P450 17α Research Articles

Role and mechanism of the p-JAK2/p-STAT3 signaling pathway in follicular development in PCOS rats

ObjectiveTo identify the association between the phosphorylated Janus kinase 2/phosphorylated signal transducer and activator of transcription (p-JAK2/p-STAT3) signaling pathway and follicular development in polycystic ovary syndrome (PCOS) rats, and explore the underlying mechanism. To evaluate the role of exogenous JAK2 inhibitor AG490 in the model and the associations among luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), cytochrome P450 17α (CYP17a), cytochrome P450 19 (CYP19), and PCOS. ResultsRat models of PCOS was established. PCOS rats were intraperitoneally treated with double-distilled water (ddH2O)/DMSO/AG490. The rate of ovarian morphological recovery in the AG490 group was significantly higher compared with the DMSO group (83.3 % vs 9.1 %, X2 = 12.68, P < 0.001). Moreover, the short in the time the estrous cycle was resumed in the AG490 group (hazard ratio = 16.32, P < 0.001) compared with the DMSO group. Compared with the controls, p-JAK2, p-STAT3, LHCGR, and CYP17a expression levels were increased whereas that of FSHR and CYP19 were decreased in the ovaries of PCOS rats. However, an opposite trend was observed after treatment with AG490. Software prediction revealed that the p-STAT3 bound to the promoter regions of LHCGR, FSHR, CYP17a, and CYP19 genes. This finding was confirmed by results of correlation analysis (R = 0.834, −0.836, 0.875 and −0.712, respectively, all P < 0.001). ConclusionThis study demonstrated that the p-JAK2/p-STAT3 signaling pathway was involved in follicular development in PCOS rats by upregulating LHCGR and CYP17a expression, and downregulating that of FSHR and CYP19. AG490 treatment exerted beneficial effects. LHCGR, FSHR, CYP17a, and CYP19 are candidate genes associated with follicular development in PCOS rats.

Prostaglandin E2 triggers cytochrome P450 17α hydroxylase overexpression via signal transducer and activator of transcription 3 phosphorylation and promotes invasion in endometrial cancer.

Prostaglandin E2 (PGE2) is the most common prostaglandin in the human body, meaning that its malfunction impacts on the development of numerous diseases. Prostaglandin E synthase 2 (PTGES2) is involved in the synthesis of PGE2. In the present study, immunohistochemistry of PTGES2 was performed in 152 patients with endometrial cancer and in 66 patients with normal endometria. The results indicate a notable association among increased expression of PTGES2 and age (P=0.0092) and the depth of myometrial invasion (P<0.0001). Reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that cytochrome P450 17α hydroxylase (CYP17), an enzyme for androgen synthesis, is overexpressed following PGE2 stimulation via signal transducer and activator of transcription 3 (STAT3) phosphorylation. ELISA also detected increased androgen (testosterone) secretion. Further invasion of endometrial cancer cells was induced at high androgen levels and when CYP17 was overexpressed. Furthermore, the present study observed that CYP17 is overexpressed via STAT3 phosphorylation in endometrial cancer cells, which grow at a high concentration of PGE2, resulting in increased androgen secretion. Concentrations of estrogen and progesterone were not elevated, while the concentration of androgens was. Overall, a high concentration of androgens caused increased invasion of endometrial cancer cells. A high concentration of androgens, which is initiated by a high expression of PTGES2 and a high concentration of PGE2, is an important promoter of myometrial invasion in endometrial cancer.

Maternal fructose intake disturbs ovarian estradiol synthesis in rats

AimsRecent increases in fructose consumption have raised concerns regarding the potential adverse intergenerational effects, as maternal fructose intake may induce physiological dysfunction in offspring. However, no reports are available regarding the effect of excess maternal fructose on reproductive tissues such as the ovary. Notably, the maternal intrauterine environment has been demonstrated to affect ovarian development in the subsequent generation. Given the fructose is transferred to the fetus, excess fructose consumption may affect offspring ovarian development. As ovarian development and its function is maintained by 17β-estradiol, we therefore investigated whether excess maternal fructose intake influences offspring ovarian estradiol synthesis. Rats received a 20% fructose solution during gestation and lactation. After weaning, offspring ovaries were isolated. Key findingsOffspring from fructose-fed dams showed reduced StAR and P450(17α) mRNA levels, along with decreased protein expression levels. Conversely, attenuated P450arom protein level was found in the absence of mRNA expression alteration. Consistent with these phenomena, decreased circulating levels of estradiol were observed. Furthermore, estrogen receptor α (ERα) protein levels were also down-regulated. In accordance, the mRNA for progesterone receptor, a transcriptional target of ERα, was decreased. These results suggest that maternal fructose might alter ovarian physiology in the subsequent generation.

