The Relationship between Dioxin-Like Polychlorobiphenyls and IGF-I Serum Levels in Healthy Adults: Evidence from a Cross-Sectional Study

OBJECTIVE: Insulin-like growth factor I (IGF-I) and dioxin-like polychlorobiphenyls (DL-PCBs) have been associated with the pathogenesis of several diseases like cancer, diabetes and growth disorders. Because it has been suggested that organohalogenated contaminants could influence IGF-I levels in adults, the potential relationship between DL-PCBs and IGF-I serum levels was studied in 456 healthy adults from a representative sample of the general population of the Canary Islands (Spain). DESIGN: Free circulating serum levels of IGF-I and IGFBP-3 were measured through an ELISA methodology, while the serum levels of the 12 DL-PCBs congeners (IUPAC numbers # 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189) were measured by gas chromatography/mass spectrometry (GC-MS). RESULTS: DL-PCBs 156 and 167, Total DL-PCBs body burden (∑PCBs: sum over the 12 measured DL-PCBs), and Total toxic burden (in terms of toxic equivalence to dioxins: ∑TEQs) showed a trend of inverse association with IGF-I serum levels in the whole studied population. After adjusting for potential confounders, including gender, body mass index (BMI), age, and IGF-binding protein-3 (IGFBP-3), younger (18-45 years) women with lower BMI (<27 kg/m(2)) and detectable levels of DL-PCB-156 showed significantly lower IGF-I levels than those in the same age and BMI subgroup with non-detectable levels of DL-PCB-156 (p<0.001). Similarly, ∑PCBs and ∑TEQs showed a tendency to an inverse association with IGF-I levels in the same group of women (p=0.017 and p=0.019 respectively). CONCLUSIONS: These findings suggest that DL-PCBs could be involved in the regulation of the IGF-system in a way possibly influenced by gender, age and BMI. Although these results should be interpreted with caution, such circumstances could contribute to explain the development of diseases associated to the IGF system

[H-3] Dexamethasone Binding-Activity In Liver-Microsomes Is Modulated Differently By 17-Alpha-Alkylated Androgens And Testosterone In-Vivo

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Identification of a specific binding site for the anabolic steroid stanozolol in male rat liver microsomes

Male rat liver microsomes contain a [H-3]dexamethasone binding site, capable of binding glucocorticoids and progesterone. We have shown previously that the 17 alpha-alkylated androgen, stanozolol, can inhibit the [H-3]dexamethasone binding to microsomes through a negative allosteric mechanism, which gives rise to the possibility of its interaction with a different binding site. In this study, the existence of a single-saturating binding site, capable of binding the radioactive steroid with a maximum number of the specific binding site of 49 +/- 2 pmol/mg of protein and a K-d of 37 +/- 1.3 nM was demonstrated by using [H-3]stanozolol. In competition experiments, only stanozolol and danazol were able to compete with [H-3]stanozolol for its binding to microsomes, among more than 60 steroids and other compounds tested. The binding of [H-3]stanozolol was depressed after protease treatment of the microsomes, or after the administration of cycloheximide to adult male rats for 24 hr, which suggest its proteic nature. The [H-3]stanozolol binding site was detected in many tissues of the rat, with the highest concentrations being found in the liver. It was detected from birth,increasing afterward in concentration and reaching a peak at 2 to 3 months of age. This is the first experimental verification of the existence in liver microsomes of a specific binding site for some 17 alpha-alkylated androgens, such as stanozolol and danazol, different from the androgen receptor or the [H-3]dexamethasone binding site.112911237SCI

Estrogen antagonism on T-3 and growth hormone control of the liver microsomal low-affinity glucocorticoid binding site (LAGS)

Male rat liver microsomes contain a low-affinity glucocorticoid binding site (LAGS) capable of binding all natural glucocorticoids and progesterone with a K-d from 20 to 100 nM. The LAGS level is under endocrine control by T-3, glucocorticoids and GH. These hormones act synergistically at physiological concentrations to increase the LAGS level. Since female rats show a LAGS level that is much lower than the males (0.15 vs 23 pmol/mg protein, respectively), here we investigated whether estradiol could decrease the LAGS in the male rat. Orchiectomized (OX) male rats showed a higher LAGS level than intact rats. This effect was reversed by implanting a Sylastic capsule containing testosterone. When the OX rats were implanted for 20 days with estrogen capsules that provided an estradiol level in serum of 40 pg/ml, their LAGS level decreased from 23 to 0.2 pmol/mg protein. This effect was not observed in intact male rats and can be partially reversed by testosterone implants into OX rats. Both hypophysectomized male rats and hypothyroid-orchiectomized male rats showed very low levels of LAGS. Administration of physiological doses of GH and/or T-3 to these rats greatly increased their LAGS level (from 0.3 to 15 and 16 pmol/mg protein, respectively). Implantation of estrogen capsules to these rats two weeks prior to starting treatment completely inhibited the increase in the LAGS level in response to T-3, and significantly decreased the response to hGH, and to a combination of hGH and T-3. These results suggest that physiological estradiol levels call antagonize the LAGS induction by T-3 and hGH in the male rat, and could be responsible for the low level of LAGS in the female rat. Moreover, estrogen capsules also inhibited the increase in the body and hepatic weights observed after hGH treatment, which suggests a powerful inhibitory effect of low estradiol levels on the male rat liver functions under regulation by T-3 and/or GH. (C) 1997 Elsevier Science Ltd. All rights reserved.228219101,709Q2SCI

Evaluation of the Potential Protective Effect of 21-Aminosteroid U-74389G on Liver Injury Induced by Reduced and Prolonged Partial Hepatic Ischaemia Reperfusion in Rats

The protective effect of the 21-aminosteroid U-74389G was studied in an experimental model of partial ischaemia reperfusion liver injury. Previous studies have proven the remarkable potency of 21-aminosteroids to prevent oxidant-induced cell injury in vitro and in vivo. However, the capability of these compounds to limit oxidative injury in clinical trials has been considered to be less certain. The potential protective effect exerted by U-74389G on reduced and prolonged models of ischaemia reperfusion liver injury was studied in male rats subjected to 75 min. of segmentary hepatic ischaemia followed by 1 or 24 hr of reperfusion. Liver injury was evaluated by measuring serum levels of liver enzymes and by histopathological studies. The oxidative status of liver cells was measured by evaluating the levels of liver lipid peroxidation products such as malondialdehyde and the levels of reduced glutathione. Our results lead us to think that treatment with U-74389G (6 mg/kg) does not bring about any protective effect neither in the levels of transaminases nor in the percentage of hepatocellular necrosis and cellular infiltration observed in any reperfusion-period groups. In fact and in contrast with our expectations, U-74389G seemed to increase enzyme release. Furthermore, at the dose used, this 21-aminosteroid is not capable of inhibiting the lipoperoxidation processes, although it induced an important increase of GSH levels at any time-period of reperfusion. This last finding seem to suggest that U-74389G could increase the resistance to oxidant-induced liver tissue damage. However, our results show that, at the dose used, this compound did not exert any protective effect on liver tissue, thus explaining, at least partially, the absence of beneficial effects on the part of these compounds in clinical trials carried out to limit organ injury in transplants.2432381,302Q