Pre-pubertal obesity compromises ovarian oxidative stress, DNA repair and chemical biotransformation.

Obesity in adult females impairs fertility by altering oxidative stress, DNA repair and chemical biotransformation. Whether prepubertal obesity results in similar ovarian impacts is under-explored. The objective of this study was to induce obesity in prepubertal female mice and assess puberty onset, follicle number, and abundance of oxidative stress, DNA repair and chemical biotransformation proteins basally and in response to 7,12-dimethylbenz(a)anthracene (DMBA) exposure. DMBA is a polycyclic aromatic hydrocarbon that has been shown to be ovotoxic. Lactating dams (C57BL6J) were fed either a normal rodent containing 3.5% kCal from fat (lean), or a high fat diet comprised of 60% kCal from fat, and 9% kCal from sucrose. The offspring were weaned onto the diet of their dam and exposed at postnatal day 35 to either corn oil or DMBA (1 mg/kg) for 7 d via intraperitoneal injection. Mice on the HFD had reduced (P < 0.05) age at puberty onset as measured by vaginal opening but DMBA did not impact puberty onset. Heart, spleen, kidney, uterus and ovary weight were increased (P < 0.05) by obesity and liver weight was increased (P < 0.05) by DMBA exposure in obese mice. Follicle number was largely unaffected by obesity or DMBA exposure, with the exception of primary follicle number, which were higher (P < 0.05) in lean DMBA exposed and obese control relative to lean control mice. There were also greater numbers (P < 0.05) of corpora lutea in obese relative to lean mice. In lean mice, DMBA exposure reduced (P < 0.05) the level of CYP2E1, EPHX1, GSTP1, BRCA1, and CAT but this DMBA-induced reduction was absent in obese mice. Basally, obesity reduced (P < 0.05) the abundance of CYP2E1, EPHX1, GSTP1, BRCA1, SOD1 and CAT. There was greater (P < 0.05) fibrotic staining in obese DMBA-exposed ovaries and PPP2CA was decreased (P < 0.05) in growing follicles by both obesity and DMBA exposure. Thus, prepubertal obesity alters the capacity of the ovary to respond to DNA damage, ovotoxicant exposure and oxidative stress.

Abatacept Decreases Renal T-cell Infiltration and Renal Inflammation and Ameliorates Progressive Renal Injury in Obese Dahl Salt-sensitive Rats Before Puberty.

ABSTRACT: Prepubertal obesity is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats was associated with increased T-cell infiltration and activation before puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SS LepR mutant rats before puberty. Four-week-old SS and SS LepR mutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T cells by almost 50% in SS LepR mutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha while increasing IL-4 in SS LepR mutant rats without affecting SS rats. While not having an impact on blood glucose levels, abatacept reduced hyperinsulinemia and plasma triglycerides in SS LepR mutant rats without affecting SS rats. We did not observe any differences in the mean arterial pressure among the groups. Proteinuria was markedly higher in SS LepR mutant rats than in SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SS LepR mutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SS LepR mutant rats versus SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SS LepR mutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with prepubertal obesity.

F-53B mediated ROS affects uterine development in rats during puberty by inducing apoptosis.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as pollutants, can cause palpable environmental and health impacts around the world, as endocrine disruptors, can disrupt endocrine homeostasis and increase the risk of diseases. Chlorinated polyfluoroalkyl ether sulfonate (F-53B), as a substitute for PFAS, was determined to have potential toxicity. Puberty is the stage when sexual organs develop and hormones change dramatically, and abnormal uterine development can increase the risk of uterine lesions and lead to infertility. This study was designed to explore the impact of F-53B on uterine development during puberty. Four-week-old female SD rats were exposed to 0.125 and 6.25 mg/L F-53B during puberty. The results showed that F-53B interfered with growth and sex hormone levels and bound to oestrogen-related receptors, which affected their function, contributed to the accumulation of reactive oxygen species, promoted cell apoptosis and inhibited cell proliferation, ultimately causing uterine dysplasia.