Fructose intake during gestation and lactation differentially affects the expression of hippocampal neurosteroidogenic enzymes in rat offspring

ABSTRACTNeurosteroids, steroidal hormones synthesized de novo from cholesterol within the brain, stimulate hippocampal functions such as neuron protection and synapse formation. Previously, we examined the effect of maternal fructose on the transcriptional regulation of neurosteroidogenic enzymes. We found that the mRNA expression level of the steroidogenic acute regulatory protein (StAR), peripheral benzodiazepine receptor (PBR), cytochrome P450(11β), 11β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD was altered. However, we could not determine whether maternal fructose intake played a role in the gestation or lactation period because the dam rats were fed fructose solution during both periods. Thus, in this study, we analyzed the hippocampi of the offspring of dams fed fructose during the gestation or lactation period. Maternal fructose consumption during either the gestation or lactation period did not affect the mRNA levels of StAR, P450(17α), 11β-HSD-2, and 17β-HSD-1. PBR expression was down-regulated, even when rats consumed fructose during the lactation period only, while fructose consumption during gestation tended to activate the expression of P450(11β)-2. We found that maternal fructose intake during gestation and lactation differentially affected the expression of hippocampal neurosteroidogenic enzymes in the offspring.

CYP17 inhibitors in prostate cancer: latest evidence and clinical potential.

Since androgen signaling plays a pivotal role in the proliferation and metastasis of prostate cancer, androgen deprivation therapy (ADT) or castration therapy is considered the backbone of treatment for newly diagnosed metastatic prostate cancer. However, almost all men experience disease progression on ADT to a state known as metastatic castration-resistant prostate cancer (mCRPC), which continues to be driven by intratumoral androgen synthesis or androgen receptor signaling. Hence, the extragonadal ablation of androgen synthesis from pregnane precursors holds much promise. An inhibitor of cytochrome P450 17α-hydroxy/17,20-lyase (CYP17) enzymes, abiraterone acetate, has already been approved for men with mCRPC. Newer CYP17 inhibitors continue to be developed which are either more selective or have concomitant inhibitory actions on AR signaling. These include VT-464, orteronel, and galeterone. Herein, we focus on the molecular mechanism of action, efficacy, latest evidence, and clinical potential of CYP17 inhibitors in prostate cancer.

Involvement of hypoxia-inducible factor-1α in the oxidative stress induced by advanced glycation end products in murine Leydig cells

Hyperglycemia increases the formation of advanced glycation end products (AGEs), triggers oxidative impairments and influences inducible factor (HIF)-1α protein levels and transactivation function. Compromised HIF-1α in testis leads to male infertility. The aim of the study was to investigate the role of HIF-1α in oxidative stress induced by AGEs in murine Leydig TM3 cells. TM3 cells were treated with 50μg/ml of AGEs, or HIF-1α siRNA or 500μM of DMOG (dimethyloxalylglycine) respectively. The cells were also pretreated with HIF-1α siRNA or 500μM of DMOG and then were treated with 50μg/ml of AGEs. The formation of reactive oxygen species (ROS) and cell apoptosis was evaluated. The expression of caspase-3, Heme oxygenase (HO)-1, steroidogenic acute regulatory protein (StAR) and cytochrome P450 17α polypeptide 1 (CYP17A1) was examined by Western blotting. AGEs increased ROS production, induced apoptosis and activated HIF-1α and HO-1 in TM3 cells. HIF-1α attenuated the AGE-induced ROS formation and promoted apoptosis via the upregulation of caspase-3. Knockdown of HIF-1α inhibited the expression of CYP17A1 and StAR, and enhanced the inhibition of StAR and CYP17A1 by AGEs. These findings indicate that attenuated HIF-1α exacerbates the oxidative stress injury by AGEs in murine Leydig cells, and contributes to diabetic male infertility.

