Distribution of androstenedione and its effects on total free fatty acids in pregnant rats

Abstract

Androstenedione, an anabolic steroid used to enhance athletic performance, was administered in corn oil by gastric intubation once daily in the morning to nonpregnant female rats at a dose of 5 or 60 mg/kg/day, beginning two weeks before mating and continuing through gestation day (GD) 19. On GD 20, the distribution of androstenedione and other steroid metabolites was investigated in the maternal plasma and target organs, including brain and liver. The concentration of estradiol in plasma approached a statistically significant increase after treatment as compared with the controls, whereas the levels of androstenedione, testosterone and progesterone were not significantly different from the controls. In the liver, the concentrations of androstenedione and estradiol only were increased in a dose-related manner. None of these steroids was detectable in the brain. Androstenedione treatment also produced changes in the level of selected free fatty acids (FFAs) in the maternal blood, brain, liver and fetal brain. The concentrations of palmitic acid (16:0) and stearic acid (18:0) in the plasma were not significantly different between the controls and treated rats. However, oleic acid (18:1), linoleic acid (18:2) and docosahexaenoic acid (DHA, 22:6) were 17.94 +/- 2.06 microg/ml, 24.23 +/- 2.42 microg/ml and 4.08 +/- 0.53 microg/ml, respectively, in the controls, and none of these fatty acids was detectable in the treated plasma. On the other hand, palmitic, stearic, oleic, linoleic and DHA were present in both control and treated livers. Among the FFAs in liver, linoleic and DHA were increased 87% and 169%, respectively, over controls. Palmitic, stearic and oleic acids were not significantly affected by the 60 mg/kg treatment. These were present in both control maternal and fetal brains, whereas linoleic acid was found only in fetal brain control. DHA was present only in the control maternal brain (0.02 +/- 0.02 microg/mg protein) and fetal brain (0.24 +/- 0.15 microg/mg protein). The results indicated that androstenedione exhibits significantly different effects on the FFA composition among target organs during pregnancy.

Validation of an in vitro model for assessment of androstenedione hepatotoxicity using the rat liver cell line clone‐9

“…Although the in vitro study suggested significant necrotic cell death and oxidative stress at androstenedione concentrations of 10 μg ml −1 and above, there were no indications from the in vivo study of androstenedione-induced liver necrosis or oxidative stress from either biochemical or histopathological (Sprando et al, 2004) endpoints. The hepatosteatosis observed in the in vitro study is in concordance with the altered lipid profiles observed in liver, brain and serum in the in vivo study (Wiesenfeld et al, 2006;Kim et al, 2007). The significant decrease of ATP levels and caspase-3 activity observed in the clone-9 cells was also observed in intact liver in the in vivo study (Wiesenfeld et al, 2006).…”

“…An important aspect of the validation of in vitro toxicity assays is the assay's correlation with in vivo observations. As part of a reproductive toxicity study where female Sprague-Dawley rats were treated with multiple doses of androstenedione for the 2 weeks prior to pregnancy and the 3 weeks of gestation (Sprando et al, 2004), various aspects of liver toxicity were evaluated Flynn et al, 2005;Wiesenfeld et al, 2006;Kim et al, 2007). The objectives of this present study were to evaluate the hepatotoxic potential of androstenedione using a cultured liver cell line derived from a Sprague-Dawley rat (clone-9) and multiple biomarkers of cytotoxicity/hepatotoxicity, and then to compare the in vitro results with the in vivo observations.…”

Influence of Low Protein Diet-Induced Fetal Growth Restriction on the Neuroplacental Corticosterone Axis in the Rat

“…It is well-recognized that androgens are important neurodevelopmental factors (63). Androstenedione significantly alters the free fatty acid composition of the fetal brain (64). Excessive levels of androstenedione may induce cellular energy deficits and oxidative stress, potentially driving apoptosis (64).…”

“…Androstenedione significantly alters the free fatty acid composition of the fetal brain (64). Excessive levels of androstenedione may induce cellular energy deficits and oxidative stress, potentially driving apoptosis (64). Thus, it might be hypothesized that the reduced androgen levels in the brain of LP males might serve to protect these animals from these adverse effects of IUGR [reviewed by Miller et al (58)].…”