, Celsi G, Cecdatelli S (2000). "Prenatal exposure to high levels of glucocorticoids increases cerebellar granule cells´susceptibiblity to oxidative stressinduced cell death" J Clin Invest (Submitted)

VI. Rossi AD, Ahlbom E, Ögren SO, Nicotera P, Ceccatelli S (1997). "Prenatal exposure to methylmercury alters locomotor activity of male but not female rats" Exp Brain Res 117(3): 428-436
https://pubmed.ncbi.nlm.nih.gov/98099548

VII. Gimenez-Llort L, Ahlbom E, Daré E, Vahter M, Ögren SO, Ceccatelli S (2000). "Prenatal exposure to methylmercury changes dopamine-modulated motor activity during early ontogeny: age and gender-dependent effects" Environ Toxicol Pharmacol (In Print)

VIII. Ahlbom E, Grandison L, Zhivotovsky B, Ceccatelli S (1998). "Termination of lactation induces apoptosis and alters the expression of the Bcl-2 family members in the rat anterior pituitary" Endocrinology 139(5): 2465-2471
https://pubmed.ncbi.nlm.nih.gov/98224530