MeHg uptake into brain tissue, an effect that was reversed by administration of a neutral amino acid. The author concluded that MeHg was transported across the blood-brain barrier by an amino acid carrier. Subsequent studies by Kerper et al. (1992, 1996) and Mokrzan et al. (1995) showed that the amino acid carrier is an L (leucine-preferring) amino acid transporter and that MeHg is released from the brain capillary endothelial cells into the brain interstitial space as a glutathione complex.
The brains of both humans and experimental animals (rodents and primates) exposed in utero to MeHg show changes in neuronal migration and distribution patterns, cell loss, low neuronal abundance, and microcephaly, changes consistent with effects on the microtubular cytoskeleton and inhibition of cell-cycle progression (Burbacher et al. 1990). The effects of MeHg on mitotic activity and mitotic spindle function both in vivo and in cell culture have been characterized (Imura et al. 1980; Rodier et al. 1984; Brown et al. 1988; Wasteneys et al. 1988). It has been shown that MeHg directly binds to tubulin and inhibits microtubule formation (Vogel et al. 1986). Ponce et al. (1994) conducted in vitro studies using primary embryo neuronal cells to characterize MeHg’s effect on cell cycling and its role in developmental toxicity. Exposure at concentrations of 2 µM MeHg causes G2/M phase cell-cycle inhibition, and at 4 µM, all cell-cycle phases are inhibited, suggesting that the cytoskeleton and mitotic spindles might be particularly sensitive to MeHg.
Two recent studies have further characterized steps in the mechanism by which MeHg affects the cell cycle in embryos. Ou et al. (1997) used primary rodent embryonic neuronal cells to determine mRNA expression levels of two genes involved in a checkpoint pathway of cell-cycle arrest, Gadd45 and Gadd153, in response to MeHg. Exposure at 2 µM caused both GADD45 and GADD153 mRNA levels to increase. The authors concluded that activation of these Gadd genes could be a mechanism by which MeHg causes cell-cycle arrest in embryos. The same laboratory investigated the involvement of p21 (a cell-cycle regulatory gene of a checkpoint pathway of arrest of G1 and G2 phases of the cell cycle) in primary embryonic cells exposed to MeHg (Ou et al. 1999). The embryonic cells responded to MeHg exposure with a concentration-dependent increase in p21 mRNA, indicating that activation of cell-cycle regulatory genes could be one mechanism by which MeHg disrupts the cell cycle in embryos.
Vitamin A (retinol) and the structurally related retinoids have a special place in developmental toxicology, both currently and historically. Nutritional deficiency of vitamin A was the first chemical manipulation to produce congenital malformations in a mammal (Hale 1933) and thus began the whole field of experimental mammalian teratology. Now, the biologically active metabolites of vitamin A, the retinoic acids (RAs), and their synthetic derivatives have become