Gestational bisphenol A exposure advances puberty onset in female offspring: Critical time window identification.

Increasing evidence shows that the early onset of puberty in female offspring may be caused by maternal prenatal exposure to bisphenol A (BPA) during pregnancy; however, the critical time window of maternal prenatal BPA exposure remains unknown. Here, we identify the critical time window of gestational BPA exposure that induces early onset of puberty in female offspring. Pregnant CD-1 mice were gavaged with BPA (8 mg/kg) daily during the early gestational stage (GD1-GD6), middle gestational stage (GD7-GD12) or late gestational stage (GD13-GD18). We show that maternal BPA exposure during the early and middle gestational stages could advance the vaginal opening time and increase the serum levels of kisspeptin-10 and GnRH in the female offspring at PND 34. Mechanistically, maternal BPA exposure during early and middle gestation could significantly increase CpG island methylation in the Eed gene promoters but reduce the mRNA expression of Eed in the hypothalamus tissues of the female offspring. In conclusion, the critical period of maternal BPA exposure-induced early onset of puberty in female offspring is early and middle gestation; this BPA-induced early onset of puberty might be partly attributed to epigenetic programming of the Eed gene in the hypothalamus. This study provides important insights regarding the relationship and the mechanisms between BPA and offspring pubertal development.

Adolescence is a sensitive period for acrylamide-induced sex hormone disruption: Evidence from NHANES populations and experimental mice.

Acrylamide (AA) is widely contaminated in environment and diet. However, the association of AA and sex hormones has rarely been investigated, especially in adolescents, a period of particular susceptibility to sex hormone disruption. In this study, survey-weighted multivariate linear regression models were conducted to determine the association between AA Hb biomarkers [HbAA and glycidamide (HbGA)] and sex hormones [total testosterone (TT) and estradiol (E2)] in a total of 3268 subjects from National Health and Nutrition Examination Survey (NHANES) 2013-2016 waves. Additionally, adult and pubertal mice were treated with AA to assess the effect of AA on sex hormones and to explore the potential mechanisms. Among all the subjects, significant negative patterns for HbGA and sex hormones were identified only in youths (6-19 years old), with the lowest ß being - 0.53 (95% CI: -0.80 to -0.26) for TT in males and - 0.58 (95% CI: -0.93 to -0.23) for E2 in females. Stratified analysis further revealed significant negative associations between HbGA and sex hormones in adolescents, with the lowest ß being - 0.58 (95% CI: -1.02 to -0.14) for TT in males and - 0.54 (95% CI: -1.03 to -0.04) for E2 in females, while there were no significant differences between children or late adolescents. In mice, the levels of TT and E2 were dramatically reduced in AA-treated pubertal mice but not in adult mice. AA disturbed the expression of genes in the hypothalamic-pituitary-gonadal (HPG) axis, induced apoptosis of hypothalamus-produced gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus and reduced serum and hypothalamic GnRH levels in pubertal mice. Our study indicates AA could reduce TT and E2 levels by injuring GnRH neurons and disrupting the HPG axis in puberty, which manifested as severe endocrine disruption on adolescents. Our findings reinforce the idea that adolescence is a vulnerable stage in AA-induced sex hormone disruption.

Systematically improved in vitro culture conditions reveal new insights into the reproductive biology of the human parasite Schistosoma mansoni.

Schistosomes infect over 200 million people. The prodigious egg output of these parasites is the sole driver of pathology due to infection, yet our understanding of sexual reproduction by schistosomes is limited because normal egg production is not sustained for more than a few days in vitro. Here, we describe culture conditions that support schistosome sexual development and sustained egg production in vitro. Female schistosomes rely on continuous pairing with male worms to fuel the maturation of their reproductive organs. Exploiting these new culture conditions, we explore the process of male-stimulated female maturation and demonstrate that physical contact with a male worm, and not insemination, is sufficient to induce female development and the production of viable parthenogenetic haploid embryos. We further report the characterization of a nuclear receptor (NR), which we call Vitellogenic Factor 1 (VF1), that is essential for female sexual development following pairing with a male worm. Taken together, these results provide a platform to study the fascinating sexual biology of these parasites on a molecular level, illuminating new strategies to control schistosome egg production.

