Michael Collins

The focus of the research is to determine the mechanisms by which human teratogens induce congenital malformations. The model system that is utilized is the purple sea urchin, Strongylocentrotus purpuratus. The rationale for using this animal model is that it has a well-characterized early developmental gene regulatory network (GRN). The value of a defined developmental GRN is that it gives a specific set of molecular interactions as to how specific cell types in the embryo develop. It is hypothesized that the molecular targets of human teratogens will be conserved in the sea urchin since homologous signaling molecules and transcription factors are found during early development of the two organisms. However, anatomical conservation is clearly not maintained. It is interesting to note that many human teratogens perturb early sea urchin development. Gene expression in the early embryo can be determined by a technique that yields a direct count of the number of mRNA molecules in the embryo (Nanostring nCounter). The value of this procedure is that it gives very accurate and reproducible mRNA levels in biological samples (sea urchin embryos). The capacity to interpret transcriptomic data via the GRN allows a temporal as well as spatial interaction map that describes the relationship between the nodes in the GRN, thus providing information regarding the initial perturbation event. Metabolomic studies have also been performed to characterize perturbations in early sea urchin development by human teratogens. It is hypothesized that one of the major impediments to determining teratogenic mechanisms is that there is a lack of understanding of the normal embryonic development of the standard laboratory animal models and thus it is difficult to determine when a perturbation from normal development has occurred.

Selected Publications

• Lee GS, Kochhar DM, Collins MD Retinoid-induced limb malformations. Current pharmaceutical design. . 2004; 10(22): 2657-99.
• Santos-Guzman J, Arnhold T, Nau H, Wagner C, Fahr SH, Mao GE, Caudill MA, Wang JC, Henning SM, Swendseid ME, Collins MD Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture. J. Nutr. 2003; 133(11): 3561-3570.
• Mao GE, Collins MD Quantitation and localization of expression of the retinoic acid receptor-beta and -gamma mRNA isoforms during neurulation in mouse embryos with or without spina bifida. Teratology 2002; 66: 331-343.
• Collins MD, Mao GE Teratology of retinoids. Ann. Rev. Pharmacol. Toxicol. 1999; 39: 399-430.
• Lee GS, Cantor RM, Abnoosian A, Park E, Yamamoto ML, Hovland DN, Collins MD A gene(s) for all-trans-retinoic acid-induced forelimb defects mapped and confirmed to murine chromosome 11. Genetics. 2005; 170(1): 345-53.
• Machado AF, Zimmerman EF, Hovland DN, Weiss R, Collins MD Diabetic embryopathy in C57BL/6J mice. Altered fetal sex ratio and impact of the splotch allele.. Diabetes. 2001; 50(5): 1193-9.
• Hovland DN, Cantor RM, Lee GS, Machado AF, Collins MD Identification of a murine locus conveying susceptibility to cadmium-induced forelimb malformations. Genomics. 2000; 63(2): 193-201.