Evaluation of p21 expression and related autism-like behavior in Bisphenol-A exposed offspring of Wistar albino rats.

BACKGROUND: Bisphenol A (BPA), an endocrine disruptor, may be involved in the etiology of autism spectrum disorders (ASD); however, the mechanism of neuronal and astrocytic damage remains ambiguous. A possible role of altered expression of p21 in autistic-like behavior in rat offspring was examined with prenatal and postnatal BPA exposure. METHODS: Wistar albino dams were exposed to BPA (5 mg/kg) intraperitoneally throughout pregnancy and until the third postnatal day (PND). Pups were examined on 21st PND for behavioral test. Blood samples were collected for serum lactate levels and pups were sacrificed. Right frontal cortices were dissected out and processed for H&E, immunohistochemical analysis, and gene expression. RESULTS: Anxiety like behavior and thigmotaxis along with reduction in serum lactate concentrations were observed in pups exposed to BPA. Decline in neuronal number and decreased astrocytic population with reduced dendritic spines were revealed by H&E and immunohistochemical analysis, respectively, in right frontal cortices. Over expression of p21 was also detected in BPA-exposed offspring. CONCLUSIONS: Over expression of p21 may be associated with autistic behavior. Further studies are recommended to explore the structural alterations in other white matter pathways in frontal cortices.

Epigenetic effects of in utero bisphenol A administration: Diabetogenic and atherogenic changes in mice offspring.

OBJECTIVES: Bisphenol A (BPA) that is a monomer of plastic products may possibly interfere with epigenetics and be involved in onset and progression of several diseases. This study was aimed to detect the epigenetic effects of in utero BPA exposure in mice offspring. MATERIALS AND METHODS: All experiments were performed according to the national guidelines for laboratory animals and after ethical approval. Thirty adult BALB/c female mice were divided into 3 equal groups, G1 (controls), G2 (ethanol 0.10 ml/100ml of PBS so that final concentration would be 0.01%) vehicle control and G3 (BPA 10 mg/kg). Chemicals were given twice a week throughout the pregnancy. Once delivered at term, female offspring were observed for body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and high-density lipoprotein cholesterol (HDLc) were measured at 5 and 15 months postnatal. Animals were sacrificed at 15 months and pancreas, kidney, adipose tissue and uterine tissue were taken and stained with either Hematoxylin and eosin (H & E) or immunostaining and examined under light microscope. RESULTS: Offspring of group G3 revealed abnormal changes of body weight, behavior and movements. Blood glucose, serum insulin, cholesterol and HDLc were high in group G3 offspring compared to controls. H & E staining showed changes in the parenchyma of pancreas, kidneys and uterus, which were confirmed by staining with anti- islet-1, kidney-specific (Ksp) cadherin, and anti- MLH antibody. CONCLUSION: In utero exposure of BPA exerts diabetogenic and atherogenic effects with less parenchymal tissue in endocrine pancreas, kidney and uterus.

The novel heterozygous Thr377Arg MYOC mutation causes severe Juvenile Open Angle Glaucoma in a large Pakistani family.

Glaucoma is one of the major causes of blindness worldwide with characteristic optic disc changes and elevated intraocular pressure. It is subcategorized into Primary Open Angle Glaucoma (POAG) and Juvenile Open Angle Glaucoma (JOAG) depending upon age of the disease onset. Myocilin (MYOC) is the frequently mutated gene in familial cases of glaucoma. MYOC mutations show variable phenotype and penetrance. This study was aimed to identify disease causing mutation in 8 affected of a consanguineous family diagnosed with severe form of Juvenile Open Angle Glaucoma. Homozygosity mapping with four microsatellite markers and subsequent direct sequencing of MYOC revealed a novel heterozygous transition c.1130 C>G, substituting Threonine in to Arginine at codon 377 (p.Thr377Arg) of MYOC. This mutation was segregating with phenotype in all affected and was not found in control subjects. Ophthalmological findings revealed JOAG with severe and rapidly progressive phenotype. The age of onset was in the first decade of life and maximum Intra Ocular Pressure (IOP) recorded was 25mmHg. Bioinformatic tools predicted C to G transition at c.1130 as pathogenic and no structural changes were predicted in protein. This is the first report of novel MYOC mutation from Pakistan; segregating as autosomal dominant trait in large family diagnosed with JOAG. Identification of novel disease causing allele in MYOC indicates genetic heterogeneity of the population. This finding will help to provide genetic counseling to the affected family and carriers of this mutation may be advised for early therapeutic intervention to avoid irreversible visual loss.