The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on foetal male rat steroidogenesis

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and widely investigated dioxin congener. In utero and lactational exposure to TCDD results in developmental and reproductive defects that are the most sensitive endpoints for TCDD toxicity. TCDD has a potential to interfere with steroid metabolism, but the mechanisms by which this occurs are not well understood. In this study, we investigated the effects of TCDD on prenatal rat steroidogenesis. Pregnant Sprague-Dawley female rats were treated once with TCDD (0, 0.3 or 1 microg/kg) by gavage on embryonic day (ED) 11 and the expression levels of androgen (AR) and estrogen receptors (ER), steroidogenic enzymes (P450scc and 3beta-HSD) and four regulatory factors (StAR, SF-1, GATA-4 and Insl-3) involved in foetal Leydig cell and adrenal function were analysed on ED 19.5. Hormonal status of male foetuses was determined by measuring testicular testosterone (T) levels, plasma luteinizing hormone (LH) and corticosterone concentrations. In utero exposure to TCDD reduced intratesticular T of foetal males (significant at 0.3 microg/kg TCDD) and tended to reduce the protein expression of ERalpha and AR of foetal male rat testis. Foetal male rat plasma LH levels were significantly reduced at the dose of 1 microg/kg TCDD, while corticosterone levels tended to be increased possibly because of the TCDD-induced stress. Only minor alterations in steroidogenesis were observed in rat adrenal. mRNA expression of developmental regulatory factors was not influenced by foetal TCDD exposure, except for significantly reduced adrenal SF-1. The results demonstrate that maternal exposure to TCDD suppressed testicular steroidogenesis of 19.5-day-old foetal male Sprague-Dawley rat. The highest dose of TCDD (1 microg/kg) had also an effect on pituitary LH secretion. Our data implicate that TCDD has direct testicular and pituitary effects on foetal male rat but with different dose-responses. These changes can lead to impaired steroidogenesis and it may result in the maldevelopment of the testis and weaken masculinization.     

The pure antiandrogen ru 23908 (anandron®), a candidate of choice for the combined antihormonal treatment of prostatic cancer: A review

The nonsteroidal antiandrogen RU 23908 (Anandron^R) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight. This is due to the property of the pure antiandrogen to neutralize the inhibitory feedback effect of androgens at the pituitary level on the LH responsiveness to LHRH, as illustrated in vitro in rat anterior pituitary cells in culture as well as in vivo in intact and castrated animals. In intact animals, neutralization of the inhibitory feedback action of endogenous androgens leads to an increased LH and testosterone secretion, which partly overcomes the direct action of the antiandrogen at the level of the prostate and seminal vesicles. In fact, the plasma testosterone concentration is more than doubled 6 hr after the administration of 10 mg of RU 23908 while plasma LH and testosterone levels are increased by 7- and 17-fold, respectively, after 14 days of similar daily treatment. Efficient neutralization of the androgenic action at the prostatic level in intact animals thus requires prevention of this escape phenomenon through inhibition of LH secretion. Although inhibition of LH release can be achieved by estrogen and progestins, an optimal inhibitory effect on the prostate is obtained by the combined administration of the antiandrogen with an LHRH agonist that causes a specific blockage of testicular androgen biosynthesis as well as an inhibition of the LH responsiveness to LHRH.     

Diverse mechanisms of anti-androgen action: impact on male rat reproductive tract development

Scientists have identified environmental chemicals that display anti-androgenic activity via multiple mechanisms of action. Early studies focused on pesticides acting as androgen receptor (AR) antagonists but it soon became apparent that was not the only endocrine mode by which compounds affected the androgen signalling pathway. Classes of chemicals currently known to interfere with the androgen signalling pathway include dicarboximide fungicides (e.g. vinclozolin), organochlorine-based insecticides (e.g. p,p'-DDT and -DDE), conazole fungicides (e.g. prochloraz), plasticizers (phthalates) and urea-based herbicides (linuron). Phthalate esters (PEs) and vinclozolin appear to act primarily via a single mechanism of action, while others such as linuron and prochloraz, appear to display dual mechanisms of action. Exposure to PEs decreases mRNA expression of key steroidogenic enzymes and also the peptide hormone insulin-like peptide 3 (insl3) from the foetal Leydig cells. Hence, both androgen- and inls3-dependent tissues are affected. Vinclozolin and procymidone act solely through binding to the AR as antagonists thus blocking the action of androgen at the cellular level but do not affect foetal testosterone synthesis or insl3 gene expression. The compounds linuron and prochloraz are AR antagonists but also inhibit foetal testosterone synthesis, although unlike the PEs, mRNA expression of steroidogenic enzymes and insl3 are not affected. All the above chemicals disrupt androgen signalling in the foetal male rat and produce some malformations in common, but the precise profiles of effects in the offspring are pathognomonic for each mode of action. For example, the 'phthalate syndrome' vs. the 'vinclozolin syndrome' each displays a profile of effects which is clearly different. In summary, as more and more molecular studies with anti-androgenic compounds are conducted, the number of mechanisms by which compounds can affect the androgen signalling pathway is likely to increase. Furthermore, the effects of mixtures of these compounds are just beginning to be explored.     

