Effects and mechanisms of endocrine disruptor bisphenol AF on male reproductive health: A mini review.

Bisphenol AF (BPAF), an analogue of bisphenol A (BPA), is commonly found in manufacturing industries and known for its endocrine-disrupting properties. Despite potential similarities in adverse effects with BPA, limited toxicological data exist specifically for BPAF and its impact on male reproductive physiology. This mini-review aims to elucidate the influence of BPAF on the male reproductive system, focusing on estrogenic effects, effects on the hypothalamus-pituitary-gonad (HPG) axis, steroidogenesis, spermatogenesis, and transgenerational reproductive toxicity. Additionally, we outline the current insights into the potential mechanisms underlying BPAF-induced male reproductive disorders. BPAF exposure, either directly or maternally, has been associated with detrimental effects on male reproductive functions, including damage to the blood-testis barrier (BTB) structure, disruptions in steroidogenesis, testis dysfunction, decreased anogenital distance (AGD), and defects in sperm and semen quality. Mechanistically, altered gene expression in the HPG axis, deficits in the steroidogenesis pathway, activation of the aromatase pathway, cascade effects induced by reactive oxygen species (ROS), activation of ERK signaling, and immunological responses collectively contribute to the adverse effects of BPAF on the male reproductive system. Given the high prevalence of male reproductive issues and infertility, along with the widespread environmental distribution of bisphenols, this study provides valuable insights into the negative effects of BPAF. The findings underscore the importance of considering the safe use of this compound, urging further exploration and regulatory attention to decrease potential risks associated with BPAF exposure.

[Male reproductive damage caused by phthalate esters: Progress in research].

Phthalate esters are plasticizers that people are often exposed to in daily life. They are closely related to our lives and generally exist in the air, soil and water. Studies show that the exposure to phthalates is associated with male reproductive damage. When the concentration of phthalates reaches a certain level in the body, it can reduce the count and motility of sperm, induce abnormalities in the reproductive system and organs, and affect male fertility. This review summarizes the advances in the studies of the metabolic pathway of phthalate esters in the human body, the mechanism underlying their damage to the male reproductive system and their antagonistic effect.

Per- and polyfluoroalkyl substances (PFAS) and male reproductive function in young adulthood; a cross-sectional study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large family of persistent industrial chemicals with endocrine disrupting properties. OBJECTIVES: To examine biomarkers of reproductive function in young adult males according to current environmental exposure to single and combined PFAS. METHODS: The study population consisted of young men (n = 1041, age 18-21) from the Fetal Programming of Semen Quality (FEPOS) cohort. These men were recruited from pregnancies included in the Danish National Birth Cohort (DNBC) between 1996 and 2002. From 2017 to 2019, participants answered an online questionnaire, completed a clinical examination and provided a blood and a semen sample. Exposure to 15 PFAS was measured in plasma. Six compounds were quantified above the limit of detection in at least 80% of the participants. We applied negative binomial regression and weighted quantile sum (WQS) regression models to assess associations between single and combined exposure to PFAS and measures of semen quality, testicular volume and reproductive hormones among the young men. RESULTS: We found no consistent associations between plasma concentrations of PFAS, semen quality and testicular volume. Higher levels of single and combined PFAS were associated with slightly higher levels of follicle-stimulating hormone (FSH) (WQS 4% difference, 95% confidence interval: 0, 9). Perfluorooctanoic acid (PFOA) was the main contributor to this finding with positive signals also from perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS). DISCUSSION: We examined exposure to a range of common PFAS in relation to biomarkers of male reproductive function and found an association with higher levels of FSH among young men from the general population in Denmark. Further studies on especially combined exposure to PFAS are needed to expand our understanding of potential endocrine disruption from both legacy and emerging compounds in relation to male reproductive function.

Generating adverse outcome pathway (AOP) of inorganic arsenic-induced adult male reproductive impairment via integration of phenotypic analysis in comparative toxicogenomics database (CTD) and AOP wiki.

