Long-term effects of early-life exposure to environmental oestrogens on ovarian function: role of epigenetics.

Oestrogens play an important role in development and function of the brain and reproductive tract. Accordingly, it is considered that developmental exposure to environmental oestrogens can disrupt neural and reproductive tract development, potentially resulting in long-term alterations in neurobehaviour and reproductive function. Many chemicals have been shown to have oestrogenic activity, whereas others affect oestrogen production and turnover, resulting in the disruption of oestrogen signalling pathways. However, these mechanisms and the concentrations required to induce these effects cannot account for the myriad adverse effects of environmental toxicants on oestrogen-sensitive target tissues. Hence, alternative mechanisms are assumed to underlie the adverse effects documented in experimental animal models and thus could be important to human health. In this review, the epigenetic regulation of gene expression is explored as a potential target of environmental toxicants including oestrogenic chemicals. We suggest that toxicant-induced changes in epigenetic signatures are important mechanisms underlying the disruption of ovarian follicular development. In addition, we discuss how exposure to environmental oestrogens during early life can alter gene expression through effects on epigenetic control potentially leading to permanent changes in ovarian physiology.

Aromatase is increased in astrocytes in the presence of elevated pressure.

After traumatic brain injury (TBI), a progressive injury and death of neurons and glia leads to decreased brain function. Endogenous and exogenous estrogens may protect these vulnerable cells. In this study, we hypothesized that increased pressure leads to an increase in aromatase expression and estrogen production in astrocytes. In this study, we subjected rat glioma (C6) cells and primary cortical astrocytes to increased pressure (25 mm Hg) for 1, 3, 6, 12, 24, 48, and 72 h. Total aromatase protein and RNA levels were measured using Western analysis and RT-PCR, respectively. In addition, we measured aromatase activity by assaying estrone levels after administration of its precursor, androstenedione. We found that increased pressure applied to the C6 cells and primary cortical astrocytes resulted in a significant increase in both aromatase RNA and protein. To extend these findings, we also analyzed aromatase activity in the primary astrocytes during increased pressure. We found that increased pressure resulted in a significant (P < 0.01) increase in the conversion of androstenedione to estrone. In conclusion, we propose that after TBI, astrocytes sense increased pressure, leading to an increase in aromatase production and activity in the brain. These results may suggest mechanisms of brain estrogen production after increases in pressure as seen in TBI patients.

Dobutamine enhances both contractile function and energy reserves in hypoperfused canine right ventricle.

Although the beta(1)-adrenergic agent dobutamine is used clinically to provide inotropic support to the failing myocardium, it could jeopardize the myocardium by depleting energy reserves. This investigation delineated the contractile and energetic effects of low versus high dobutamine doses in the hypoperfused right ventricular (RV) myocardium. The right coronary artery (RCA) of anesthetized dogs was cannulated for controlled perfusion with arterial blood, and regional RV contractile function was measured. RCA perfusion pressure was lowered from 100 mmHg baseline to 40 mmHg, and flow fell by 54%. At 15-min hypoperfusion, dobutamine was infused into the RCA at either 0.01 (low-dose dobutamine) or 0.06 microgram. kg(-1). min(-1) (high-dose dobutamine) for 15 min. Regional power (systolic segment shortening x isometric developed force x heart rate) stabilized at 63% of baseline during hypoperfusion. Low-dose dobutamine restored power to baseline but did not increase RV myocardial O(2) consumption (MVO(2)) and thus increased myocardial O(2) utilization efficiency (O(2)UE:power/MVO(2)). At 5 min, high-dose dobutamine enhancement of power was similar to that of low-dose dobutamine, but by 15 min, power and O(2)UE fell to untreated levels. Remarkably, low-dose dobutamine tripled cytosolic phosphorylation potential; in contrast, high-dose dobutamine lowered phosphorylation potential to 45% of the untreated value. Analyses of glucose uptake and glycolytic intermediates revealed sustained enhancement of glycolysis by low-dose dobutamine, but glycolysis became limited at glyceraldehyde 3-phosphate dehydrogenase during high-dose dobutamine treatment. In summary, low-dose dobutamine improved mechanical performance and efficiency of the hypoperfused RV myocardium while increasing myocardial energy reserves, but high-dose dobutamine failed to sustain improved function and depleted energy reserves. Dobutamine is capable of improving both contractile function and cellular energetics in the hypoperfused RV myocardium, but dosage should be carefully selected.