Presence of a low capacity androgen receptor in the gubernaculum of the pig fetus

The aim of our study was to investigate the theory that the gubernaculum is an androgen-responsive structure responsible for fetal testicular descent. Using 3H-methyltrienolone (3H-R1881) as ligand, we performed a seven-point Scatchard analysis of androgen receptor binding in the gubernaculum, prostate, urethra and striated muscle tissue obtained from pig fetuses between 60 and 109 days of gestation. The gubernaculum demonstrated androgen receptor binding with an affinity and capacity significantly lower than that of fetal pig prostate and urethra, but not significantly different from that of striated muscle taken from both male and female fetuses. A marked increase in the size and mass of the gubernaculum of male (but not female) fetuses is known to accompany testicular descent. If the dramatic increase in the mass of the gubernaculum observed in male (but not female) fetuses were the result of androgen stimulation, it may be expected that the striated muscle mass (and therefore total body mass) of male fetuses should be greater than that of female fetuses, since the androgen receptor affinity and capacity of the gubernaculum is similar to that of striated muscle. However, we found no significant difference in total body mass between male and female pig fetuses at the same period of gestation. These findings raise doubt concerning the theory that growth of the gubernaculum during descent is the result of androgen stimulation.     

Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model.

The role of androgen receptor-mediated androgen action on bone was investigated in testicular feminized male (Tfm) mice. Cortical bone was found to be unresponsive to testosterone (T) in orchidectomized Tfm mice, whereas cortical thickness as well as trabecular BMD and structure were fully maintained by T in the corresponding Tabby control mice. These data show an essential role for androgen receptor-mediated androgen action in periosteal bone formation. INTRODUCTION: Androgens can affect the male skeleton both directly-through activation of the androgen receptor (AR)-and indirectly-through stimulation of estrogen receptors after aromatization. We assessed the importance of AR-mediated androgen action on bone in a mouse model of androgen resistance. MATERIALS AND METHODS: Eight-week-old androgen-resistant testicular feminized male (Tfm) and Tabby control mice were orchidectomized (ORX) and treated for 4 weeks with a slow-release testosterone (T) pellet (delivering 167 microg/day) or a placebo pellet. A comprehensive analysis of the skeletal effects of androgen deficiency and replacement was performed using histomorphometry, QCT, and biochemical assessment of bone turnover. RESULTS: As expected, T increased trabecular BMD, volume, number, and width in ORX Tabby mice. In ORX Tfm mice, however, T had less effect on trabecular BMD and no effect on trabecular bone structure. T action on trabecular bone was associated with opposite changes in bone turnover: trabecular and endocortical bone turnover and serum levels of osteocalcin were all reduced by T in ORX Tabby mice, but not in ORX Tfm mice. T also increased cortical thickness (+16%), area, and density in ORX Tabby mice, but not in Tfm mice, resulting in greater bone strength in the Tabby control strain. The positive effects of T on cortical bone reflected a stimulatory effect on periosteal bone formation (+137%), which was again absent in Tfm mice. CONCLUSIONS: These data show that, in male mice, AR-mediated T action is essential for periosteal bone formation and contributes to trabecular bone maintenance.     