BACKGROUND: Inorganic arsenic (iAs) is a worldwide environmental pollutant which exerts complicated and various toxic effects in organisms. Increasingly epidemic studies have revealed the association between iAs exposure and adult male reproductive impairment. Consistent with the proposal for toxicity testing in the 21st century (TT21C), the adverse outcome pathway (AOP) framework may help unravel the iAs-caused molecular and functional changes leading to male reproductive impairment. METHOD: Combining CTD's phenotype-disease inference data, iAs-phenotypes were anchored to five male reproductive diseases induced by iAs, and local network topological algorithm was applied in prioritizing their interference significance. Through integrating analysis in AOP Wiki knowledge base, filtered phenotypes were linked to key events consisting of AOPs and assembled together based on evidentially upstream and downstream relationships. RESULTS: A subset of 655 phenotypes were filtered from CTD as potential key events and showed a significant coherence in five reproductive diseases wherein 39 significant phenotypes showed a good clustering features involving cell cycle, ROS and mitochondria function. Two AOP subnetworks were enriched in AOP Wiki where testosterone reduction and apoptosis of sperm served as focus events respectively. Besides, a candidates list of molecular initialing events was provided of which glucocorticoid receptor activation was overall assessed as an example. CONCLUSION: This study applied computational and bioinformatics methods in generating AOPs for arsenic reproductive toxicity, which identified the imperative roles of testosterone reduction, response to ROS, spermatogenesis and provided a global view about their internal association. Furthermore, this study helped address the existing knowledge gaps for future experimental verification.

Evaluation of dietary dose administration as an alternative to oral gavage in the rodent uterotrophic and Hershberger assays.

The rodent uterotrophic and Hershberger assays evaluate potential estrogenic and (anti)-androgenic effects, respectively. Both US EPA and OECD guidelines specify that test substance is administered daily either by subcutaneous injection or oral gavage. However, dietary administration is a relevant exposure route for agrochemical regulatory toxicology studies due to potential human intake via crop residues. In this study, equivalent doses of positive control chemicals administered via dietary and gavage routes of administration were compared in the uterotrophic (17α-ethinyl estradiol) and Hershberger (flutamide, linuron, dichloro-2,2-bis(4-chlorophenyl) ethane; 4,4'-DDE) assays in ovariectomized and castrated rats, respectively. For all positive control chemicals tested, statistically significant changes in organ weights and decreases in food consumption were observed by both routes of test substance administration. Decreased body weight gain observed for dietary linuron and 4,4'-DDE indicated that the maximum tolerated dose was exceeded. Hershberger dietary administration resulted in a similar blood exposure (AUC24) for each positive control chemical when compared to gavage. Overall, the correlation in organ weight changes for both the uterotrophic and Hershberger assays suggest that dietary administration is an acceptable route of exposure with similar sensitivity to oral gavage dosing for evaluation of the endocrine potential of a test substance and represents a more appropriate route of test substance administration for most environmental exposure scenarios.

Metal Oxide Nanoparticles: Evidence of Adverse Effects on the Male Reproductive System.

Metal oxide nanoparticles (MONPs) are inorganic materials that have become a valuable tool for many industrial sectors, especially in healthcare, due to their versatility, unique intrinsic properties, and relatively inexpensive production cost. As a consequence of their wide applications, human exposure to MONPs has increased dramatically. More recently, their use has become somehow controversial. On one hand, MONPs can interact with cellular macromolecules, which makes them useful platforms for diagnostic and therapeutic interventions. On the other hand, research suggests that these MONPs can cross the blood-testis barrier and accumulate in the testis. Although it has been demonstrated that some MONPs have protective effects on male germ cells, contradictory reports suggest that these nanoparticles compromise male fertility by interfering with spermatogenesis. In fact, in vitro and in vivo studies indicate that exposure to MONPs could induce the overproduction of reactive oxygen species, resulting in oxidative stress, which is the main suggested molecular mechanism that leads to germ cells' toxicity. The latter results in subsequent damage to proteins, cell membranes, and DNA, which ultimately may lead to the impairment of the male reproductive system. The present manuscript overviews the therapeutic potential of MONPs and their biomedical applications, followed by a critical view of their potential risks in mammalian male fertility, as suggested by recent scientific literature.

Differential Disrupting Effects of Prolonged Low-Dose Exposure to Dichlorodiphenyltrichloroethane on Androgen and Estrogen Production in Males.

