Sex-based differences in gene expression in hippocampus following postnatal lead exposure.

The influence of sex as an effect modifier of childhood lead poisoning has received little systematic attention. Considering the paucity of information available concerning the interactive effects of lead and sex on the brain, the current study examined the interactive effects of lead and sex on gene expression patterns in the hippocampus, a structure involved in learning and memory. Male or female rats were fed either 1500 ppm lead-containing chow or control chow for 30 days beginning at weaning.Blood lead levels were 26.7±2.1 µg/dl and 27.1±1.7 µg/dl for females and males, respectively. The expression of 175 unique genes was differentially regulated between control male and female rats. A total of 167 unique genes were differentially expressed in response to lead in either males or females. Lead exposure had a significant effect without a significant difference between male and female responses in 77 of these genes. In another set of 71 genes, there were significant differences in male vs. female response. A third set of 30 genes was differentially expressed in opposite directions in males vs. females, with the majority of genes expressed at a lower level in females than in males. Highly differentially expressed genes in males and females following lead exposure were associated with diverse biological pathways and functions. These results show that a brief exposure to lead produced significant changes in expression of a variety of genes in the hippocampus and that the response of the brain to a given lead exposure may vary depending on sex.

Transcriptional regulatory network analysis of developing human erythroid progenitors reveals patterns of coregulation and potential transcriptional regulators.

Deciphering the molecular basis for human erythropoiesis should yield information benefiting studies of the hemoglobinopathies and other erythroid disorders. We used an in vitro erythroid differentiation system to study the developing red blood cell transcriptome derived from adult CD34+ hematopoietic progenitor cells. mRNA expression profiling was used to characterize developing erythroid cells at six time points during differentiation (days 1, 3, 5, 7, 9, and 11). Eleven thousand seven hundred sixty-three genes (20,963 Affymetrix probe sets) were expressed on day 1, and 1,504 genes, represented by 1,953 probe sets, were differentially expressed (DE) with 537 upregulated and 969 downregulated. A subset of the DE genes was validated using real-time RT-PCR. The DE probe sets were subjected to a cluster metric and could be divided into two, three, four, five, or six clusters of genes with different expression patterns in each cluster. Genes in these clusters were examined for shared transcription factor binding sites (TFBS) in their promoters by comparing enrichment of each TFBS relative to a reference set using transcriptional regulatory network analysis. The sets of TFBS enriched in genes up- and downregulated during erythropoiesis were distinct. This analysis identified transcriptional regulators critical to erythroid development, factors recently found to play a role, as well as a new list of potential candidates, including Evi-1, a potential silencer of genes upregulated during erythropoiesis. Thus this transcriptional regulatory network analysis has yielded a focused set of factors and their target genes whose role in differentiation of the hematopoietic stem cell into distinct blood cell lineages can be elucidated.

Analysis and neuronal modeling of the nonlinear characteristics of a local cardiac reflex in the rat.

Previous experimental results have suggested the existence of a local cardiac reflex in the rat. In this study, the putative role of such a local reflex in cardiovascular regulation is quantitatively analyzed. A model for the local reflex is developed from anatomical experimental results and physiological data in the literature. Using this model, a systems-level analysis is conducted. Simulation results indicate that the neuromodulatory mechanism of the local reflex attenuates the nonlinearity of the relationship between cardiac vagal drive and arterial pressure. This behavior is characterized through coherence analysis. Furthermore, the modulation of phase-related characteristics of the cardiovascular system is suggested as a plausible mechanism for the nonlinear attenuation. Based on these results, it is plausible that the functional role of the local reflex is highly robust nonlinear compensation at the heart, which results in less complex dynamics in other parts of the reflex.