Short-Term dermal absorption and penetration of chemicals from aqueous solutions: theory and experiment.

Dermal penetration of organic chemical-contaminated water from showering and bathing scenarios is a concern of regulatory agencies that have been tasked with determining safe exposure levels. During household showering and bathing, nearly the entire surface area of the body is exposed for short periods of time (5-15 minutes). The primary means of predicting body burden during brief exposures is to estimate total chemical penetrated from the steady-state penetration rate using a skin permeability coefficient. A variety of approaches has been recommended to estimate "body burden." The purpose of this investigation was to collect experimental data from short-term exposures to an organic chemical (dibromomethane [DBM]) in aqueous solution so that methods for estimating body burden could be compared. Rat skins were exposed in vitro to saturated aqueous solutions of DBM for 20 minutes and the amount of chemical in the receptor solution and the skin was analyzed. The total DBM mass in the receptor solution and the skin was taken to represent an in vivo body burden. These results were compared with the estimates of penetration from steady-state calculations, square root of time calculations, and a biologically based mathematical model. Results indicated that the amount of chemical in the skin and its fate during short exposures is important. The square root of time approach predicted total amount of chemical absorbed and penetrated better than did the steady-state approach. The biologically based mathematical model accurately predicted total body burden and could be used to distinguish between the amount of chemical in the skin and the amount of chemical that penetrated through the skin, which would be useful for understanding local toxicity.

Photoreceptor localization of the KIF3A and KIF3B subunits of the heterotrimeric microtubule motor kinesin II in vertebrate retina.

The heterotrimeric microtubule motor kinesin II has been shown to be required for morphogenesis and maintenance of both motile flagella and immotile sensory cilia. Recently, we showed that the KIF3A subunit of kinesin II is concentrated in the inner segment and connecting cilium of fish photoreceptors. Here we report the gene structure of human KIF3A (HsKIF3A) and describe its localization in human and monkey retina. We also describe the localization of both KIF3A and KIF3B kinesin II subunits in Xenopus retina. Using a portion of HsKIF3A we had amplified from adult human retinal cDNA, we found by a GenBank database search that an identical sequence had already been obtained by the Human Genome Center at Lawrence Berkeley National Laboratories in a direct sequencing analysis of 680 kb of human chromosome 5q31. By comparing the genomic sequence of HsKIF3A to the open reading frame (ORF) of the highly homologous mouse Kif3A, we determined that the HsKIF3A gene has 17 exons and an ORF of approximately 2.1 kb, predicting a protein of 80.3 kDa. Antibodies against sea urchin KRP85, a KIF3A homologue, bound to a single band of approximately 85 kDa in immunoblots of total retina protein from human, monkey and Xenopus. In these same samples, a single band of approximately 95 kDa is recognized by antibodies against Xklp3, a Xenopus KIF3B homologue. In sections of Xenopus retina, both antibodies strongly labelled photoreceptor inner segments and the outer limiting membrane. Both antibodies also labelled photoreceptor axonemes. The axonemal localization of kinesin II subunits suggests that kinesin II may play a role in transport of materials from the photoreceptor cell body to the outer segment.

Cloning of a novel C-terminal kinesin (KIFC3) that maps to human chromosome 16q13-q21 and thus is a candidate gene for Bardet-Biedl syndrome.

Kinesins are a large superfamily of microtubule motors that mediate specific motile processes. In a previous study, we identified 11 kinesin family members in the retina and retinal pigment epithelium (RPE) of the striped bass, Morone saxatilus. We have now identified, cloned, and sequenced the human homologue (KIFC3) of the most abundantly expressed retinal kinesin from that study, the C-terminal kinesin FKIF2. An antibody raised against an FKIF2 peptide cross-reacted with an approximately 80-kDa protein in human retina, RPE, kidney, and lung. Since microtubule-dependent processes are critical to the function and morphogenesis of the photoreceptors and RPE, the abundantly expressed KIFC3 was considered to be a potential candidate gene for causing human retinal degeneration. Chromosomal localization of the KIFC3 gene revealed that it maps to chromosome 16q13-q21, within the critical region for a Bardet-Biedl syndrome locus (BBS2). Bardet-Biedl syndrome is a genetically heterogeneous, autosomal recessive disorder characterized by retinal dystrophy, polydactyly, obesity, hypogonadism, renal abnormalities, and mental retardation. The chromosomal localization and expression pattern of KIFC3 suggest that it may be an excellent candidate for families linked to BBS2.