Effects of hypoxia on the reproductive endocrine axis of the pejerrey (Odontesthes bonariensis).

Recently, hypoxic areas have been identified in water bodies of the Pampas region due to human activity. The objective of this work was to study the effect of low concentrations of dissolved oxygen (hypoxia) on the reproductive endocrine axis of a pampas fish (Odontesthes bonariensis). Groups of 8 males and 8 females were subjected to severe hypoxia (2-3 mg l-1) and normoxia (7-9 mg l-1) in 3000 l tanks by duplicate during the reproductive season (spring). After 21 days, 4 males and 4 females from each tank were sacrificed, and blood was drawn to measure estradiol (E2) and testosterone (T). The brain, pituitary gland and a portion of the gonads were extracted and processed to measure the expression of: gnrh1, cyp19a1b, fshß, lhß, fshr, lhcgr and cyp19a1a. From the second experimental week, no spawning was found in the hypoxic females, while at the end of the treatment period no male released sperm. Fish under hypoxic conditions showed signs of gonadal regression, reduction of GSI and plasma levels of sex steroids. Furthermore, the expression of gnrh1 in both sexes, cyp19a1b and fshr in males and only fshß and cyp19a1a in females decreased in comparison with normoxic fish. After 40 days under normal conditions, signs of reproductive recovery were observed in the treated fish. The results obtained demonstrated that hypoxia generated an inhibition of some components of the pejerrey's reproductive endocrine axis, but the effect was reversible.

Per- and Polyfluoroalkyl Substances (PFAS) Affect Female Reproductive Health: Epidemiological Evidence and Underlying Mechanisms.

PFAS (per- and polyfluoroalkyl substances) have been extensively used across numerous industries and consumer goods. Due to their high persistence and mobility, they are ubiquitous in the environment. Exposure to PFAS occurs in people via multiple pathways such as dermal contact, water supply, air inhalation, and dietary intake. Even if some PFAS are being phased out because of their persistent presence in the environment and harmful impacts on human health, mixes of replacement and legacy PFAS will continue to pollute the ecosystem. Numerous toxicological investigations have revealed harmful effects of PFAS exposure on female reproductive health, e.g., polycystic ovaries syndrome, premature ovarian failure, endometriosis, reproductive system tumors, pregnancy complications, and adverse pregnancy outcomes. Despite extensive epidemiological studies on the reproductive toxicity of PFAS, research findings remain inconsistent, and the underlying mechanisms are not well understood. In this review, we give an in-depth description of the sources and pathways of PFAS, and then review the reproductive toxicity of PFAS and its possible mechanisms.

Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis.

BACKGROUND: The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis. METHODS: Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction. RESULTS: Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880-1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970-1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350-1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983-1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671-1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919-1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644-1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137-1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results. CONCLUSION: The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.

Endocrine toxicity of atrazine and its underlying mechanisms.

Atrazine (ATR) is one of the most widely utilized herbicides globally and is prevalent in the environment due to its extensive use and long half-life. It can infiltrate the human body through drinking water, ingestion, and dermal contact, and has been recognized as an environmental endocrine disruptor. This study aims to comprehensively outline the detrimental impacts of ATR on the endocrine system. Previous research indicates that ATR is harmful to various bodily systems, including the reproductive system, nervous system, adrenal glands, and thyroi d gland. The toxic effects of ATR on the endocrine system and its underlying molecular mechanisms are summarized as follows: influencing the expression of kisspeptin in the HPG axis, consequently affecting steroid synthesis; disrupting DNA synthesis and meiosis, as well as modifying DNA methylation levels, leading to reproductive and developmental toxicity; impacting dopamine by altering Nurr1, VMAT2, and DAT expression, consequently affecting dopamine synthesis and transporter expression, and influencing other neurotransmitters, resulting in neurotoxicity; and changing adipose tissue synthesis and metabolism by reducing basal metabolism, impairing cellular oxidative phosphorylation, and inducing insulin resistance. Additionally, a compilation of natural products used to mitigate the toxic effects of ATR has been provided, encompassing melatonin, curcumin, quercetin, lycopene, flavonoids, vitamin C, vitamin E, and other natural remedies. It is important to note that existing research predominantly relies on in vitro and ex vivo experiments, with limited population-based empirical evidence available.