Effects of peripheral oxytocin administration on body weight, food intake, adipocytes, and biochemical parameters in peri- and postmenopausal female rats.

Recent studies have revealed that the administration of oxytocin has beneficial effects on the regulation of body weight, food intake, and metabolic functions, especially in obese individuals. Obesity is common in women after the menopause and drives many components of metabolic syndrome. Weight gain in menopausal women has been frequently reported. Although obesity and associated metabolic disorders are frequently observed in peri- and postmenopausal women, there are few medical interventions for these conditions. In this study, we evaluated the effects of chronic oxytocin administration on appetite, body weight, and fat mass in peri- and postmenopausal female rats. Sixteen naturally premenopausal or menopausal rats were intraperitoneally injected with oxytocin (1,000 µg/day) for 12 days. The daily changes in their body weight and food intake were measured at the same time as the oxytocin and vehicle injections. Intraperitoneally administering oxytocin for 12 days significantly reduced food intake, body weight, and visceral adipocyte size. In addition, oxytocin administration caused reductions in serum triglyceride and low-density lipoprotein-cholesterol levels, while it did not disturb hepatic or renal functions or locomotor activity. This is the first study to show the effects of oxytocin on the metabolic and feeding functions of peri- and postmenopausal female rats. Oxytocin might be a useful treatment for metabolic disorders caused by the menopause or aging.

Melatonin Administration Accelerates Puberty Onset in Mice by Promoting FSH Synthesis.

Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHß in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHß increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.

In vitro follicle culture shows that progestagens are the maturation-inducing hormones (MIH) and possible regulators of the ovulation-mediating hormone PGE2 in female Eurasian perch Perca fluviatilis.

In European aquaculture, Eurasian perch, Perca fluviatilis L., is perceived as one of the most highly valuable freshwater fish species and a strong candidate for the development of freshwater aquaculture. In the pursuit of improving the quality of reproduction in this domesticated species, investigating the hormones mediating the final oocyte maturation (FOM) is therefore indispensable. But, the exact nature of the maturation-inducing hormone (MIH) in Eurasian perch is unknown. To further validate the existence of a maturation-inducing activity behind potential hormonal candidates in this species, we in vitro tested a group of nine hormones: cortisol (Co), 11-deoxycortisol (11-D), corticosterone (coS), 11-deoxycorticosterone (DOC), 17α,20ßdihydroxy-4-pregnen-3-one (DHP) and 17α,20ß,21 trihydroxy-4-pregnen-3-one (THP), prostaglandin E2 (PGE2), estradiol-17ß (E2) and testosterone (T), in their ability to trigger FOM advancement and the production of sex steroids potentially involved in FOM. Using mature female perch, two in vitro experiments were conducted with oocytes at the start of the FOM. The follicles were incubated for 62 h in Cortland media with and without human chorionic gonadotropin (hCG). By the end of the incubation, only DHP and THP triggered the full advancement in FOM even at low doses with the effect of DHP being in vivo validated. However, the de novo productions of E2 and DHP were not shown to be regulated by either of the MIH candidates. Progestagens are hence more credible candidates as MIH than corticosteroids in Eurasian perch. Our in vitro study also revealed that both PGE2 and DHP are strongly associated with ovulation and that PGE2 might have slightly contributed to such DHP activity.

Progesterone receptor membrane component 1 is required for mammary gland development†.

The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross Talk in Postpubertal Skeletal Development.

Commensal gut microbiota-host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell-mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk.

Moderate episodic prenatal alcohol does not impact female offspring fertility in rats.

