Prenatal Hyperandrogenization Induces Metabolic and Endocrine Alterations Which Depend on the Levels of Testosterone Exposure

Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS during the adult life

Atrazine in sub-acute exposure results in sperm DNA disintegrity and nuclear immaturity in rats

This study was designed to evaluate the detrimental effect of atrazine (ATR) on germinal epitheliums (GE) cytoplasmic carbohydrate (CH) and unsaturated fatty acids (UFA) ratio and to clarify the effect of ATR on serum levels of FSH, LH, testosterone and inhibin-B (INH-B). The impact of ATR exposure on total antioxidant capacity (TAC), sperm DNA packing and integrity were also investigated. Seventy two Wistar rats were used. The rats in control group received vehicle and the animals in test groups received 100, 200 and 300 mg kg-1 BW of ATR orally on daily bases for 12, 24 and 48 days. In ATR-received groups the spermatogenesis cell were presented with dense reactive sites for lipidophilic staining associated with faint cytoplasmic CH accumulation. Dissociated germinal epithelium, negative tubular and repopulation indexes were manifested. The serum levels of testosterone, FSH, LH and INH-B decreased by 85% after 48 days exposure to high dose of ATR. TAC was reduced in a time- and dose-dependent manner. The sperm DNA damage was marked in animals which exposed to high dose of ATR (72.50 ± 2.25%) and the percentage of nuclear immature sperm increased up to 83.40 ± 0.89%. In conclusion, ATR not only induced its detrimental effect on the endocrine function of the testes and pituitary gland but also affected the cytoplasmic CH ratio and consequently leads to inadequate energy supplement in spermatogenesis cells. Therefore the imbalanced oxidative stress occurs in testicular tissue, which in turn enhances the sperm DNA disintegrity and nuclear immaturity

Testicular biohistochemical alterations following experimental varicocele in rats

Background: The exact pathophysiology of testicular degeneration, following varicocele has not been completely understood yet. Objective: The current study was designed to determine the effect of varicocele on germinal epithelium (GE) cytoplasmic biohistochmical alterations. Materials and Methods: To follow-up this study, left varicocele was induced in test groups. Non-varicocelized rats were served as control-sham (n=6). Following 4, 6 and 8 months, right and left testes were dissected out and the blood serum sample was taken. The GE cytoplasmic carbohydrate, lipid accumulation, lipase and alkaline-phosphates (ALP) ratios were analyzed. Serum levels of LH, FSH and testosterone were measured. Results: Observations demonstrated that in varicocele-induced rats, the spermatogenesis cell lineage exhibited lower number of cells with periodic acid shift positive cytoplasm, higher number of cells with lipid and ALP positive stained cytoplasm in comparison to control animals. Lipase enzyme decreased by the time in the test animals. In varicocelized groups the number of Leydig cells decreased in to 2.25±0.41 and 1.16±0.75 per one mm2 in left and right testicles respectively after 8 months, and these cells demonstrated an ALP positive feature. In test groups, the serum levels of LH and FSH reduced into 1.12±0.01 and 2.03±0.05 ng/ml respectively after 8 months. Although testosterone level diminished by the time in the test animals, and this decreasing was significant (p=0.031) after 8 months (3.08±0.10 ng/ml). Conclusion: Our results suggest that following varicocele induction major alterations occur in GE, which may lead to loss of GE cells physiological function and ultimately result in fertility problems

Testicular biohistochemical alterations following experimental varicocele in rats

Background: The exact pathophysiology of testicular degeneration, following varicocele has not been completely understood yet.Objective: The current study was designed to determine the effect of varicocele on germinal epithelium (GE) cytoplasmic biohistochmical alterations.Materials and Methods: To follow-up this study, left varicocele was induced in test groups. Non-varicocelized rats were served as control-sham (n=6). Following 4, 6 and 8 months, right and left testes were dissected out and the blood serum sample was taken. The GE cytoplasmic carbohydrate, lipid accumulation, lipase and alkaline-phosphates (ALP) ratios were analyzed. Serum levels of LH, FSH and testosterone were measured.Results: Observations demonstrated that in varicocele-induced rats, the spermatogenesis cell lineage exhibited lower number of cells with periodic acid shift positive cytoplasm, higher number of cells with lipid and ALP positive stained cytoplasm in comparison to control animals. Lipase enzyme decreased by the time in the test animals. In varicocelized groups the number of Leydig cells decreased in to 2.25±0.41 and 1.16±0.75 per one mm2 in left and right testicles respectively after 8 months, and these cells demonstrated an ALP positive feature. In test groups, the serum levels of LH and FSH reduced into 1.12±0.01 and 2.03±0.05 ng/ml respectively after 8 months. Although testosterone level diminished by the time in the test animals, and this decreasing was significant (p=0.031) after 8 months (3.08±0.10 ng/ml).Conclusion: Our results suggest that following varicocele induction major alterations occur in GE, which may lead to loss of GE cells physiological function and ultimately result in fertility problems

Non-coding RNAs and macrophage interaction in tumor progression

The macrophages are abundantly found in TME and their M2 polarization is in favor of tumor malignancy. On the other hand, non-coding RNAs (ncRNAs) can modulate macrophage polarization in TME to affect cancer progression. The miRNAs can dually induce/suppress M2 polarization of macrophages and by affecting various molecular pathways, they modulate tumor progression and therapy response. The lncRNAs can affect miRNAs via sponging and other molecular pathways to modulate macrophage polarization. A few experiments have also examined role of circRNAs in targeting signaling networks and affecting macrophages. The therapeutic targeting of these ncRNAs can mediate TME remodeling and affect macrophage polarization. Furthermore, exosomal ncRNAs derived from tumor cells or macrophages can modulate polarization and TME remodeling. Suppressing biogenesis and secretion of exosomes can inhibit ncRNA-mediated M2 polarization of macrophages and prevent tumor progression. The ncRNAs, especially exosomal ncRNAs can be considered as non-invasive biomarkers for tumor diagnosis