Reproductive endocrine disruption effect and mechanism in male zebrafish after life cycle exposure to environmental relevant triclosan.

Triclosan (TCS) is a wide-spectrum antibacterial agent that is found in various water environments. It has been reported to have estrogenic effects. However, the impact of TCS exposure on the reproductive system of zebrafish (Danio rerio) throughout their life cycle is not well understood. In this study, zebrafish fertilized eggs were exposed to 0, 10, and 50 µg/L TCS for 120 days. The study investigated the effects of TCS exposure on brain and testis coefficients, the expression of genes related to the hypothalamus-pituitary-gonadal (HPG) axis, hormone levels, vitellogenin (VTG) content, histopathological sections, and performed RNA sequencing of male zebrafish. The results revealed that life cycle TCS exposure had significant effects on zebrafish reproductive parameters. It increased the testis coefficient, while decreasing the brain coefficient. TCS exposure also led to a decrease in mature spermatozoa and altered the expression of genes related to the HPG axis. Furthermore, TCS disrupted the balance of sex hormone levels and increased VTG content of male zebrafish. Transcriptome sequencing analysis indicated that TCS affected reproductive endocrine related pathways, including PPAR signaling pathway, cell cycle, GnRH signaling pathway, steroid biosynthesis, cytokine-cytokine receptor interaction, and steroid hormone biosynthesis. Protein-protein interaction (PPI) network analysis confirmed the enrichment of hub genes in these pathways, including bub1bb, ccnb1, cdc20, cdk1, mcm2, mcm5, mcm6, plk1, and ttk in the brain, as well as fabp1b.1, fabp2, fabp6, ccr7, cxcl11.8, hsd11b2, and hsd3b1 in the testis. This study sheds light on the reproductive endocrine-disrupting mechanisms of life cycle exposure to TCS.

Study on epigenotoxicity, sex hormone synthesis, and DNA damage of benzo[a]pyrene in the testis of male Ruditapes philippinarum.

Research on the mechanisms of reproductive toxicity caused by persistent organic pollutants (POPs) in marine animals has received significant attention. One group of typical POPs, called polycyclic aromatic hydrocarbons (PAHs), has been found to cause various reproductive toxicities in aquatic organisms, including epigenotoxicity, reproductive endocrine disruption, DNA damage effects and other reproductive toxicity, thereby affecting gonadal development. Interestingly, male aquatic animals are more susceptible to the disturbance and toxicity of environmental pollutants. However, current studies primarily focus on vertebrates, leaving a large gap in our understanding of the reproductive toxicity and mechanisms of PAHs interference in marine invertebrates. In this study, male Ruditapes philippinarum was used as an experimental subject to investigate reproduction-related indexes in clams under the stress of benzo[a]pyrene (B[a]P) at different concentrations (0, 0.8, 4 and 20 µg/L) during the proliferative, growth, maturity, and spawning period. We analyzed the molecular mechanisms of reproductive toxicity caused by PAHs in marine bivalves, specifically epigenotoxicity, reproductive endocrine disruption, and gonadal damage-apoptotic effect. The results suggest that DNA methylation plays a crucial role in mediating B[a]P-induced reproductive toxicity in male R. philippinarum. B[a]P may affect sex hormone levels, impede spermatogenesis and testis development in clams, by inhibiting the steroid hormone synthesis pathway and downregulating genes critical for cell proliferation, testis development, and spermatid expulsion. Moreover, the spermatids of male R. philippinarum were severely impaired under the B[a]P stress, leading to reduced reproductive performance in the clams. These findings contribute to a better understanding of the reproductive toxicity response of male marine invertebrates to POPs stress.

Causal association between lipid-lowering drugs and female reproductive endocrine diseases: a drug-targeted Mendelian randomization study.

Purpose: The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs. Methods: In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility. Results: PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea. Conclusion: The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.