Association of CYP17A1 gene -34T/C polymorphism with polycystic ovary syndrome in Han Chinese population

Purpose: To investigate the influence of the cytochrome P450 17α (CYP17A1) gene -34T/C polymorphism in the pathogenesis of polycystic ovary syndrome (PCOS) in Han Chinese population.Methods: Three-hundred eighteen patients with PCOS and 306 controls were recruited and the CYP17A1 -34T/C polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Furthermore, the relationship of CYP17A1 -34T/C polymorphism and clinical feature parameters of PCOS patients was also analyzed.Results: The prevalence rates of CYP17A1 genotype TT, TC and CC were 49.69%, 43.71% and 6.6% in the case group and those were 44.77%, 46.08% and 9.15% in the control group. The frequencies of CYP17A1 T and C alleles were 71.54% and 28.46% in the case group, and those were 67.81% and 32.19% in the control group. Neither the genotypic nor the allelic distribution was significantly different between the cases and controls. However, the PCOS patients with the genotype of CC had significantly higher total testosterone levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) than those with the genotype of TT or TC.Conclusions: The CYP17A1 gene -34T/C polymorphism might not be directly correlated with the PCOS, but might influence PCOS via the association of testosterone level and the HOMA-IR.

Stimulation of estradiol biosynthesis by tributyltin in rat hippocampal slices

Hippocampal functions are influenced by steroid hormones, such as testosterone and estradiol. It has been demonstrated that hippocampus-derived steroid hormones play important roles in neuronal protection and synapse formation. Our research groups have demonstrated that estradiol is de novo synthesized in the rat hippocampus. However, the mechanism(s) regulating this synthesis remains unclear. It has been reported that tributyltin, an environmental pollutant, binds to the retinoid X receptor (RXR) and modifies estrogen synthesis in human granulosa-like tumor cells. This compound can penetrate the blood brain barrier, and tends to accumulate in the brain. Based on these facts, we hypothesized that tributyltin could influence the hippocampal estradiol synthesis. A concentration of 0.1 μM tributyltin induced an increase in the mRNA content of P450(17α) and P450arom in hippocampal slices, as determined using real-time PCR. The transcript levels of other steroidogenic enzymes and a steroidogenic acute regulatory protein were not affected. The estradiol level in rat hippocampal slices was subsequently determined using a radioimmunoassay. We found that the estradiol synthesis was stimulated by ∼2-fold following a 48-h treatment with 0.1 μM tributyltin, and this was accompanied by transcriptional activation of P450(17α) and P450arom. Tributyltin stimulated de novo hippocampal estradiol synthesis by modifying the transcription of specific steroidogenic enzymes.

Exposure of mice to atrazine and its metabolite diaminochlorotriazine elicits oxidative stress and endocrine disruption

Effects of atrazine (ATZ) and its metabolite diaminochlorotriazine (DACT) on the induction of oxidative stress and endocrine disruption were studied in mice. Body and liver weights decreased in all ATZ and DACT treated groups. Hepatic activities of superoxide dismutase (SOD) increased significantly after 1 week of intraperitoneal injection of 200mg/kg ATZ, 100 and 200mg/kg DACT. Hepatic activities of catalase (CAT) and glutathione S-transferase (GST) were also affected by the treatment with 200mg/kg DACT. In serum, the glutathione peroxidase (GPX) and GST activities and glutathione (GSH) content decreased significantly in the 200mg/kg DACT treated group. Moreover, the administration of ATZ and DACT decreased the transcription levels of key genes related to cholesterol transport and testosterone (T) synthesis including scavenger receptor class B type 1 (SR-B1), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and cytochrome P450 17α-hydroxysteroid dehydrogenase (P450 17α) in testes. Furthermore, the treatment with 200mg/kg DACT significantly decreased the serum and testicular T levels, while the treatment with 200mg/kg ATZ significantly decreased the testicular T levels. The results indicated that the acute exposure to ATZ and DACT induced oxidative stress and endocrine disruption in mice, and DACT showed much more toxic than ATZ did.

