Quantitative trait locus mapping for ethanol teratogenesis in BXD recombinant inbred mice.

BACKGROUND: Individual differences in susceptibility to the detrimental effects of prenatal ethanol (EtOH) exposure have been demonstrated. Many factors, including genetics, play a role in susceptibility and resistance. We have previously shown that C57BL/6J (B6) mice display a number of morphological malformations following an acute dose of EtOH in utero, while DBA/2J (D2) mice are relatively resistant. Here, we present the results of quantitative trait locus (QTL) mapping for EtOH teratogenesis in recombinant inbred strains derived from a cross between B6 and D2 (BXD RIs). METHODS: Pregnant dams were intubated with either maltose-dextrin or 5.8 g/kg EtOH on day 9 of gestation (GD9). On GD 18, dams were sacrificed and fetuses and placentae were removed. Placentae and fetuses were weighed; fetuses were sexed and examined for gross morphological malformations. Fetuses were then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in EtOH for subsequent skeletal examinations. QTL mapping for maternal weight gain (MWG), prenatal mortality, fetal weight (FW) at c-section, placental weight (PW), and several morphological malformations was performed using WebQTL. RESULTS: Heritability for our traits ranged from 0.06 for PW to 0.39 for MWG. We found suggestive QTLs mediating all phenotypes and significant QTLs for FW and digit and rib malformations. While most QTL regions are large, several intriguing candidate genes emerged based on polymorphisms between B6 and D2 and gene function. CONCLUSIONS: In this first mapping study for EtOH teratogenesis, several QTLs were identified. Future studies will further characterize these regions. Identification of genes and epigenetic modifications mediating susceptibility to the teratogenic effects of alcohol in mice will provide targets to examine in human populations.

Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model.

The teratogenicity of antiepilepsy drug valproic acid (VPA) mostly is found in genetic and somatic levels, causing teratogenesis involving neurotubular defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta. A diversity of nutraceutics have been tried to alleviate the risk of VPA-teratogenicity. The effect was varying. In order to promote the preventive prescription, to find out its action mechanism can be rather crucial. We used chicken embryo model to try the effect of folic acid (FA), ascorbic acid (AA), and N-acetyl cysteine (NAC). VPA at 30mM showed the higher malformation rate (66.7%) with the least mortality (22.2%). Pathological findings indicated that the cervical muscle was more susceptible to VPA injury than the ankle muscle. VPA downregulated levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate, and upregulated H(2)O(2) and homocysteine. FA, AA, and NAC significantly upregulated SOD, but only AA alone activated GSH. AA and NAC downregulated H(2)O(2), while FA was totally ineffective. All three nutraceutics comparably rescued HDAC with simultaneously suppressed homocysteine accumulation and folate re-elevation, although less effectively by NAC. Based on these data, we conclude VPA possesses "Multiple Point Action Mechanism". In addition to affecting the cited transcription and translation levels, we hypothesize that VPA competitively antagonize the glutamic acid to couple with pteroic acid in biosynthesis of dihydrofolic acid (DHFA). H(2)O(2) directly destroyed the NADPH reducing system at dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) levels, while completely restored by AA, an implication in preservation of intact apoenzymes. In addition, the GSH-GSSG system is sandwiched between the reducing systems NADPH/NADP and DHA-AA, its net balance is highly dependent on in situ in vivo Redox state, hence folic acid transformation is varying. To rescue the VPA-induced teratogenicity, simultaneous multiple prescriptions are suggested.

A comparison of mixed effects logistic regression models for binary response data with two nested levels of clustering.

We compare mixed effects logistic regression models for binary response data with two nested levels of clustering. The comparison of these models occurs in the context of developmental toxicity data sets, for which multiple types of outcomes (first level) are measured on each rat pup (second level) nested within a litter (third level). Because the nested nature of such data is occasionally accommodated by ignoring one level of clustering, we consider three models: (i) a three-level model adjusting for clustering due to both pup and litter (M1); (ii) a two-level model adjusting for just pup (M2); and (iii) another two-level model adjusting for just litter (M3). The three types of effects of interest are: (i) differences among malformation types (first-level effects); (ii) differences among groups of pups (for example, sex of pup, second-level effects); and (iii) differences among groups of litters (for example, dose, third-level effects). Simulations and data analyses suggest that the M3 model leads to more bias than the M1 or M2 models for all three types of effects. In terms of coverage of confidence intervals for fixed effects log odds ratio parameters, the M1 model achieves nominal coverage, whereas the M2 model reduces coverage for the third-level effects and the M3 model obtains poor coverage for both first- and second-level effects. These reductions in coverage for certain model-parameter combinations worsen as baseline risk increases. The data analyses support these simulation-based conclusions to some extent.

Vincristine treatment triggering the expression of asymptomatic Charcot-Marie-Tooth disease.

A 16-year-old male suffering from Ewing's sarcoma of the pelvis was treated with vincristine as part of his chemotherapeutic protocol. The boy was never known to suffer from any neurological problems. His father had a mild limp, attributed to prolonged "taxi driving," that was never investigated medically. The first course of treatment, which included 2 mg of vincristine, resulted in clinical improvement. However, at the same time the patient developed severe weakness of both upper and lower limbs, areflexia, and gradually a pes cavus deformity. Nerve conduction studies were suggestive of severe peripheral sensorimotor neuropathy, axonal and demyelinative. A definite diagnosis of Charcot-Marie-Tooth was confirmed by molecular analysis showing the typical duplication of 1.5 megabases at 17 p11.2. This unique manifestation of vincristine neurotoxicity is reported and discussed.