Histopathological and transcriptomic analyses reveal the reproductive endocrine-disrupting effects of decabromodiphenyl ethane (DBDPE) in mussel Mytilus galloprovincialis.

The novel brominated flame retardant DBDPE has become a widespread environmental contaminant and could affect reproductive endocrine system in vertebrates. However, information about reproductive endocrine-disrupting effects of DBDPE on invertebrates is totally unknown. In this study, mussels Mytilus galloprovincialis were exposed to 1, 10, 50, 200 and 500 µg/L DBDPE for 30 days. Histopathological and transcriptomic analyses were performed to assess the reproductive endocrine-disrupting effects of DBDPE in mussels and the potential mechanisms. DBDPE promoted the gametogenesis in mussels of both sexes according to histological observation, gender-specific gene expression (VERL and VCL) and histological morphometric parameter analysis. Transcriptomic analysis demonstrated that DBDPE suppressed the genes related to cholesterol homeostasis and transport in both sexes via different LRPs- and ABCs-mediated pathways. DBDPE also disturbed nongenomic signaling pathway including signaling cascades (GPR157-IP3-Ca2+) in males and secondary messengers (cGMP) in females, and subsequently altered the expression levels of reproductive genes (VMO1, ZAN, Banf1 and Hook1). Additionally, dysregulation of energy metabolism in male mussels induced by DBDPE might interfere with the reproductive endocrine system. Overall, this is the first report that DBDPE evoked reproductive endocrine-disruptions in marine mussels. These findings will provide important references for ecological risk assessment of DBDPE pollution in marine environment.

Time- and dose-dependent detoxification and reproductive endocrine disruption induced by tetrabromobisphenol A (TBBPA) in mussel Mytilus galloprovincialis.

As a typical brominated flame retardant (BFR), tetrabromobisphenol A (TBBPA) has been frequently detected in both biotic and abiotic matrices in marine environment. Our previous study found that genes related to metabolism phase I/II/III as well as steroid metabolism in Mytilus galloprovincialis were significantly altered by TBBPA treatment. However, the time- and dose-dependent response profiles of these genes to TBBPA exposure were rarely reported. In this study, the time- and dose-dependent effects of TBBPA on detoxification and reproductive endocrine disruption in M. galloprovincialis were explored by evaluating the responses of related gene expressions, enzymatic activities and gametogenesis to different concentrations of TBBPA (0.6, 3, 15, 75 and 375 µg/L) for different durations (14, 21 and 28 days). The results showed that the TBBPA accumulation increased linearly with the increases of exposure time and dose. Cytochrome P450 family 3 (CYP3A1-like) cooperated with CYP4Y1 for phase I biotransformation of TBBPA in mussels. The dose-response curves of phase II/III genes (glutathione-S-transferase (GST), P-glycoprotein (ABCB), and multidrug resistance protein (ABCC)) showed similar response profiles to TBBPA exposure. The common induction of phase I/II/III (CYPs, GST, ABCB and ABCC) suggested TBBPA detoxification regulation in mussels probably occurred in a step-wise manner. Concurrently, direct sulfation mediated by sulfotransferases (SULTs) on TBBPA was also the vital metabolic mechanism for TBBPA detoxification, which was supported by the coincidence between up-regulation of SULT1B1 and TBBPA accumulation. The significant promotion of steroid sulfatase (STS) might result from TBBPA-sulfate catalyzed by SULT1B1 due to its chemical similarity to estrone-sulfate. Furthermore, the promotion of gametogenesis was consistent with the induction of STS, suggesting that STS might interrupt steroids hydrolysis process and was responsible for reproductive endocrine disruption in M. galloprovincialis. This study provides a better understanding of the detoxification and endocrine-disrupting mechanisms of TBBPA.

A case study: temporal trends of environmental stressors and reproductive health of smallmouth bass (Micropterus dolomieu) from a site in the Potomac River Watershed, Maryland, USA.

