Steroidal and non-steroidal estrogen-like chemicals (xenoestrogens, XE), and agents that otherwise impact estrogen-mediated regulatory pathways, are widespread in the general environment and common contaminants at Superfund sites. XE are prototypical """"""""endocrine disruptors"""""""" and likely candidates as neurodevelopmental toxicants. Cytochrome P450 aromatase (P450arom, estrogen synthetase) and estrogen receptors (ER), the two major players in estrogen signaling, are expressed in many regions of the CNS prior to birth and throughout life. Estrogens are known to have organizational effects in the developing CNS and have been implicated in the regulation of brain structure and function postnatally and in the adult organism, including humans. Zebrafish (Danio rerio) are an advantageous experimental model for investigating the role of XE as neurodevelopmental toxicants and, together with Fundulus heteroclitus, an indigenous telosteam species, have potential as sentinels for neuroactive XE in the aquatic environment. Compared to other vertebrates, teleost fish have exaggerated levels of neural P450arom and retain a remarkable potential for neurogenesis and neuroregeneration. Moreover, separate and distinct CYP19 gene loci encode different P450arom isoforms in neural and non-neural tissues, which allows recognition of brain-specific processes. The brain P450arom (-B) isoform is transcribed from the earliest stages of embryogenesis and is estrogen- inducible. The estrogen response system in zebrafish is mediated by ERalpha, ERbeta, and a novel third isoform (ERgamma). Proposed studies will investigate the following proposition: (a) XE present in the environment disrupt P450arom/ER-dependent processes of neurodevelopment, neuroplasticity and neuroregeneration; and (b) effects of XE, even at low doses and transient exposures, are amplified by a regulatory cascade involving estrogen-induced enhancement of P450aromB and changes in neural ER expression.
Specific aims are to: (1) develop and validate a whole animal, in vitro screening system using the brain form of P450arom as a mechanism-based molecular marker of neuroactive XE; (2) define XE-induced alterations in temporal, spatial, quantitative and isoform-specific patterns of P450arom and ER expression in the developing and adult CNS; (3) determine the consequences of inappropriate estrogen signaling for CNS development neuroplasticity and neural functions; and (4) characterize the molecular mechanisms of XE actions on estrogen mediated signaling pathways in the developing CNS.
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