Dichlorodiphenyltrichloroethane (DDT) is the most widespread, persistent pollutant and endocrine disruptor on the planet. Although DDT has been found to block androgen receptors, the effects of its low-dose exposure in different periods of ontogeny on the male reproductive system remain unclear. We evaluate sex steroid hormone production in the pubertal period and after maturation in male Wistar rats exposed to low doses of o,p'-DDT, either during prenatal and postnatal development or postnatal development alone. Prenatally and postnatally exposed rats exhibit lower testosterone production and increased estradiol and estriol serum levels after maturation, associated with the delayed growth of gonads. Postnatally exposed rats demonstrate accelerated growth of gonads and higher testosterone production in the pubertal period. In contrast to the previous group, they do not present raised estradiol production. All of the exposed animals exhibit a reduced conversion of progesterone to 17OH-progesterone after sexual maturation, which indicates putative attenuation of sex steroid production. Thus, the study reveals age-dependent outcomes of low-dose exposure to DDT. Prenatal onset of exposure results in the later onset of androgen production and the enhanced conversion of androgens to estrogens after puberty, while postnatal exposure induces the earlier onset of androgen secretion.

The Role of Selected Natural Biomolecules in Sperm Production and Functionality.

Emerging evidence from in vivo as well as in vitro studies indicates that natural biomolecules may play important roles in the prevention or management of a wide array of chronic diseases. Furthermore, the use of natural compounds in the treatment of male sub- or infertility has been proposed as a potential alternative to conventional therapeutic options. As such, we aimed to evaluate the effects of selected natural biomolecules on the sperm production, structural integrity, and functional activity. At the same time, we reviewed their possible beneficial or adverse effects on male reproductive health. Using relevant keywords, a literature search was performed to collect currently available information regarding molecular mechanisms by which selected natural biomolecules exhibit their biological effects in the context of male reproductive dysfunction. Evidence gathered from clinical trials, in vitro experiments and in vivo studies suggest that the selected natural compounds affect key targets related to sperm mitochondrial metabolism and motion behavior, oxidative stress, inflammation, DNA integrity and cell death. The majority of reports emphasize on ameliorative, stimulating and protective effects of natural biomolecules on the sperm function. Nevertheless, possible adverse and toxic behavior of natural compounds has been indicated as well, pointing out to a possible dose-dependent impact of natural biomolecules on the sperm survival and functionality. As such, further research leading to a deeper understanding of the beneficial or adverse roles of natural compounds is necessary before these can be employed for the management of male reproductive dysfunction.

The effects of cannabidiol on male reproductive system: A literature review.

Cannabidiol (CBD) is one of the most abundant phytocannabinoids present in the plant Cannabis sativa (marijuana). There have been several studies of CBD in the last few decades, mainly focused on its neuroprotective properties, particularly after the identification of the endocannabinoid system and its participation in the central nervous system. On the other hand, the peripheral effects of CBD, particularly on reproductive physiology, were also evidenced. A narrative review was conducted using the PubMed database to identify studies that analyzed the pharmacological effects of CBD on the male reproductive system of vertebrates and invertebrates. Thirty-two citations (in vivo and in vitro) were identified. Among the vertebrates, the studies were carried out with men, monkeys, rats and mice. Studies with invertebrates are centered exclusively on the sea urchin. The CBD treatment periods include mostly acute and subacute evaluations. Exposure to CBD is associated with a reduction in mammalian testis size, the number of germ and Sertoli cells in spermatogenesis, fertilization rates, and plasma concentrations of hypothalamic, pituitary and gonadal hormones. Moreover, chronic doses of CBD have impaired sexual behavior in mice. From the studies identified in this review, it is possible to conclude that CBD has negative effects on the reproductive system of males. However, knowledge is still limited, and additional research is required to elucidate fully the mechanisms of action, as well as the reversibility of CBD effects on the reproductive system.

In vivo effects of black tea on the male rat reproductive system and functions of the kidney and liver.