Decades of poor reproductive success and young-of-the-year survival, combined with adult mortality events, have led to a decline in the smallmouth bass (SMB; Micropterus dolomieu) population in sections of the Potomac River. Previous studies have identified numerous biologic and environmental stressors associated with negative effects on SMB health. To better understand the impact of these stressors, this study was conducted at the confluence of Antietam Creek and the Potomac River from 2013 to 2019 to identify temporal changes associated with SMB reproductive health. Surface water samples were collected and analyzed for over 300 organic contaminants, including pesticides, phytoestrogens, pharmaceuticals, hormones and total estrogenicity (E2Eq). Adult SMB were collected and sampled for multiple endpoints, including gene transcripts associated with reproduction (molecular), histopathology (cellular), and organosomatic indices (tissue). In males, biomarkers of estrogenic endocrine disruption, including testicular oocytes (TO) and plasma vitellogenin (Vtg) were assessed. Numerous agriculture-related contaminants or land use patterns were associated with gene transcript abundance in both male and female SMB. Positive associations between pesticides in the immediate catchment with TO severity and E2Eq with plasma Vtg in males were identified. In males, the prevalence of TO and detectable levels of plasma Vtg, liver vitellogenin transcripts (vtg) and testis vtg were high throughout the study. Peaks of complex mixtures of numerous contaminants occurred during the spring/early summer when spawning and early development occurs and to a lesser extent in fall/winter during recrudescence. Management practices to reduce exposure during these critical and sensitive periods may enhance reproductive health of these economically important sportfishes.

Critical Roles of the Circadian Transcription Factor BMAL1 in Reproductive Endocrinology and Fertility.

Brain and muscle aryl-hydrocarbon receptor nuclear translocator like protein1 (BMAL1), a core component of circadian oscillation, is involved in many physiological activities. Increasing evidence has demonstrated the essential role of BMAL1 in reproductive physiology. For instance, BMAL1-knockout (KO) mice were infertile, with impaired reproductive organs and gametes. Additionally, in BMAL1-KO mice, hormone secretion and signaling of hypothalamus-pituitary-gonadal (H-P-G) hormones were also disrupted, indicating that H-P-G axis was impaired in BMAL1-KO mice. Moreover, both BMAL1-KO mice and BMAL1-knockdown by small interfering RNA (siRNA) in vitro cultured steroidogenic cells showed that BMAL1 was associated with gonadal steroidogenesis and expression of related genes. Importantly, BMAL1 also participates in pathogenesis of human reproductive diseases. In this review, we elaborate on the impaired reproduction of BMAL1-KO mice including the reproductive organs, reproductive endocrine hormones, and reproductive processes, highlighting the vital role of BMAL1 in fertility and reproductive endocrinology.

Dietary Modification for Reproductive Health in Women With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Objective: Diet has been reported as the first-line management of polycystic ovary syndrome (PCOS). However, the relationship between diet and fertility in PCOS is still controversial. This meta-analysis aimed to evaluate whether diet could promote reproductive health in women with PCOS while providing evidence-based nutrition advice for clinical practice. Methods: Seven databases, including Cochrane Central Register of Controlled Trials, PubMed, Embase, Web of Science, and some Chinese database, were searched up to January 31, 2021. Randomized controlled trials evaluating the effects of diet in women with PCOS were included. Based on a preregistered protocol (PROSPERO CRD42019140454), the systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Two reviewers made study selection, data extraction and bias assessment independently. Risk ratios and mean difference with 95% confidence intervals were assessed by a random-effects model. Statistical heterogeneity within comparisons was evaluated by Cochran's Q test and quantified by the I-squared (I2 ) statistic. Results: Twenty RCTs with 1113 participants were included. Results showed diet significantly related to improved fertility outcomes (increasing clinical pregnancy, ovulation and menstrual regularity rate; reducing miscarriage rate), reproductive endocrine [increasing sex hormone-binding globulin (SHBG); decreasing Anti-Müllerian Hormone (AMH), free androgen index (FAI), total testosterone (T)] and clinical hyperandrogenism (hirsutism assessed by Ferriman-Gallwey score) in PCOS. Specifically, subgroup analyses indicated low-carbohydrate diets were superior in optimizing reproductive outcomes and calorie restriction was critical in ameliorating hyperandrogenism. Additionally, the positive effects were associated with the treatment duration. The longer the duration, the greater the improvement was. Conclusion: Overall, diet is an effective intervention for improving fertility health, thus professional and dynamic dietary advice should be offered to all PCOS patients, based on the changeable circumstances, personal needs and expectations of the individuals.

