Some environmental agents exert their effects directly upon or through central nervous system (CNS). These effects may change neurotransmitter or hormonal secretion, that regulate many physiological functions. Our studies have concentrated upon luteinizing hormone-releasing hormone (LHRH), a peptide transmitter in the CNS and a hormone that regulates puberty and mammal reproduction, through LH secretion. We have shown that different glial-derived growth factors activating protein kinase C in LHRH neurons, can also regulate processing of the pro-LHRH to LHRH. In this way, growth factors can control pituitary secretion of LH and FSH, and thus, the timing of puberty. We also have examined the signal transduction pathways in LHRH neurons controlling gene expression, pro- LHRH processing and secretion. Activation of NMDA receptors stimulates NO synthase, guanylyl cyclase, and protein kinase G, which repress LHRH gene expression, at the transcriptional level. Studies are underway to fully describe the LHRH promoter elements that are involved. Norepinephrine, through alpha1-adrenoceptors, regulates LH surge. Activation of these receptors in LHRH neurons leads to inositol phosphate production, and arachidonic acid (AA) release that metabolizes to epoxyeicosatrienoic acids (EETs) or prostaglandin E2 (PGE2). EETs can inhibit LHRH secretion. PGE2 affects LHRH secretion through the EP1 and the EP3 receptors. Activation of EP1 stimulates LHRH secretion, while EP3 receptor mediates both, inhibition of LHRH secretion (through inhibition of adenylyl cyclase), or stimulation of LHRH secretion (through phospholipase C or adenylyl cyclase stimulation). Since EETs and PGE2 can be secreted by glia, immunological cells and neurons, these lipids may coordinate the responses of the immune, endocrine and neuronal systems. Finally, we found that LHRH neurons can both synthesize and respond to """"""""neurosteroids"""""""" that have weak estrogenic and androgenic activities. Thus, certain environmental steroids may exert pronounced affects on LHRH neurons, thereby directly influencing neuronal and reproductive functions.