This study focused on the effects of black tea on the male reproductive system as well as the kidney and liver functions. Male Wistar rats were given aqueous extract of black tea (2% and 5%) for 52 days as the only means of drinking fluid, while control rats received tap water. Black tea enhanced sperm vitality (44%-49%), total sperm motility (10%-12%) and acrosome reaction (2%-9%) (p < .05). Body weight gain, testis, epididymis, seminal vesicles, prostate, liver weight, testosterone level, sperm concentration, ferric reducing antioxidant power (FRAP) and antioxidant levels in the testes, liver and kidney remained unchanged (p > .05). Black tea (5%) increased kidney weight (p < .05). Testis and epididymis showed normal histological appearance. However, black tea significantly reduced the diameter (9%-10%) and epithelial height (9%-10%) of the seminiferous tubule, but increased the epithelial height of the cauda epididymis (8%-24%) (p < .05). A significant reduction in serum levels of alanine aminotransaminase (ALT) (38%) and aspartate aminotransaminase (AST) (23%-34%) was observed (p < .05); creatinine level, on the other hand, increased (8%-72%) (p < .05). Black tea improved several sperm parameters, but may cause subtle changes in certain reproductive organs and the kidney functions.

[Mechanism of Effects of Genistein on the Reproductive System of Prepubertal Male Rats].

OBJECTIVE: To study the effects of genistein (GEN) on reproductive system in prepubertal male rats. METHODS: Thirty SPF-rated male SD rats were randomly divided into control group (Con group), low-dose group (G1 group) and high-dose group (G2 group), with 10 rats in each group. Corn oil, 150 mg/kg and 300 mg/kg GEN dissolved in corn oil of equal volume were respectively administered every day and weighed the next day. After 6 weeks, the rats were sacrificed, and the testis, epididymis and prostate were dissected, and organ coefficients were calculated. Histopathological changes of testis was observed. The number of sperm was counted and the rate of sperm malformation was calculated. The concentrations of serum testosterone and estradiol were detected by radioimmunoassay. The protein phosphatase 2, regulatory subunit B, gamma (PPP2R2C) protein expression in testicular tissue was detected by immunofluorescence assay. The mRNA and protein expression levels of PPP2R2C and cyclin dependent protein kinases 2 (CDK2) in rat testis were detected by real-time quantitative fluorescence PCR (RT-qPCR) and Western blot, respectively. The protein phosphatase 2A (PP2A) activity in testicular tissue was detected by immunoprecipitation. RESULTS: There were no statistically significant differences in body mass, sperm number, serum estradiol and PP2A enzyme activity among the groups ( P>0.05). The pathological structure of testicular in G2 group was disordered. Sperm abnormality rate in G1 and G2 groups was higher than that in Con group ( P<0.05). Serum testosterone concentration in G2 group was lower than that in Con group ( P<0.05). The expression of PPP2R2C and CDK2 in G2 group was higher than that in Con group ( P<0.05), but the protein level was lower than that in Con group ( P<0.05). PPP2R2C protein was expressed in testicular tissue in each group. CONCLUSION: Long-term exposure to high dose (300 mg/kg) GEN during prepuberty may cause adverse effects on reproductive function in adult male rats. Further investigation is needed to determine whether PPP2R2C-PP2A-CDK2 phosphorylation pathway affects reproductive system in rats.

[Effect of Tripterygium Glycosides Tablets on reproductive toxicity in male rats with â ¡ type collagen induced arthritis].