The Effect of Free Androgen Index on the Quality of Life of Women With Polycystic Ovary Syndrome: A Cross-Sectional Study.

Purpose: Free androgen index (FAI) and anti-Mullerian hormone (AMH) are independently associated with polycystic ovary syndrome (PCOS). This study aimed to describe the relationship between these two markers and health-related quality of life (HR-QoL) in women with PCOS. Methods: This cross-sectional study consisted of 81 women in the Hull PCOS biobank, who fulfilled the Rotterdam consensus criteria for the diagnosis of PCOS. The primary outcome was to measure the various domains of the QoL in the modified polycystic ovary syndrome questionnaire (MPCOSQ). Results: Mean age of the study participants was 28 ± 6.0 years, mean body mass index (BMI) 33.5 ± 7.8 kg/m2, mean FAI (6 ± 5.5), free testosterone (2.99 ± 0.75) and mean AMH (3.5 ± 0.8 units). In linear regression analysis, the FAI was associated with overall mean MPCOSQ score (Beta = 0.53, P-value = 0.0002), and with depression (Beta = 0.45, P-value = 0.01), hirsutism (Beta = 0.99, P-value = 0.0002) and menstrual irregularity (Beta = 0.31, P-value = 0.04). However, with adjustment for age and BMI, FAI was only associated with the hirsutism domain (Beta = 0.94, P-value = 0.001) of the MPCOSQ. FAI was also associated with the weight domain (Beta = 0.63 P-value = 0.005) of MPCOSQ. However, AMH was not associated with the overall mean MPCOSQ score or with any of its domains. Conclusion: FAI but not AMH was associated with QoL in women with PCOS, and this effect was mediated by BMI.

Changes in thyroid function during controlled ovarian hyperstimulation (COH) and its impact on assisted reproduction technology (ART) outcomes: a systematic review and meta-analysis.

BACKGROUND: To investigate the thyroid function changes during controlled ovarian hyperstimulation (COH) and ascertain its impact on reproductive outcomes. METHODS: We conducted meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed to identify studies reported changes in thyroid parameters during COH. We analyzed thyroid-stimulating hormone (TSH) levels, free thyroxin (fT4) levels, changes in estrogens (E2), thyroxine-binding globulin (TBG), relative risks (RRs) of clinical pregnancy rate (CPR), live birth rate (LBR), and mean difference (MD) of TSH increment between the miscarriage group and ongoing pregnancy group. RESULTS: This meta-analysis included fifteen individual studies (n = 1665 subjects). At the end of COH, the mean TSH (2.53 mIU/L; 95% CI, 2.19 to 2.88; I2 = 92.9%) exceeded the upper limit (2.5 mIU/L) and remained above the threshold until one month following embryo transfer (ET). Thyroxin decreased from baseline to the end of COH (-0.18 ng/l; 95% CI, -0.35 to 0.00; I2 = 92.2%). The CPR and LBR of patients with TSH exceeding the cutoff after COH were significantly lower than those of patients with TSH below the threshold (CPR: RR, 0.62; 95% CI, 0.47 to 0.82; I2 = 0.0% and LBR: RR, 0.64; 95% CI, 0.44 to 0.92; I2 = 0.0%). The MD of the increment in TSH levels between the miscarriage and ongoing pregnancy groups was 0.40 mIU/L (95% CI, 0.15 to 0.65; I2 = 0.0%). CONCLUSIONS: This meta-analysis shows that TSH increases and fT4 decreases during COH. COH-induced thyroid disorder impairs reproductive outcomes.

The impact of the gut microbiota on the reproductive and metabolic endocrine system.

