We are interested in how xenobiotics, particularly toxic heavy metals, disturb brain development. The fetus and child are at risk from neurotoxicants, many of which disrupt the complex, highly orchestrated events underpinning brain morphogenesis. A large number of morphoregulatory molecules participate in brain development, many of which are transiently expressed and thus serve highly selective functions during restricted developmental periods. Molecules for which specific roles in morphogenesis have been firmly established are the adhesion molecules NCAM, LI, N-cadherin and the Eph family of repulsion molecules. Since the appropriate expression of these molecules is critical to the control of neuronal migration, targeted guidance of neurites and establishment of topographic patterns of pathways and synaptic targets, the perturbation by toxicants during development has potentially catastrophic consequences for the neurological integrity of the child.
We hypothesize that neurotoxic metals and other xenobiotics perturb brain development/morphogenesis by disrupting the co-regulated expression and function of critical morphoregulatory adhesion and repulsion molecules.

The following questions are being investigated:

1. Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during critical stages of brain development, and thereby compromise morphogenesis? Are all metal-induced alterations equally developmental stage dependent and anatomically specific?

2. Do selective transcriptional, translational or postranslational processes mediate metal-induced changes in adhesion and repulsion molecules?

3. What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules?

4. Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies?

These specific questions are being addressed using a multidisciplinary approach: molecular, biochemical, morphological and behavioral measures. Such studies will help define potential mechanisms by which these chemicals exert developmental neurotoxicity.

	Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression. Halladay AK, Wilson DT, Wagner GC and Reuhl KR. Neurotoxicology 2006 Mar;27(2):137-46. Epub 2006 Jan 19.
	Methylmercury alters Eph and ephrin expression during neuronal differentiation of P19 embryonal carcinoma cells. Wilson DT, Polunas MA , Zhou R, Halladay AK, Lowndes HE, Reuhl KR.
	The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17beta-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16alpha-hydroxyestradiol, and 4-hydroxyestrone. Turan VK, Sanchez RI, Li JJ, Li SA, Reuhl KR, Thomas PE, Conney AH, Gallo MA, Kauffman FC, Mesia-Vela S. J Endocrinol. 2004 Oct;183(1):91-9.
	Dietary clofibrate inhibits induction of hepatic antioxidant enzymes by chronic estradiol in female ACI rats. Mesia-Vela S, Sanchez RI, Reuhl KR, Conney AH, Kauffman FC. Toxicology. 2004 Aug 5;200(2-3):103-11.