Prenatal alcohol exposure (PAE) has been associated with reproductive dysfunction in offspring. However, studies in females, particularly examining long-term infertility or impacts on ovarian reserve, are lacking. The current study utilised a moderate, episodic exposure model in rats to mimic 'special occasion' drinking, which is reported to be common during pregnancy. Our objective was to examine the consequences of this prenatal alcohol exposure on reproductive parameters in female offspring. Pregnant Sprague-Dawley rats were treated with either an ethanol gavage (1 g EtOH/kg body weight), or an equivalent volume of saline, on embryonic days 13.5 and 14.5 of pregnancy, resulting in a peak blood alcohol concentration of ~0.04%. Neonatal female offspring were examined for molecular markers regulating early follicle numbers in the ovary, and unbiased stereology was used to quantify primordial and early growing follicle numbers. Puberty onset (age at vaginal opening and first estrous) was measured post-weaning, and estrous cycles, reproductive hormones (progesterone and estradiol) and pregnancy success was measured in adults (5-6 months of age). We found no evidence that any of these reproductive parameters were significantly altered by PAE in this model. This animal study provides some reassurance for women who may have consumed a small amount of alcohol during their pregnancy. However, previously published effects on offspring metabolism using this model reinforce avoidance of alcohol during pregnancy.

Neonatal exposure to bisphenol A advances pubertal development in female rats.

Neonatal exposure to bisphenol A (BPA) is hypothesized to advance pubertal development. However, the effects of neonatal BPA exposure on pubertal development has not been described. In this study, female Sprague-Dawley rats were exposed to 0.05, 0.5, 5, or 10 mg·kg-1 ·day-1 BPA, or corn oil vehicle alone from postnatal day 1 (PND1) to PND10 via subcutaneous injection. We evaluated day of vaginal opening (DVO), ovarian morphology, serum hormone concentrations, and hypothalamic expression of Gnrh1 and Kiss1 in female rats at PND35. DVO was significantly advanced in rats exposed to 5 and 10 mg·kg-1 ·day-1 BPA. Serum hormone concentrations increased as BPA dose increased. Additionally, hypothalamic Gnrh1 and Kiss1 expression were increased with BPA exposure; rats exposed to 10 mg·kg-1 ·day-1 BPA had significantly upregulated hypothalamic Gnrh1 and Kiss1 expressions in terms of both messenger RNA and protein levels. Our results suggest that exposure to a 10 mg·kg-1 ·day-1 dose of BPA might advance pubertal development significantly. In addition, within the range of 0 to 10 mg·kg-1 ·day-1 , neonatal exposure to BPA may affect pubertal development in a dose-dependent manner.

Effects of dietary fatty acids on the social life of male Guinea pigs from adolescence to adulthood.

Dietary intake of polyunsaturated fatty acids (PUFAs) or saturated fatty acids (SFAs) differently modulates neurophysiological and behavioral functions in response to altered hypothalamic-pituitary-adrenal (HPA)-axis activity and an individual's development. In this context, an individual's social environment, including social interactions and social hierarchies, is closely related to hormone concentrations and possibly interacts with dietary fatty acid effects. We investigated if dietary supplementation with walnut oil (high in PUFAs) and coconut fat (high in SFAs), compared to a control group, affects body mass gain, cortisol and testosterone concentrations, plasma fatty acids, and social behavior in male domestic guinea pigs from adolescence to adulthood. For analyses of cortisol and testosterone concentrations, social interactions were included as covariates in order to consider effects of social behavior on hormone concentrations. Our results revealed that SFAs increased escalated conflicts like fights and stimulated cortisol and testosterone concentrations, which limited body mass gain and first-year survival. PUFAs did not remarkably affect social behavior and hormone concentrations, but enabled the strongest body mass gain, which probably resulted from an energetic advantage. Neither sociopositive nor agonistic behaviors explained age-specific differences in hormone concentrations between groups. However, a high number of subdominant individuals and lower testosterone concentrations were related to increased cortisol concentrations in adult PUFA males. Our findings demonstrate the importance of dietary fatty acids regarding behavioral and endocrine developmental processes and adaptations to the social environment by modulating HPA-axis function and body homeostasis.