As the gut microbiota exerts various effects on the intestinal milieu which influences distant organs and pathways, it is considered to be a full-fledged endocrine organ. The microbiota plays a major role in the reproductive endocrine system throughout a woman's lifetime by interacting with estrogen, androgens, insulin, and other hormones. Imbalance of the gut microbiota composition can lead to several diseases and conditions, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome (PCOS), endometriosis, and cancer; however, research on the mechanisms is limited. More effort should be concentrated on exploring the potential causes and underlying the mechanisms of microbiota-hormone-mediated disease, and providing novel therapeutic and preventive strategies.As the gut microbiota exerts various effects on the intestinal milieu which influences distant organs and pathways, it is considered to be a full-fledged endocrine organ. The microbiota plays a major role in the reproductive endocrine system throughout a woman's lifetime by interacting with estrogen, androgens, insulin, and other hormones. Imbalance of the gut microbiota composition can lead to several diseases and conditions, such as pregnancy complications, adverse pregnancy outcomes, polycystic ovary syndrome (PCOS), endometriosis, and cancer; however, research on the mechanisms is limited. More effort should be concentrated on exploring the potential causes and underlying the mechanisms of microbiota-hormone-mediated disease, and providing novel therapeutic and preventive strategies.

GnRH-a-Induced Perimenopausal Rat Modeling and Black Cohosh Preparations' Effect on Rat's Reproductive Endocrine.

Background: Endometriosis (EMS) is an estrogen-dependent disease, which easily recurs after operation. Gonadotropin-releasing hormone agonist (GnRH-a), an estrogen-inhibiting drug, can effectively inhibit the secretion of gonadotropin by pituitary gland, so as to significantly decrease the ovarian hormone level and facilitate the atrophy of ectopic endometrium, playing a positive role in preventing postoperative recurrence. The application of GnRH-a can lead to the secondary low estrogen symptoms, namely the perimenopausal symptoms, and is a main reason for patients to give up further treatment. The add-back therapy based on sex hormones can well address the perimenopausal symptoms, but long-term use of hormones may cause the recurrence of EMS, as well as liver function damage, venous embolism, breast cancer and other risks, which has long been a heated topic in the industry. Therefore, it is necessary to find effective and safe anti-additive drugs soon. Studies at home and abroad show that, as a plant extract, isopropanolic extract of cimicifuga racemosa (ICR) can well relieve the perimenopausal symptoms caused by natural menopause. Some studies have preliminarily confirmed that black cohosh preparations can antagonize perimenopausal symptoms of EMS patients treated with GnRH-a after operation. Objective: To establish a rat model of perimenopausal symptoms induced by GnRH-a injection, for the purposes of laying a foundation for further research and preliminarily exploring the effect of black cohosh preparations on reproductive endocrine of the rat model. Method: The rat model of perimenopausal symptoms was established by GnRH-a injection, and normal saline (NS injection) was used as the control. The rats were randomly divided into four groups according to different modeling methods and drug intervention schemes. GnRH-a injection + normal saline intervention group (GnRH-a + NS), normal saline injection control + normal saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparations intervention group (GnRH-a + ICR). After modelling was assessed to be successful with the vaginal smear method, the corresponding drugs were given for intervention for 28d. In the process of rat modeling and drug intervention, the skin temperature and anus temperature of the rat tails were measured every other day, the body weights of the rats were measured every other day, and the dosage was adjusted according to the body weight. After the intervention was over, the serum sex hormone level, the uterine weight, the uterine index, and the endometrial histomorphology changes, as well as the ovarian weight, the ovarian index, and the morphological changes of ovarian tissues of each group were measured. Results: (1) The vaginal cell smears of the control group (NS + NS) showed estrous cycle changes, while other model rats had no estrous cycle of vaginal cells. (2) The body weight gains of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups were significantly higher than that of the NS + NS control group. The intervention with E2 and ICR could delay the weight gain trend of rats induced by GnRH-A. (3) After GnRH-a injection, the temperature of the tail and anus of rats showed an overall upward trend, and the intervention with E2 and ICR could effectively improve such temperature change. (4) The E2, FSH, and LH levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups were significantly lower than those in the NS + NS group (P < 0.01). The E2 level was significantly higher and the LH level was significantly lower in the GnRH-a + E2 group than those in the GnRH-a + NS and GnRH-a + ICR groups (P < 0.05). Compared with those of the GnRH-a + NS and GnRH-a + ICR groups, the FSH level of the GnRH-a + E2 group showed a slight downward trend, but the difference was not statistically significant (P > 0.05). There was no significant difference in the levels of sex hormones between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (5) Compared with those of the NS + NS group, the uterine weight and uterine index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). In a comparison between the groups, the uterine weight and uterine index in the GnRH-a + NS and GnRH-a + ICR groups were significantly lower than those in the GnRH-a + E2 group (P < 0.01). There was a statistical difference in the uterine weight and uterine index between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (6) Compared with those of the NS + NS group, the ovarian weight and ovarian index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). There was no statistical difference in the ovarian weight and ovarian index among the GnRH-a + E2, GnRH-a + NS and GnRH-a + ICR groups (P > 0.05). (7) Compared with those in the NS + NS group, the number of primordial follicles increased significantly, while the number of growing follicles and mature follicles decreased significantly in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups (P < 0.01), but there was a statistical difference in the total number of follicles among the four groups (P > 0.05). Conclusions: The GnRH-a injection could achieve the desired effect. The animal model successfully achieved a significant decrease in the E2, FSH, and LH levels in rats, and could cause the rats to have rising body surface temperature similar to hot flashes in the perimenopausal period. The intervention with E2 and ICR could effectively relieve such "perimenopausal symptoms", and ICR had no obvious effect on the serum sex hormone level in rats.