Allopregnanolone-mediated protective effects of progesterone on tributyltin-induced neuronal injury in rat hippocampal slices

Increasing evidence shows that progesterone, a neuroactive steroid, has protective actions in central nervous system, but there is little evidence to show the protective mechanism of progesterone on neurotoxicity induced by environmental chemicals. In this study, we examined the effects of progesterone on neuronal injury induced by tributyltin (TBT) in rat hippocampal slices. Treatment with progesterone dose-dependently suppressed hippocampal neuronal injury induced by TBT. The neuroprotective action of progesterone was completely canceled with pretreatment by finasteride, a 5α-reductase inhibitor, but it was not affected by mifepristone, a progesterone receptor antagonist, or by SU-10603, a cytochrome P450 17α inhibitor. The content of allopregnanolone in the slices was significantly increased by treatment with progesterone, and this increment was greatly suppressed with a pretreatment of finasteride. Treatment with allopregnanolone attenuated neuronal injury induced by TBT in a dose-dependent manner. The neuroprotective effects not only of progesterone but also of allopregnanolone were canceled by bicuculline, a potent gamma-aminobutyric acid A (GABAA) receptor antagonist. Pretreatment with muscimol, a GABAA receptor agonist, attenuated hippocampal neuronal injury elicited by TBT. Taken together, allopregnanolone converted from progesterone in hippocampal slices could protect neurons from TBT-induced neurotoxicity due to a GABAA receptor-dependent mechanism. One of the physiological roles of neuroactive steroids might be neuroprotection from environmental chemicals.

The impact of maternal synthetic glucocorticoid administration in late pregnancy on fetal and early neonatal hypothalamic-pituitary-adrenal axes regulatory genes is dependent upon dose and gestational age at exposure.

In this study, we determined the gene and/or protein expression of hypothalamic-pituitary-adrenal (HPA) axis regulatory molecules following synthetic glucocorticoid exposures. Pregnant sheep received intramuscular saline or betamethasone (BET) injections at 104 (BET-1), 104 and 111(BET-2) or 104, 111 and 118 (BET-3) days of gestation (dG). Samples were collected at numerous time-points between 75 dG and 12 weeks postnatal age. In the BET-3 treatment group, fetal plasma cortisol levels were lower at 145 dG than controls and gestational length was lengthened significantly. The cortisol:adrenocorticotropic hormone (ACTH) ratio in fetal plasma of control and BET-3 fetuses rose significantly between132 and 145 dG, and remained elevated in lambs at 6 and 12 weeks of age; this rise was truncated at day 145 in fetuses of BET-3 treated mothers. After BET treatment, fetal and postnatal pituitary proopiomelanocortin mRNA levels were reduced from 109 dG to 12 weeks postnatal age; pituitary prohormone convertase 1 and 2 mRNA levels were reduced at 145 dG and postnatally; hypothalamic arginine vasopressin mRNA levels were lowered at all time-points, but corticotrophin-releasing hormone mRNA levels were reduced only in postnatal lambs. Maternal BET increased late fetal and/or postnatal adrenal mRNA levels of ACTH receptor and 3β hydroxysteroid dehydrogenase but decreased steroidogenic acute regulatory protein and P450 17-α hydroxylase. The altered mRNA levels of key HPA axis regulatory proteins after maternal BET injections suggests processes that may subserve long-term changes in HPA activity in later life after prenatal exposure to synthetic glucocorticoids.

Effect of nanoparticle-rich diesel exhaust on testosterone biosynthesis in adult male mice

The effect of nanoparticle-rich diesel exhaust (NR-DE) on the testicular function and factors related with the biosynthesis of testosterone gene expression were investigated in mice. Male C57BL/Jcl mice were exposed to clean air, low-dose NR-DE (Low NR-DE), high-dose NR-DE (High NR-DE) or filtered diesel exhaust (F-DE) for 8 weeks. We found that the mice exposed to High NR-DE had significantly higher testosterone levels than those in the control and F-DE groups. To determine the effects of NR-DE on testicular testosterone production, interstitial cells dissected from the male mice which were exposed to NR-DE, F-DE, or clean air for 8 weeks were incubated with or without human chorionic gonadotropin (hCG; 0.1 IU/mL) for 4 h. The concentrations of testosterone in the culture media were measured. The testosterone production was significantly increased in with or without hCG of High NR-DE exposed group, and significantly decreased in both with or without hCG of F-DE exposed groups. Moreover, several genes, which is associated with testicular cholesterol synthesis, HMG-CoA, LDL-R, SR-B1, PBR, and P450scc, P450 17α, and 17β-HSD were determined in the testis of adult male mice. The results showed High NR-DE exposure significantly increased the expression of these genes. Whereas, the levels in the F-DE exposure group returned to those in the control group, implicating that the nanoparticles in DE contribute to the observed reproductive toxicity. We conclude that enhancement of testosterone biosynthesis by NR-DE exposure may be regulated by increasing testicular enzymes of testosterone biosynthesis.

Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring

Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. As expected, a high concentration of Pb was measured in the kidneys and liver of pups whose mothers were exposed to Pb during lactation. In addition, maternal Pb exposure during lactation elevated, to a less extent, Pb content in testes of weaning pups. Testis weight in weaning pups was significantly decreased when maternal mice were exposed to Pb during lactation. The level of serum and testicular T was reduced in Pb-exposed pups. The expression of P450scc, P450(17α) and 17β-HSD, key enzymes for T synthesis, was down-regulated in testes of weaning pups whose mothers were exposed to Pb during lactation. Interestingly, the level of serum and testicular T remained decreased in adult offspring whose mothers were exposed to Pb during lactation. Importantly, the number of spermatozoa was significantly reduced in Pb-exposed male offspring. Taken together, these results suggest that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupts testicular development and steroidogenesis in male offspring.

Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα

Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPARα on this reproductive toxicity, ammonium perfluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild-type ( mPPARα), Pparα-null and PPARα-humanized ( hPPARα) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPARα and hPPARα mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450 17α involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Pparα-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPARα and hPPARα mice, which may, in part, be related to APFO-induced mitochondrial damage.

Complete derivation of the active site of the cytochrome P-450 enzyme 17α-hydroxylase/17, 20-lyase (P450 17α) using the novel substrate-haem complex approach

Complete derivation of the active site of the cytochrome P-450 enzyme 17α-hydroxylase/17, 20-lyase (P450 17α) using the novel substrate-haem complex approach

Cypermethrin exposure during puberty induces oxidative stress and endocrine disruption in male mice

Cypermethrin (CYP) is one of the most common contaminants in the ecosystem. The effects of CYP exposure on the induction of oxidative stress and endocrine disruption were studied in adolescent male ICR mice. The hepatic activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and total antioxidant capacity (T-AOC) increased significantly after 3weeks (postnatal day 21–42) of oral administration of 20mgkg−1 CYP. In accordance with the enzyme activities, the mRNA levels for the genes encoding these antioxidant proteins, such as Sod1, Sod2, Gpx1 and Gpx2, were also up-regulated significantly in the 10 and 20mgkg−1 CYP treatment groups. Furthermore, we also found that the 3-week oral administration of CYP decreased transcription levels of key genes in pathways of cholesterol synthesis and transport and testosterone synthesis including HMG-CoA synthase, steroidogenic acute regulatory protein (StAR) and cytochrome P450 17α-hydroxysteroid dehydrogenase (P450 17α in the liver and testes. Serum testosterone levels also decreased significantly in mice after treatment with 20mgkg−1 CYP. Taken together, the results indicated that CYP can induce endocrine disruption in adolescent mice. The findings will be helpful in elucidating the mechanism of toxicity induced by CYP in adolescent mice.

Effects of pubertal fenvalerate exposure on testosterone and estradiol synthesis and the expression of androgen and estrogen receptors in the developing brain

Fenvalerate is a potential endocrine disruptor. Several studies have demonstrated that fenvalerate disrupts testosterone (T) synthesis in testes. T and estradiol (E 2) are de novo synthesized in the developing brain. Thus, the aim of the present study was to investigate the effects of pubertal fenvalerate exposure on the synthesis of T and E 2 and the expression of androgen receptor (AR) and estrogen receptors (ERs) in cerebral cortex. CD-1 mice were orally administered daily with either vehicle or fenvalerate (7.5 or 30 mg/kg) from postnatal day (PND) 28 to PND56. The level of T and E 2 in cerebral cortex was significantly decreased in males exposed to fenvalerate. In agreement with the decrease in T and E 2 syntheses, the expression of 17β-HSD, a key enzyme for T synthesis, was significantly reduced in cerebral cortex of fenvalerate-exposed males. Conversely, in females, the expression of 17β-HSD in cerebral cortex was mildly up-regulated by fenvalerate and the level of T and E 2 was mildly increased. Pubertal fenvalerate exposure had no effect on the expression of StAR, P450 17α and P450scc, the key enzymes for T synthesis, and P450 aromatase, the key enzyme for E 2 synthesis, in cerebral cortex of males and females. Interestingly, the expression of AR in cerebral cortex was up-regulated in male and female mice exposed to fenvalerate, whereas pubertal fenvalerate exposure did not affect the level of ERα and ERβ in cerebral cortex. Taken together, these results suggest that pubertal fenvalerate exposure disrupts T and E 2 synthesis and the expression of AR in cerebral cortex. These changes of steroid status in the developing brain might be deleterious for neurobehavioral development.