The effects of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on testicular steroidogenesis in infantile male rats

Exposure of adult male animals to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decreases serum androgen concentrations. Reduction in androgen levels after maternal exposure has also been reported, but these results have not been reproduced. We have earlier shown that TCDD stimulates rather than inhibits testosterone synthesis in the prenatal rat testis. The aim of the present study was to elucidate in utero-induced effects of TCDD on testicular steroidogenesis in the 14-day-old infant rats. At that time the foetal Leydig cell population is still the prevailing source of androgens. Pregnant Sprague-Dawley dams were given a single oral dose of TCDD (0, 0.04, 0.2, or 1.0 microg/kg) on day 13 of pregnancy. On postnatal day 14, the body weight of male offspring was reduced after exposure to 1.0 microg/kg TCDD (from 33.9 +/- 1.66 g to 31.6 +/- 2.67 g). Relative testis weight, plasma testosterone, luteinizing hormone and follicle-stimulating hormone levels remained unaltered in all exposure groups. Moreover, in ex vivo incubations, testosterone and cAMP production was not affected. StAR protein level in the freshly isolated testes was increased in the 0.2 microg/kg group, and seminiferous cord diameter in the 0.04 microg/kg group. The present study confirms our earlier findings in in utero TCDD-exposed foetal testis indicating that maternal TCDD exposure does not negatively influence the developmental testosterone production of foetal type Leydig cells in rats.     

Androgenic and antiandrogenic control on epidermal growth factor,epidermal growth factor receptor,and androgen receptor expression in human prostate cancer cell line LNCaP

Both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor (AR). We studied the modification of the expression of epidermal growth factor (EGF), of its receptor (EGF-R), and of androgen receptor (AR) in the LNCaP cell line, under basal conditions and during androgen (R1881) and antiandrogen hydroxy-flutamide (OH-FLU) treatment. After prolonged R1881 administration, a marked increase of EGF release was observed, completely blocked by the addition of OH-FLU. The Scatchard plot analysis of EGF-R binding revealed two classes of binding sites with high and low affinity. The administration of OH-FLU alone or combined with R1881 did not modify the affinity constants, while the low-affinity component disappeared after androgen administration. Both androgen and antiandrogen administration led to a significant increase of the EGF-R high-affinity component. AR mRNA and protein levels were downregulated by R1881 treatment. Following OH-FLU administration, AR mRNA was slightly downregulated, and there was not a strict parallelism between AR mRNA levels and AR binding capacity. When combined with R1881, OH-FLU partially counteracted the androgen-induced AR downregulation. Our data show that EGF-R binding capacity is the only parameter constantly raised in cell proliferation with respect to quiescent cells, and highlights the nonunivocal action of OH-FLU on androgen-induced effects.     

Thyroid hormones: their role in testicular steroidogenesis

Thyroid hormones are important for growth and development of many tissues. Altered thyroid hormone status causes testicular abnormalities. For instance, juvenile hypothyroidism/neonatal transient hypothyroidism induces macroorchidism, increases testicular cell number (Sertoli, Leydig, and germ cells) and daily sperm production. Triiodothyronine (T3) receptors have been identified in sperm, developing germ cells, Sertoli, Leydig, and peritubular cells. T3 stimulates Sertoli cell lactate secretion as well as mRNA expression of inhibin-alpha, androgen receptor, IGF-I, and IGFBP-4. It also inhibits Sertoli cell mRNA expression of Müllerian inhibiting substance (MIS), aromatase, estradiol receptor, and androgen binding protein (ABP) and ABP secretion. T3 directly increases Leydig cell LH receptor numbers and mRNA levels of steroidogenic enzymes and steroidogenic acute regulatory protein. It stimulates basal and LH-induced secretion of progesterone, testosterone, and estradiol by Leydig cells. Steroidogenic factor-1 acts as a mediator for T3-induced Leydig cell steroidogenesis. Although the role of T3 on sperm, germ, and peritubular cells has not yet been completely studied, it is clear that T3 directly regulates Sertoli and Leydig cell functions. Further studies are required to elucidate the direct effect of T3 on sperm, germ, and peritubular cells.     

A possible direct action of oxytocin on spermatogenesis and steroidogenesis in pre‐pubertal mouse

The aim of this study was to evaluate the effects of in vivo and in vitro treatments of oxytocin (OT) on the testis of pre‐pubertal mice. The OT treatment produced significant changes in the spermatogenic and steroidogenic activity by increasing expression of OT‐receptor in the testis of pre‐pubertal mice. Treatment with OT showed increased proliferation of germ cells as indicated by increased number of spermatocytes and round spermatids. Dose‐dependent increase in expression of PCNA, Bcl‐2 and AR proteins was observed in the testis of OT‐treated mice as compared with the control and further supports the role of OT in germ cell proliferation and survival. The pre‐pubertal mice treated with increasing dose of OT showed significant increase in testosterone synthesis due to dose‐dependent stimulatory effects on 3β‐HSD activity and increased expression of STAR, LH‐receptor (LH‐R) and gonadotrophin‐releasing hormone receptor (GnRH‐R) proteins in the testis. The in vitro study has confirmed in vivo finding showing direct action of OT on testicular steroidogenesis. Thus, OT stimulates testicular spermatogenesis and steroidogenesis by directly acting on testis in mice.     

Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model

Androgen ablation is standard therapy for advanced prostate carcinoma. It can be administered either as a monotherapy or as a combined androgen blockade. In the present study we have investigated molecular mechanisms which are responsible for the development of resistance to therapy in advanced prostate cancer. For this purpose, we have cultured LNCaP cells in steroid-depleted medium for 1 year. The newly generated subline LNCaP-abl was characterized. In early passages (<75) LNCaP-abl cells showed a biphasic hypersensitive response to androgenic stimulation. Passages later than 75 are inhibited by androgen. Proliferation of LNCaP-abl cells was stimulated by the pure nonsteroidal antiandrogen bicalutamide (Casodex). To improve our understanding of changes which occur during intermittent androgen ablation, we have generated the sublines LNCaP-R (reversal; cultured with fetal calf serum) and LNCaP-RA (reversal and androgen; cultured with fetal calf serum and androgen) from LNCaP-abl cells. In both cell lines an increase of the basal proliferation rate was observed. Androgen receptor expression in LNCaP-abl cells was 4-fold higher than that in parental LNCaP cells (4.7 vs. 1.2 fmol/microg protein). Androgen receptor content in LNCaP-R cells was 1.8 fmol/microg protein and in LNCaP-RA cells 1.0 fmol/microg protein. The basal androgen receptor activity was 30-fold higher in LNCaP-abl cells compared to that in parental LNCaP cells. This basal activity was reduced in LNCaP-RA cells. Both androgen and the nonsteroidal androgen receptor antagonist hydroxyflutamide induced a 2- to 4-fold higher activation of androgen receptor in LNCaP-abl than in LNCaP cells. There was a switch from an antagonist to an agonist of the nonsteroidal antiandrogen bicalutamide (Casodex) in LNCaP-abl cells. Antagonistic properties of this androgen receptor blocker were again observed in both sublines (LNCaP-R and LNCaP-RA) derived from LNCaP-abl cells. In concordance with proliferation data in vitro, growth of LNCaP-abl cells in nude mice was stimulated by bicalutamide. In contrast, supplementation of androgen led to inhibition of proliferation of these cells. The present study provides new information that is useful for a better understanding of therapy-refractory prostate cancer. It is also important for the development of new therapy strategies for advanced carcinoma of the prostate.     

Gibberellic acid acts as an agonist of steroidogenesis in male rats

Testicular steroidogenesis has significant implication in male reproductive function. Although the effects of various signalling molecules on testicular functions have been studied earlier, the influence of the plant hormone gibberellic acid (GA₃) on steroidogenesis has not been investigated. Acute (4 h) and subacute (15 days) studies using this compound through oral administration (150 μg day^?1) to groups of normal and diabetic Wistar male rats were therefore carried out. Results indicate that (i) enhanced activity of steroidogenic markers 3β‐hydroxysteroid dehydrogenase (3β‐HSD), 17β‐hydroxysteroid dehydrogenase (17β‐HSD), elevated tissue testosterone (T) content, increased steroidogenic acute regulatory protein (StAR) and androgen binding protein (ABP) levels with reduced lipid peroxidation and improved antioxidant defence in this treatment group of normal and diabetic rat testis, and (ii) elevated lipid peroxidation and diminished antioxidant defence, with insignificant change in 3β‐HSD and 17β‐HSD activity and testosterone level in acute treatment group of normal and diabetic rats testis, were noted. The observed increase in the activity of testicular 3β‐HSD and 17β‐HSD along with elevated testosterone content established GA₃ as an inducer of steroidogenesis in rat.     

