2-hydroxyestradiol and Body-Weight

Women are more likely to suffer from a bingeing-related eating disorder, which is surprising, since estradiol reduces meal size and is associated with reduced binge frequency. This apparent contradiction may involve the estradiol metabolite, 2-hydroxyestradiol. We previously reported that female rats had faster escalations in shortening intake during the development of bingeing than did males, but acute administration of 2-hydroxyestradiol increased the intake of vegetable shortening to a greater extent in male rats once bingeing was established. Here, we report two separate studies that follow up these previous findings. In the first, we hypothesized that chronic exposure to 2-hydroxyestradiol would promote escalation of bingeing during binge development in ovariectomized female rats. In the second, we hypothesized that acute exposure to 2-hydroxyestradiol would enhance dopamine signaling in the prefrontal cortex after bingeing was established in male rats. In study 1, non-food-deprived female rats were separated into 3 groups: ovariectomized (OVX) with chronic 2-hydroxyestradiol supplementation (E), OVX with vehicle supplementation (O), and intact with vehicle (I). Each group was given access to an optional source of dietary fat (shortening) on Mon, Wed, and Fri for 4 weeks. 2-hydroxyestradiol supplementation prevented OVX-induced weight gain and enhanced escalation of shortening intake over the four-week period (ps<0.05). Additionally, in week 4, rats in the E group ate significantly more shortening than I controls, less chow than either the O or I group, and had a higher shortening to chow ratio than O or I (ps<0.05). Study 2 indicated that acute injection of 2-hydroxyestradiol abolished shortening-evoked dopamine efflux in the prefrontal cortex of bingeing male rats (p<0.05). Together, these studies indicate that 2-hydroxyestradiol can exacerbate bingeing as it develops and can suppress dopamine signaling in the prefrontal cortex once bingeing is established.

Topics: Animals; Behavior, Animal; Body Weight; Bulimia; Disease Models, Animal; Dopamine; Eating; Estradiol; Feeding Behavior; Female; Male; Prefrontal Cortex; Rats; Rats, Sprague-Dawley

Pulmonary arterial hypertension (PH) is a deadly disease characterized by pulmonary arterial vasoconstriction and hypertension, pulmonary vasculature remodeling, and right ventricular hypertrophy. Our previous in vivo studies, performed in several models of cardiac, vascular, and/or renal injury, suggest that the metabolites of 17beta-estradiol may inhibit vascular and cardiac remodeling. The goal of this study was to determine whether 2-methoxyestradiol (2ME), major non-estrogenic estradiol metabolite, prevents the development and/or retards the progression of monocrotaline (MCT)-induced PH. First, a total of 27 male Sprague Dawley rats were injected with distillated water (Cont, n=6) or monocrotaline (MCT; 60 mg/kg, i.p.; n=21). Subsets of MCT animals (n=7 per group) received 2ME or its metabolic precursor 2-hydroxyestradiol (2HE; 10 microg/kg/h via osmotic minipumps) for 21 days. Next, an additional set (n=24) of control and MCT rats was monitored for 28 days, before right ventricular peak systolic pressure (RVPSP) was measured. Some pulmonary hypertensive animals (n=8) were treated with 2ME (10 microg/kg/h) beginning from day 14 after MCT administration. MCT caused pulmonary hypertension (ie, increased right ventricle/left ventricle+septum [RV/LV+S] ratio and wall thickness of small-sized pulmonary arteries, and elevated RVPSP) and produced high and late (days 22 to 27) mortality. Pulmonary hypertension was associated with strong proliferative response (PCNA staining) and marked inflammation (ED1+cells) in lungs. Both metabolites significantly attenuated the RV/LV+S ratio and pulmonary arteries media hypertrophy and reduced proliferative and inflammatory responses in the lungs. Furthermore, in diseased animals, 2ME (given from day 14 to 28) significantly decreased RVPSP, RV/LV+S ratio and wall thickness, and reduced mortality by 80% (mortality rate: 62.5% vs. 12.5%, MCT vs. MCT+2ME day 14 to 28). This study provides the first evidence that 2ME, a major non-estrogenic, non-carcinogenic metabolite of estradiol, prevents the development and retards the progression of monocrotaline-induced pulmonary hypertension. Further evaluation of 2ME for management of pulmonary arterial hypertension is warranted.

Topics: 2-Methoxyestradiol; Animals; Blood Pressure; Body Weight; Cell Proliferation; Disease Progression; Estradiol; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Male; Monocrotaline; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Time Factors; Tubulin Modulators

Potential effects of xenobiotics on humans are largely derived from studies with animal models. However, due to species-specific processing of xenobiotics, susceptibilities to xenobiotic-dependent adverse effects are known to differ between species. We analysed the basal expression of cytochrome P450 (CYP) enzymes in several organs of minipigs and rats, and their inducibility upon oral intake of soils containing polycyclic aromatic hydrocarbons (PAH). CYP-specific enzymatic activities were determined in duodenum, liver and kidney microsomes. Upon ingestion of PAH-contaminated soils, CYP1A1 is differentially induced in a tissue-specific and dose-dependent manner in duodenum, liver and kidney of minipigs and rats. In the duodenum, the induction response is low in rats (about 4-fold) but it is high in minipigs (8-230-fold). By contrast, induced hepatic CYP1A1-dependent EROD-activity is higher in rats than in minipigs. The dose-response profile for renal CYP1A1 parallels that in the liver of either species but EROD-activities are 10-20 times lower than in the liver. Liver microsomal CYP2E1 is only slightly modulated in its expression by ingestion of PAH-contaminated soils in both species, whereas CYP3A-dependent testosterone 2beta- and 6beta-hydroxylation is increased in liver of rats but not in minipigs. The hepatic capacity for catechol oestrogen formation, i.e., the 2-hydroxylation of 17beta-oestradiol, is markedly increased in rats but not in minipigs by ingested PAH. It is concluded that different metabolic and transport pathways are used by minipigs and rats to process ingested PAH. Whereas in minipigs the duodenum appears as the first efficient barrier, rats respond by efficient metabolism in the liver. What is not known is which response profile is operative in man.

Topics: Administration, Oral; Animals; Body Weight; Chlorzoxazone; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Duodenum; Enzyme Induction; Estradiol; Female; Kidney; Liver; Male; Microsomes; Microsomes, Liver; Polycyclic Aromatic Hydrocarbons; Rats; Rats, Sprague-Dawley; Soil; Species Specificity; Swine; Swine, Miniature; Testosterone; Tissue Distribution; Xenobiotics