The recent focus on the hormone-like effects of many xenobiotics has led to a renewed interest in both the reproductive and nonreproductive actions of estrogen. Its protective or age-retardive actions are well established for multiple body systems including skin, bone and teeth, colon, blood vessels and heart. Clinical and epidemiological studies suggest neuroprotective properties in Parkinson's and Alzheimer's disease. In vitro and in vivo experimental data indicate estrogen may prevent the neuronal cell damage and necrosis observed following excitotoxic, metabolic and oxidative insult. Conversely, protracted estrogen exposure whether due to age or exogenous administration damages certain brain areas. Mechanisms mediating these protective or pathological actions may include activation of pathways or release of substances through specific intracellular receptor-mediated actions; direct, rapid, nongenomic effects at the cell membrane, at membrane receptor sites and ion channels or at cyclic AMP response elements; altered metabolic profile of critical brain enzymes; and alteration of neurotransmitter and neuropeptide transmitter mechanism in brain. Utilization of transgenic technology has been useful in elucidating the mechanism of estrogen's protective effects in the vasculature and bone and should be useful in examining its CNS protective and pathological actions. Whether compounds with estrogen agonist, antagonist or mixed actions (e.g., tamoxifen, phytoestrogens, triphenyletbylenes) can interfere with or mimic the neuroprotective or neuropathological actions of estrogen has received little scrutiny or debate. Tamoxifen can, however, block some but not all of the neuroprotective actions of 17alpha or beta-estradiol in vitro and can modulate certain aspects of nigral striatal function including release of dopamine in response to stimulation and the response to dopaminergic neurotoxic insult. Actions of other estrogenic agents in these models is unknown.
The Toxicologist. Society of Toxicology 38th Annual Meeting, March 14-18, 1999, New Orleans, Louisiana