The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors

PURPOSE: The role of androgen receptor coactivators in testicular development and cancer formation is unclear. p44/Mep50 was identified as an androgen receptor coactivator that functions in a complex with protein arginine methyltransferase 5. We studied the expression of p44 and protein arginine methyltransferase 5 in developing fetal testis and adult testicular tumors, including seminomas and Leydig cell tumors. MATERIALS AND METHODS: A total of 30 human fetal testes from abortuses at a gestational age of 10 to 40 weeks, 33 human seminomas and 11 human Leydig cell tumors were retrieved from the archives of the departments of pathology. Immunohistochemistry was performed with affinity purified p44 and IgG purified protein arginine methyltransferase 5 polyclonal antibodies. RESULTS: Protein arginine methyltransferase 5 and p44 were expressed predominantly as nuclear proteins in fetal Leydig cells and human adult nonneoplastic testes, including germ cells and Leydig cells, while they were expressed in the cytoplasm of germ cells of the fetal testis. Expression was strongest in the fetal testis during the second trimester. Compared to adult nonneoplastic testes, human seminoma and Leydig tumor cells showed a marked decrease in nuclear expression of p44 and protein arginine methyltransferase 5 with a concomitant marked increase in cytoplasmic expression of these proteins. Furthermore, average testicular size was increased by 29% in p44(+/-) heterzygotic mice. CONCLUSIONS: These results suggest distinct functions of the nuclear and the p44/protein arginine methyltransferase 5 complexes in the developing fetal testis and in the oncogenesis of testicular tumors. Further studies are needed to confirm the functional relevance of these findings.     

Hidden in plain sight: the mammary line in males may be the missing link regulating inguinoscrotal testicular descent

Background/Purpose

Inguinoscrotal testicular descent is controlled by androgens and the genitofemoral nerve, but the trigger for what makes the gubernaculum become a migratory organ like a limb bud remains unknown. Recent observations in the flutamide-treated rat suggested a link with the mammary line. We aimed, therefore, to reassess histologic anatomy in 2 different rodent models of androgen blockade, the testicular feminisation mouse (TFM) and the flutamide-treated rat.

Methods

Neonatal TFM mice and fetal and neonatal rats after pretreatment of dams with an antiandrogen, flutamide (75 mg/kg; sunflower oil; days 16-19), were prepared for histologic analysis of the inguinal region and compared with fetal and neonatal controls.

Results

Fetal control rats (E15.5 days) showed a mammary bud just outside the future inguinal canal adjacent to the gubernaculum. Neonatal TFM mice showed persistence of the inguinal breast bud supplied by the genitofemoral nerve. Flutamide-treated rats (D2) showed the gubernaculum surrounded by a persisting breast bud.

Conclusions

The inguinal mammary line is adjacent to the gubernaculum in fetal rodents, and after androgen blockade, the gubernaculum becomes connected to the breast. The male mammary line, which is hidden in plain sight outside the inguinal canal, is made visible by androgen blockade. It may be the missing link in testicular descent, regulating gubernacular migration.     

Combined long-term treatment with an LHRH agonist and a pure antiandrogen blocks androgenic influence in the rat

Daily administration for 5 months of the potent LHRH agonist (D-Ser(TBU)⁶, des-Gly-NH₂¹⁰) LHRH ethylamide (250 ng) in combination with the pure antiandrogen RU23908 (5 mg) to adult male rats causes a marked inhibition of ventral prostate and seminal vesicle weight to 9% and 15% of control, respectively. At the doses used, owing to readjustments of the pituitary-testicular axis, neither treatment alone has an effect on prostate weight and exerts only minimal inhibitory effects on seminal vesicle weight. Whereas treatment with the LHRH agonist alone markedly inhibits testicular LH and PRL receptor levels, the antiandrogen alone stimulates the concentration of the two receptors and reverses the inhibitory effect of the LHRH agonist treatment on LH receptors. Treatment with the LHRH agonist decreases plasma PRL levels, whereas the antiandrogen increases the concentration of circulating LH and FSH by 250%. Treatment with the LHRH agonist decreases the concentration of testosterone and its precursors of the Δ⁴-pathway while stimulating 5α-reductase activity in both the absence and presence of simultaneous treatment with the antiandrogen. The present data show that blockage of the Δ⁴-steroidogenic pathway induced by treatment with an LHRH agonist prevents the escape phenomenon observed during long-term treatment with a pure antiandrogen, and permits maximal inhibitory effects of the two treatments on secondary sex organ weight. Such combined treatment with an LHRH agonist (to block androgen formation) and an antiandrogen (to neutralize remaining androgens of testicular and adrenal origin) should be the hormonal therapy of choice in prostatic carcinoma.     