Insulin-like androgenic gland hormone 1 (IAG1) regulates sexual differentiation in a hermaphrodite shrimp through feedback to neuroendocrine factors.

Insulin-like androgenic gland hormone (IAG) is regarded as a key sexual differentiation regulator in gonochoristic crustaceans. However, until now the knowledge concerning its functions in hermaphroditic crustaceans is scanty. Herein, we investigated the function of IAG (Lvit-IAG1) in peppermint shrimp Lysmata vittata, a species that possesses protandric simultaneous hermaphroditism (PSH) reproductive system, which is rare among crustaceans. Lvit-IAG1 was exclusively expressed in the androgenic gland. The qRT-PCR demonstrated that its mRNA expression level was relatively high at the functional male phase but decreased sharply in the subsequent euhermaphrodite phase. Both the short-term and long-term silencing experiments showed that Lvit-IAG1 negatively regulated both the gonad-inhibiting hormone (Lvit-GIH) and crustacean female sex hormone (Lvit-CFSH) expressions in the eyestalk ganglion. Besides, Lvit-IAG1 gene knockdown induced a retarded development of the appendices masculinae (AM) and male gonopores while suppressing the germ cells at the primary spermatocyte stage. Also, Lvit-IAG1 gene silencing hindered ovarian development. This in turn led to small vitellogenic oocytes and decreased expression of vitellogenin and vitellogenin receptor genes in hepatopancreas and ovarian region, respectively. Generally, this study's findings imply that Lvit-IAG1 modulated the male sexual differentiation in PSH species L. vittata, and exhibited negative feedback on Lvit-GIH and Lvit-CFSH genes expression in the species' eyestalk ganglion.

Prenatal exposure of female mice to perfluorononanoic acid delays pubertal activation of the reproductive endocrine axis through enhanced hepatic FGF21 production.