Serotonin type-3 receptors differentially modulate anxiety and aggression during withdrawal from adolescent anabolic steroid exposure.

Male Syrian hamsters (Mesocricetus auratus) administered anabolic/androgenic steroids during adolescent development display increased aggression and decreased anxious behavior during the adolescent exposure period. Upon withdrawal from anabolic/androgenic steroids, this neurobehavioral relationship shifts and hamsters exhibit decreased aggression and increased anxious behavior. This study investigated the hypothesis that alterations in anterior hypothalamic signaling through serotonin type-3 receptors modulate the behavioral shift between adolescent anabolic/androgenic steroid-induced aggressive and anxious behaviors during the withdrawal period. To test this, hamsters were administered anabolic/androgenic steroids during adolescence then withdrawn from drug exposure for 21 days and tested for aggressive and anxious behaviors following direct pharmacological manipulation of serotonin type-3 receptor signaling within the latero-anterior hypothalamus. Blockade of latero-anterior hypothalamic serotonin type-3 receptors both increased aggression and decreased anxious behavior in steroid-treated hamsters, effectively reversing the pattern of behavioral responding normally observed during anabolic/androgenic steroid withdrawal. These findings suggest that the state of serotonin neural signaling within the latero-anterior hypothalamus plays an important role in behavioral shifting between aggressive and anxious behaviors following adolescent exposure to anabolic/androgenic steroids.

Regulation of actions and habits by ventral hippocampal trkB and adolescent corticosteroid exposure.

In humans and rodents, stress promotes habit-based behaviors that can interfere with action-outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent-primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB-ERK42/44 tone determines long-term behavioral outcomes.

Design, production and purification of a novel recombinant gonadotropin-releasing hormone associated peptide as a spawning inducing agent for fish.

GnRH is a neuropeptide known to regulate reproduction in vertebrates. The purpose of this study was to design and produce recombinant gonadotropin-releasing hormone associated peptide (rGnRH/GAP) as an alternative of the previous GnRHs and native extracted hormone from tissue, to induce final maturation in fish. Decapeptide as well as GAP area sequences were compared between GnRH1, GnRH2, and mGnRH from Acipenser sp and Huso huso, respectively. Considering the conserved amino acids and the replacement of un-stable amino acids with those that were more stable against proteolytic digestion as well as had a longer half-life, the sequence was designed. The sequences of decapeptide and GAP region were synthesized and then cloned on pET28a expression vector and transformed into expression host Escherichia coli BL21(DE3). The supernatant of cultured recombinant bacteria was used for purification using TALON Metal affinity resin. The purity of the GnRH/GAP was confirmed by single 8 kDa band on SDS-PAGE and Western blot. Bioinformatics studies were performed for evaluation of homology between GnRH protein sequences and prediction of 3D protein structure using Swiss Model. The result showed that the structure prediction of the recombinant GnRH decapeptide was relatively similar to decapeptide of GnRH2 from Beluga (Huso huso). The GAP structure was similar to GAP1 of Nile tilapia (Oreochromis niloticus) and sturgeon and GnRH2 of Chinese sturgeon (Acipenser sinensis). The mass analysis showed that the sequence was exactly the same as designated sequence. Biology activity of rGnRH/GAP was tested in mature goldfish (Carassius auratus) and results showed that rGnRH/GAP had a positive effect in final maturation. Indeed 17α, 20ß-dihydroxy-4-pregnen-3-one (DHP) was increased 17 h and 24 h after injection with rGnRH/GAP and spawning stemmed from that injection. These novel findings introduce the potential of utilizing rGnRH/GAP in aquaculture.

Effect of paracetamol treatment on maternal care and reproductive outcomes in female rat offspring.