Molecular and anatomical studies of testicular descent

The mechanism of testicular descent is multifactorial, and the process is known to occur in two steps accompanied by different anatomies and hormonal regulation. In the first step, the testis descends from the lower pole of the kidney to the pelvic cavity near the bladder neck as a result of the swelling reaction of the gubernaculum. Next, in the second step, the testis descends into the scrotum through the inguinal canal via the gubernacular migration. The first step is androgen-independent, whereas the second step depends on the androgen action. Recently, several molecular studies on testicular descent have been reported. Several factors, such as androgen, calcitonin gene-related peptide (CGRP), epidermal growth factor (EGF), Hoxa-10 and insulin-like factor 3 (INSL3) have been suggested to be possible regulators of testicular descent. Because cryptorchidism has been frequently shown in androgen-insensitive human and mice (TFM-mice), androgen has been thought to play an important role in testicular descent. CGRP, which is released from the genitofemoral nerve, has been suggested to mediate the inguinoscrotal testicular descent. The epidermal growth factor (EGF) may promote both testosterone-induced wollfian duct differentiation and testicular descent by activating the androgen responsive systems. In male mice, a targeted disruption of the HOXA 10 gene causes cryptorchidism and the cryptorchid testes in these mutant mice are located in the lower abdominal cavity, whereas the cryptorchid testes in male mice lacking the INSL3 gene or its receptor Lgr8 were located in the abdominal cavity high. Recently, estrogens or environmental endocrine disruptors have also been suspected to induce a down-regulated INSL3 expression and thus disturb testicular descent.     

Local hyperthermia for prostatic disease: in vitro studies on human prostatic cancer cell lines.

Local hyperthermia for benign and malignant prostatic disease remains largely empirical. In an attempt to understand the biological action of hyperthermia, and its potentiation by antiandrogen seen in clinical practice, the interaction of the two has been studied in prostatic cancer cell lines. Human prostatic cancer cell lines LNCaP and DU 145 were studied to examine the effects of heat shock treatment (HST), androgen (5 alpha-dihydrotestosterone: 5 alpha DHT) and antiandrogen (hydroxyflutamide: OH-Flut) on cell growth and survival. Response (measured as increased DNA content) to 5 alpha DHT demonstrated that LNCaP was androgen sensitive, whereas DU 145 was androgen insensitive; OH-Flut stimulated LNCaP growth but had no effect on DU 145 growth. Thermotolerance was exhibited by DU 145 cells but not by LNCaP cells. The combination of HST followed by OH-Flut markedly reduced survival of LNCaP cells compared with HST alone. This effect was not observed in DU 145 cells. The enhanced cytotoxic effect of antiandrogen and hyperthermia could minimise the effect of thermotolerance in malignant cells surviving initial hyperthermia treatment and might suggest real clinical value for the combination or sequence.     

Biochemical and reproductive effects of gestational/lactational exposure to lead and cadmium with respect to testicular steroidogenesis, antioxidant system, endogenous sex steroid and cauda-epididymal functions

This study investigated the effects of gestational and lactational exposure to lead and cadmium on testicular steroidogenesis, antioxidant system and male accessory gland functions in F1 generation rats to understand the biochemical mechanisms involved in endocrine disruptions. Pregnant rats were subcutaneously administered with 0.05 mg kg(-1) body wt\ day(-1) of sodium acetate (control), lead acetate, cadmium acetate and (lead acetate + cadmium acetate) throughout the gestational-lactational period, and all animals from each of the experimental groups were sacrificed by decapitation on post-natal day 56 for performing various biochemical assays. We observed significant reduction in the activities of testicular key steroidogenic enzymes and serum testosterone concentration along with significant depletion in cholesterol, ascorbic acid and reduced glutathione contents in all the metal-treated groups. Reductions in the activities of catalase and superoxide dismutase with concomitant increase in the levels of thiobarbituric acid reactive substance were observed in experimental groups. Both sperm contents and sperm motility patterns were significantly altered in all the metal-treated groups, suggesting the direct/indirect spermotoxic effects of lead and cadmium. The inhibitory effects of lead, cadmium and combined exposure on testicular steroidogenesis machinery, along with the male accessory gland functions, are indicative of multiple targets of lead and cadmium to disrupt male reproductive functions.