The developmental toxicity of perfluorononanoic acid (PFNA), a ubiquitous environmental contaminant, has been associated with the activation of PPARα. This study investigated influence of prenatal exposure to PFNA in pubertal activation of reproductive endocrine axis in female mice and explored underlying molecular mechanisms. Herein, we show that when PFNA (3 mg kg-1 body weight) was orally administered during gestational days 1-18, dams showed an increase in liver weight and hepatic FGF21 synthesis via PPARα activation, and their female offspring (PFNA mice) showed an increase in liver weight and hepatic FGF21 synthesis from postnatal day (PND) 1 to PND21, which were corrected by the administration of the PPARα antagonist GW6471 from PND1-14 (pup-GW). Expression of vasopressin (VAP) in the hypothalamic suprachiasmatic nucleus (SCN) was reduced in PND14-30 PFNA mice, and could be rescued by pup-GW. Pubertal activation of kisspeptin neurons in anteroventral periventricular nucleus (AVPV) and hypothalamic GnRH neurons in PND21-30 PFNA mice was obviously suppressed, but were recovered by pup-GW or PND21-30 application of VAP. The times of vaginal opening and first estrus were delayed in PFNA mice with a decrease in ovary size and the numbers of primary, secondary and antral follicles, and corpora lutea, which were relieved by pup-GW or application of VAP. The findings indicate that prenatal exposure to PFNA through increased FGF21 production in postnatal female offspring impedes postnatal activation of SCN-VAP neurons, which suppresses pubertal onset in AVPV-kisspeptin neurons and reproductive endocrine axis, leading to delayed puberty and dysfunction of ovaries.

Benzo[a]pyrene exposure induced reproductive endocrine-disrupting effects via the steroidogenic pathway and estrogen signaling pathway in female scallop Chlamys farreri.

Benzo[a]pyrene (B[a]P), as one of the typical polycyclic aromatic hydrocarbons and environmental contaminants, may cause endocrine disrupting effects and reproductive impairments in bivalves. However, the molecular mechanisms are still not fully understood. In this study, three reproductive stages (proliferative stage, growing stage and mature stage) of female scallops Chlamys farreri were exposed to B[a]P at 0, 0.38 and 3.8 µg/L. The present study determined the adverse effects of B[a]P on gonadosomatic index, circulating hormone concentrations, endocrine-associated gene expression and ovarian histology. Significant decrease in sex hormones including progesterone (P), testosterone (T) and 17ß-estradiol (E2), was observed in B[a]P-treated C. farreri at growing stage and mature stage. These effects were associated with down-regulated expression of steroidogenic enzymes, including 3ß-HSD, CYP17 and 17ß-HSD, which were regulated by the upstream adenylate cyclase (Adcy) - protein kinase (PKA) signaling pathway. Ovarian transcript levels of estrogen receptor (ER) and caveolin-1 (cav-1) were decreased in B[a]P-treated C. farreri. Vitellogenin (Vtg), an estrogen-mediated gene involved in ovarian development, was down-regulated by B[a]P. Furthermore, ovarian histology was investigated to clarify the impairment of B[a]P on ovaries at growing stage and mature stage. Overall, the present results elucidated the anti-estrogenic mechanisms along the steroidogenic pathway and estrogen signaling pathway for the stage-dependent endocrine-disrupting effects of B[a]P. This finding provides important information regarding to the underlying molecular mechanisms of B[a]P-induced endocrine disruption in different reproductive stages of bivalves. In addition, the adverse effects should be taken into concertation during protection of bivalves germplasm resources and comprehensive evaluation of ecological risks.

Review of the Reproductive Toxicity of T-2 Toxin.

T-2 toxin, an inevitable environmental pollutant, is the most toxic type A trichothecene mycotoxin. Reproductive disruption is a key adverse effect of T-2 toxin. Herein, this paper reviews the reproductive toxicity of T-2 toxin and its mechanisms in male and female members of different species. The reproductive toxicity of T-2 toxin is evidenced by decreased fertility, disrupted structures and functions of reproductive organs, and loss of gametogenesis in males and females. T-2 toxin disrupts the reproductive endocrine axis and inhibits reproductive hormone synthesis. Furthermore, exposure to T-2 toxin during pregnancy results in embryotoxicity and the abnormal development of offspring. We also summarize the research progress in counteracting the reproductive toxicity of T-2 toxin. This review provides information toward a comprehensive understanding of the reproductive toxicity mechanisms of T-2 toxin.