Cross-Generational Transmission of Early Life Stress Effects on HPA Regulators and Bdnf Are Mediated by Sex, Lineage, and Upbringing

Early life stress (ELS) is a potent developmental disruptor and increases the risk for psychopathology. Various forms of ELS have been studied in both humans and rodents, and have been implicated in altered DNA methylation, gene transcription, stress hormone levels, and behavior. Although recent studies have focused on stress-induced epigenetic changes, the extent to which ELS alters HPA axis function and stress responsivity across generations, whether these effects are sex-specific, and how lineage interacts with upbringing to impact these effects, remain unclear. To address these points, two generations of rodents were utilized, with the first generation subjected to ELS via maternal separation, and the second to a balanced cross-fostering paradigm. We hypothesized that ELS would disrupt normative development in both generations, manifesting as altered methylation and expression of genes associated with stress signaling pathways (Nr3c1, Nr3c2, and Bdnf), blunted corticosterone (CORT), and anxiety-like behaviors. Additionally, we expected deficits in the second generation to be modulated by caretaking environment and for the pattern of results to differ between the sexes. Results suggest that direct exposure to ELS leads to sex-specific effects on gene regulation and HPA functioning in adulthood, with maternal separation leading to increases in Bdnf methylation in both sexes, decreases in Bdnf expression in females, and decreases in Nr3c1 methylation in males, as well as blunted CORT and less anxiety-like behavior in females. These alterations converged with caretaking to impart perturbations upon the subsequent generation. Across sex, ELS lineage led to decreased methylation of Nr3c1, and increased methylation of Bdnf. In fostered animals, upbringing by a previously stressed mother interacted with offspring lineage to impact methylation of Nr3c1 and Bdnf. Upbringing was also implicated in altered anxiety-like behavior in males, and baseline CORT levels in females. Such effects may correspond with observed alterations in maternal behavior across groups. In conclusion, ELS conferred enduring sex-specific alterations, both first-hand and trans-generationally via lineage and upbringing. Importantly, lineage of cross-fostered pups was sufficient to normalize or disturb maternal behavior of foster-dams, an observation requiring further elucidation. These results have implications for multi-generational effects of ELS in humans and may motivate early interventions

Androgen Action and Stress

Androgens belong to a class of steroid hormones that circulate at high levels in males. However, androgens should not be thought of as exclusively male hormones since they are also produced in females, though at much lower levels. The predominant mode of androgen action is through binding in target tissues to a specific receptor termed the androgen receptor. This receptor can regulate the expression of a set of androgen-responsive genes. The synthesis, transport, and release of androgens to the bloodstream, their actions on target tissues, and their effects on stressor related neuroendocrine function and behaviors are addressed here.https://nsuworks.nova.edu/cps_facbooks/1655/thumbnail.jp

Labelling of the solvent DMSO as side reaction of methylations with n.c.a [11C]CH3I

Competing labelling of solvent dimethyl sulfoxide (DMSO) can occur during the C-11-methylation of amine precursors. A kinetic analysis of the methylation reaction of DMSO with n.c.a. [C-11]CH3I was performed at 120 degreesC resulting in rate constants. The rate constant for the formation of the intermediate, methylated DMSO ([C-11]DMSO-M). is compared to the reaction of [C-11]CH3I with two tertiary amines. namely Dexetimide and Desmethyloxotremorine-M. The specific activity of the labelled product is reduced due to partial C-12-methylation of the precursor amines by [C-11]DMSO-M in cases of significant DMSO labelling as side reaction. (C) 2001 Elsevier Science Ltd. All rights reserved