Neurosteroid Biosynthesis and Function in the Brain of Domestic Birds

It is now established that the brain and other nervous systems have the capability of forming steroids de novo, the so-called “neurosteroids.” The pioneering discovery of Baulieu and his colleagues, using rodents, has opened the door to a new research field of “neurosteroids.” In contrast to mammalian vertebrates, little has been known regarding de novo neurosteroidogenesis in the brain of birds. We therefore investigated neurosteroid formation and metabolism in the brain of quail, a domestic bird. Our studies over the past two decades demonstrated that the quail brain possesses cytochrome P450 side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3β-HSD), 5β-reductase, cytochrome P450 17α-hydroxylase/c17,20-lyase (P45017α,lyase), 17β-HSD, etc., and produces pregnenolone, progesterone, 5β-dihydroprogesterone (5β-DHP), 3β, 5β-tetrahydroprogesterone (3β, 5β-THP), androstenedione, testosterone, and estradiol from cholesterol. Independently, Schlinger’s laboratory demonstrated that the brain of zebra finch, a songbird, also produces various neurosteroids. Thus, the formation and metabolism of neurosteroids from cholesterol is now known to occur in the brain of birds. In addition, we recently found that the quail brain expresses cytochrome P4507α and produces 7α- and 7β-hydroxypregnenolone, previously undescribed avian neurosteroids, from pregnenolone. This paper summarizes the advances made in our understanding of neurosteroid formation and metabolism in the brain of domestic birds. This paper also describes what are currently known about physiological changes in neurosteroid formation and biological functions of neurosteroids in the brain of domestic and other birds.

Synthesis and biochemical evaluation of a range of (4-substituted phenyl)sulfonate derivatives of 4-hydroxybenzyl imidazole-based compounds as potent inhibitors of 17α-hydroxylase/17,20-lyase (P450 17α) derived from rat testicular microsomes

We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of (4-substituted phenyl)sulfonate derivatives of 4-hydroxybenzyl imidazole against the two components of 17α-hydroxylase/17,20-lyase (P450 17α), namely, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show the compounds to be highly potent inhibitors with limited selectivity towards the lyase component [e.g., toluene-4-sulfonic acid 4-imidazol-1-ylmethyl-phenyl ester ( 4) possessed an IC 50 value of 40 nM against 17α-OHase and 30 nM against lyase].

Maternal fenvalerate exposure during pregnancy persistently impairs testicular development and spermatogenesis in male offspring

Fenvalerate, a widely used pyrethroid insecticide, has been associated with poor semen quality. As yet, little is known about the effects of prenatal fenvalerate exposure on testicular development. The present study investigated the effects of prenatal fenvalerate exposure on testicular development and spermatogenesis. The pregnant mice were administered fenvalerate (30 mg/kg) by gavage daily from gestational day (gd) 13 to gd 18. The weights of testes and epididymides were significantly decreased in mice whose mothers were exposed to fenvalerate during pregnancy. Importantly, maternal fenvalerate exposure during pregnancy markedly decreased the number of mature seminiferous tubules (stages VII and VIII) in testes of adult male offspring. In addition, maternal fenvalerate exposure during pregnancy significantly reduced the number of epididymal spermatozoa in adult male offspring. Additional experiments showed that the level of serum testosterone (T) was significantly decreased in male fetuses whose mothers were exposed to fenvalerate during pregnancy. Correspondingly, mRNA and protein levels of P450 17α, a T synthetic enzyme, were significantly decreased in fetal testes. Moreover, the disruptive effect of prenatal fenvalerate exposure on testicular T synthesis was irreversible. In conclusion, prenatal fenvalerate exposure irreversibly impairs testicular development and spermatogenesis at least into early adulthood.