Paracetamol (PAR) is one of the most commonly used drugs by pregnant women because it is considered safe for the mother and fetus. However, PAR is transferred into breast milk and crosses the blood-placental barrier, being present in the progeny during important stages of development. Intrauterine exposure to PAR may decrease the anogenital distance and follicle reserve in female rodent offspring. Therefore, the aim of the present study was to evaluate whether maternal PAR treatment altered the reproductive behaviour of dams and the sexual development of female rat offspring. Pregnant Wistar rats were gavaged daily with 350mg kg-1 day-1 PAR or water during gestation (from Gestation Day (GD) 6 until delivery) or during gestation and lactation (from GD6 until weaning). Maternal PAR treatment had maternal effects (increased grooming behaviour), and resulted in impaired sexual behaviour, decreased follicle reserve and increased plasma oestradiol concentrations in female offspring.

Final height in growth hormone-deficient childhood cancer survivors after growth hormone therapy.

PURPOSE: Growth hormone deficiency (GHD) is the most prevalent hypothalamic-pituitary (HP) disorder found in childhood cancer survivors (CCS). The published studies assessing GHD in CCS concluded that recombinant human GH (rhGH) does not restore final height (FH) to that predicted from mid-parental height (MPH). Thus, wider analyses on final height outcomes after rhGH in CCS are needed. METHODS: Retrospective study on final height (FH) in 87 CCS treated with rhGH. Patients were divided into: Group A (n =48) who underwent cranial radiotherapy or had non-irradiated tumours of HP area, and B (n =39) who were treated with craniospinal or total body irradiation (TBI). 19/87 patients with central precocious/early puberty also received GnRH analogues. RESULTS: Height (HT) gain after 1 and 2 years of rhGH was 0.38 ± 0.35 SDS and 0.18 ± 0.30 SDS, respectively (P < 0.0001); mean FH was in the normal range (- 0.85 ± 1.34 SDS), though not significantly different from HT SDS at baseline. 67% overall failed to reach MPH especially in Group B (P < 0.0001). However, height loss (HT SDS-MPH SDS) at FH improved or remained stable compared to baseline in 26/45 patients (58%). On stepwise regression analysis, major determinants of FH were HT at baseline (P < 0.0001) and delay before start of rhGH (P = 0.012). There was no significant difference in FH when GnRHa was added to rhGH. CONCLUSION: rhGH and GnRH analogues therapy, when indicated, though failing to induce catch-up growth, prevented further height loss leading to a FH within the normal range but still below MPH, this latter being statistically significant in children who received craniospinal and TBI.

Deregulation of autophagy is involved in nephrotoxicity of arsenite and fluoride exposure during gestation to puberty in rat offspring.

Exposure to fluoride (F) or arsenite (As) through contaminated drinking water has been associated with chronic nephrotoxicity in humans. Autophagy is a regulated mechanism ubiquitous for the body in a toxic environment with F and As, but the underlying mechanisms of autophagy in the single or combined nephrotoxicity of F and As are unclear. In the present study, we established a rat model of prenatal and postnatal exposure to F and As with the aim of investigating the mechanism underlying nephrotoxicity of these pollutants in offspring. Rats were randomly divided into four groups that received NaF (100 mg/L), NaAsO2 (50 mg/L), or NaF (100 mg/L) with NaAsO2 (50 mg/L) in drinking water or clean water during pregnancy and lactation; after weaning, pups were exposed to the same treatment as their mothers until puberty. The results revealed that F and As exposure (alone or combined) led to significant increases of arsenic and fluoride levels in blood and bone, respectively. In this context, F and/or As disrupted histopathology and ultrastructure in the kidney, and also altered creatinine (CRE), urea nitrogen (BUN) and uric acid (UA) levels. Intriguingly, F and/or As uptake induced the formation of autophagosomes in kidney tissue and resulted in the upregulation of genes encoding autophagy-related proteins. Collectively, these results suggest that nephrotoxicity of F and As for offspring exposed to the pollutants from in utero to puberty is associated with deregulation of autophagy and there is an antagonism between F and As in the toxicity autophagy process.