bromochloroacetic-acid and Eye-Abnormalities

The haloacetic acids (HAA) are a family of chemicals that are drinking water disinfection by-products. We previously reported that haloacetic acids, including several bromo- and chloro-HAAs, alter embryonic development when mouse conceptuses are directly exposed to these xenobiotics in whole embryo culture. Craniofacial dysmorphogenesis was observed in exposed embryos and a quantitative structure activity relationship (QSAR) for induction of cranial neural tube dysmorphogenesis was established for a series of 10 HAAs, which also included fluoro- and iodo-HAA representatives. In the current study, we evaluate the effects of exposing neurulation staged (3-6 somite pairs) CD-1 mouse conceptuses to bromochloro- (BCA), dibromochloro- (DBCA) and bromodichloro-acetic (BDCA) acids in whole embryo culture at concentrations ranging from 50 to 2500 microM. Morphological development was assessed after a 26 h exposure period. Exposure of conceptuses to these HAAs produced dysmorphogenesis, including prosencephalic and pharyngeal arch hypoplasia as well as eye and heart tube abnormalities. Benchmark concentrations for induction of neural tube dysmorphogenesis were 63, 500 and 536 microM for BCA, DBCA and BDCA, respectively. Our previously developed HAA QSAR accurately predicted placement of these three chemicals in the larger context of the previously tested di- and tri-HAAs, also correctly predicting that BCA would be more potent than DBCA and BDCA, and that the latter two HAAs would be near equi-potent. This study describes the concentration-dependent induction of dysmorphogenesis in whole embryo culture by three mixed chloro/bromo-HAAs and demonstrates the ability of the HAA QSAR to predict relative potencies within this family of xenobiotics.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Benchmarking; Dose-Response Relationship, Drug; Embryo Culture Techniques; Embryonic Development; Eye Abnormalities; Heart Defects, Congenital; Mice; Neural Tube Defects; Quantitative Structure-Activity Relationship

Topics: Abnormalities, Multiple; Adult; Child; Corneal Diseases; Ear, External; Epithelium, Corneal; Eye Abnormalities; Female; Fingers; Humans; Keratin-3; Keratins; Lacrimal Apparatus; Limbus Corneae; Stem Cells; Syndactyly; Syndrome; Tooth Abnormalities

Glucocorticoid hormones act through the glucocorticoid receptor (GR) and they affect almost all physiological systems in the organism. We have previously reported that transgenic mice overexpressing GR under the control of the keratin k5 promoter (K5-GR mice) display severe phenotypic alterations in the epidermis and other ectoderm derivatives (Perez et al., 2001). In this work, we aimed to characterize the pathological consequences of GR targeted overexpression in the eyelid and cornea at late developmental stages. Despite glucocorticoids being widely prescribed as a topical treatment in ophthalmology, their potential role during ocular development in the embryo is not well understood. As shown by scanning electron microscopy analysis as well as by our histopathological and immunohistochemical data, long-term and newborn transgenic embryos showed unfused eyelids, along with proptosis of the globe and exposure of the anterior surface. In addition, epithelial defects were evident at the cornea. Our results indicate that GR overexpression affected the proliferation rate of targeted epithelia of the cornea and eyelid, thus demonstrating that GR was responsible for the arrest of epithelial proliferation of the developing eyelid edges, as well as for their destruction. We conclude that constitutive targeted overexpression of GR in the eyelid and corneal epithelium dramatically impairs ocular function in these transgenic mice.

Topics: Animals; Animals, Newborn; Cell Division; Cornea; Ectoderm; Eye Abnormalities; Eyelids; Gene Expression Regulation, Developmental; Immunoenzyme Techniques; Keratin-15; Keratin-5; Keratins; Ki-67 Antigen; Mice; Mice, Transgenic; Microscopy, Electron, Scanning; Receptors, Glucocorticoid; Up-Regulation