Concordance of 3 alternative teratogenicity assays with results from corresponding in vivo embryo-fetal development studies: Final report from the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe working group 2.

An IQ DruSafe working group evaluated the concordance of 3 alternative teratogenicity assays (rat whole embryo culture, rWEC; zebrafish embryo culture, ZEC; and murine embryonic stem cells, mESC) with findings from rat or rabbit embryo-fetal development (EFD) studies. Data for 90 individual compounds from 9 companies were entered into a database. In vivo findings were deemed positive if malformations or embryo-fetal lethality were reported in either species. Each company used their own criteria for deciding whether the alternative assay predicted the in vivo findings. Standard concordance parameters were calculated, positive and negative predictive values (PPV and NPV) were adjusted for the aggregate portfolio prevalence of positive compounds (established by a survey of participating companies), and positive and negative likelihood ratios (LR+ and iLR-) were calculated. Of the 3 assays, only rWEC data were robustly predictive, particularly for negative predictions (NPVadj = 92%). However, both LR+ (4.92) and iLR- (4.72) were statistically significant for the rWEC assay. When analyzed separately for rats, the NPVadj and iLR-values for the rWEC assay increased to 96% and 9.75, respectively. These data suggest that a negative rWEC outcome could defer or replace a rat EFD study in certain regulatory settings.

Measuring cultural climate in a uniformed services medical center.

The purpose of this study was to determine the employee perceptions of the cultural climate at a large uniformed service medical center in the mid-Atlantic region of the United States. The analyses are based on the responses of 1,751 medical center employees, whose demographic characteristics were representative of the medical center population. Analyses indicate the existence of systematic perceptual differences between: (1) the medical center and Department of Defense personnel, and (2) the following cultural groups: (a) male and female personnel, (b) military and civilian personnel, and (c) majority and minority personnel. Recommendations are provided for future areas of research that need to be conducted with respect to the phenomenon of cultural diversity and the development of positive cultural climates within both the military and civilian medical settings.

Prenatal exposure to neurotoxicants dieldrin or lindane alters tert-butylbicyclophosphorothionate binding to GABA(A) receptors in fetal rat brainstem.

GABA acts as a trophic signal for cultured embryonic rat monoamine neurons by activating GABA(A) receptors. These effects are blocked by the organochlorine insecticide dieldrin and the classic GABA(A) antagonist bicuculline. Both dieldrin and another organochlorine insecticide, lindane, block the effects of GABA on the GABA(A) receptor by binding directly to the Cl- channel. Therefore, prenatal exposure to these chemicals could lead to disturbances in the trophic actions of GABA on monoamine neurotransmitter systems in the embryonic brain and produce alterations in GABA(A) receptor expression and function. Effects of daily prenatal exposure to organochlorine insecticide (dieldrin or lindane) or bicuculline from embryonic day (E)12-17 were determined in brains of E17 fetal rats using t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) binding. This radioligand was chosen because, like organochlorine insecticides, it binds directly to GABA(A) receptor/Cl- channels. [35S]TBPS binding was analyzed in extensively washed membranes from E17 brainstem and whole brain with the brainstem removed ('rest of brain') at a TBPS concentration that approximated the KD determined in [35S]TBPS saturation binding experiments performed on normal E17 rat brainstem. In utero exposure to dieldrin, lindane, or bicuculline from E12-E17 caused a significant reduction in the amount of [35S]TBPS binding in E17 brainstem compared to vehicle-injected controls, but had no significant effect on 'rest of brain'. These data suggest that in utero exposure to organochlorine insecticides that act as GABA(A) antagonists negatively regulate expression of GABAA receptors in fetal brainstem. If these effects persist, they could lead to disturbances in postnatal functions of the ascending GABAergic system, possibly with behavioral consequences.

Prenatal exposure to the pesticide dieldrin or the GABA(A) receptor antagonist bicuculline differentially alters expression of GABA(A) receptor subunit mRNAs in fetal rat brainstem.

We have previously shown that GABA acts as a trophic signal for monoamine neurons in embryonic day 14 (E14) rat brainstem cultures [Liu et al., J Neurosci 1997a; 17:2420-2428]. The organochlorine pesticide dieldrin and the classical GABA(A) receptor antagonist bicuculline interfere with the trophic actions of GABA and alter expression of several GABA(A) receptor subunit mRNA transcripts in these cultures [Liu et al., J Neurosci Res 1997b;49:645-653]. In the present study, we investigated whether prenatal exposure to dieldrin or bicuculline from E12-17 would alter mRNA expression of alpha1, beta3, gamma1, gamma2S and gamma2L GABA(A) receptor subunits in fetal (E17) rat brainstem using competitive RT-PCR to absolutely quantify these transcripts. The effects of dieldrin and bicuculline on expression of GABA(A) receptor subunit transcripts were similar across subunits. Dieldrin and bicuculline decreased expression of alpha1, beta3 and gamma1 transcripts compared to vehicle-injected controls, but did not significantly alter expression of gamma2S and gamma2L transcripts. Taken together, these studies indicate that in utero exposure to organochlorine pesticides acting as GABA(A) receptor antagonists may alter the expression and subunit composition of developing GABA(A) receptors. If these changes persist, they could have long-lasting effects on developing GABAergic neural circuitry, GABA(A) receptor function and GABA-mediated behaviors.