The aim of this paper was to observe the toxic effect of Tripterygium Glycosides Tablets on the reproductive system of Ⅱ type collagen induced arthritis(CIA) male rats, and to explore the toxic mechanism preliminarily. Fifty SD rats were randomly divided into normal control group(Con), model group(CIA), Tripterygium Glycosides Tablets clinical equivalent dose groups of 1, 2, 4 times(9, 18, 36 mg·kg~(-1)), 10 rats in each group, and were given by gavage once a day for 42 days after the first immunization. The organ index of testis and epididymis were calculated on days 21 and 42. Histopathological and morphological changes of testis and epididymis were observed under optical microscope. Sperm count, sperm malformation rate and sperm kinetic parameters in epididymal tissues were observed by computer assisted sperm analysis(CASA). The concentration of testosterone(T), nitric oxide synthase(NOS) and aromatase(CYP19 A1) in serum were detected by ELISA. Immunohistochemistry was used to observe the expression of Bax and Bcl-2 related proteins in the apoptosis pathway of testis and epididymis. The results showed that, compared with Con group, CIA group significantly increased the rate of testicular spermatogenic tubule lesion and sperm malformation, decreased the average path speed, and no significant changes were observed in other groups. Tripterygium Glycosides Tablets at 4 times clinical equivalent dose can significantly reduce the testis index(P<0.01), each dose group can reduce the epididymis index(P<0.05). Each dose group of Tripterygium Glycosides Tablets could cause different degrees of damage to the testis and epididymis, the proportion of testicular histopathology lesions increased, the number of spermatogenic cells in the seminiferous tubules decreased, and so on. It could reduce the number of sperm, increase the rate of sperm deformity, make the parameters of sperm dynamics abnormal, and so on. Tripterygium Glycosides Tablets at 4 times dose could significantly reduce the content of serum sex hormone T and key enzyme of androgen synthesis(P<0.05 or P<0.01), but had no effect on CYP19 A1. The expression of Bax and Bcl-2 in testis and epididymis were increased by 2 and 4 times doses of Tripterygium Glycosides Tablets(P<0.05, P<0.01 or P<0.01). The results showed that 21 d administration of Tripterygium Glycosides Tablets at equal or higher doses could induce obvious toxic effect to the reproductive organs of CIA male rats, and lower the level of serum sex hormone T and the key enzyme of androgen synthesis, NOS. The mechanism of abnormal changes of Bax and Bcl-2 in Testis and epididymis is still to be elucidated.

CBLB502, a Toll-like receptor 5 agonist, offers protection against radiation-induced male reproductive system damage in mice.

CBLB502, a Toll-like receptor (TLR)5 agonist derived from Salmonella flagellin, was shown to protect mammalian hematopoietic and gastrointestinal systems from acute irradiation syndrome and to stimulate regeneration. To explore whether CBLB502 can improve testicular injuries caused by irradiation, mice were intraperitoneally injected with 0.2 mg/kg CBLB502 or vehicle control 30 min prior to applying 5.0 Gy ionizing radiation (IR). We observed these mice for the following 120 days and determined that CBLB502 pretreatment alleviated IR-induced oxidative stress, alleviated the distorted architecture of seminiferous tubules, reversed the decline of sperm quantity and quality, and helped recover male mouse fertility. Additionally, CBLB502 efficiently reduced DNA damage and chromosomal aberrations in IR-treated mice and their offspring. Due to the suppression of p53-dependent apoptosis, in IR-treated mice, CBLB502 was shown to significantly activate the nuclear factor kappa B (NFκB) pathway and reduce the apoptotic rate in association with an increase in anti-apoptotic B-cell lymphoma 2 levels and a decrease in the levels of DNA repair protein and proliferating cell nuclear antigen. Moreover, an IR-induced reduction in serum testosterone and superoxide dismutase levels and an increase in malondialdehyde levels were considerably reversed in CBLB502-pretreated mice. No significant reverse effects were found in Tlr5 knockout mice, suggesting that protection of the testis against IR by CBLB502 is primarily dependent on the TLR5 signaling pathway. Our results may help further investigations into potential CBLB502 applications for the protection of the male reproductive system during radiotherapy.

Maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances during pregnancy and anogenital distance in male infants.

STUDY QUESTION: Are maternal plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFASs) during pregnancy associated with anogenital distance (AGD) in male infants at birth, 6, and 12 months of age? SUMMARY ANSWER: Higher maternal plasma concentrations of some PFASs were associated with shorter AGD in male infants at birth and 6 months of age. WHAT IS KNOWN ALREADY: Two animal studies have found that exposure to PFASs was associated with shorter AGD in male rat fetuses and wild male minks. There is only one human study on the topic that did not identify consistent patterns between maternal serum concentrations of PFASs during pregnancy and AGD in male infants. STUDY DESIGN, SIZE, DURATION: In the prospective cohort study, a total of 1292 eligible pregnant women were recruited at 12-16 weeks of gestation between April and December 2012 at the Maternal and Child Health Hospital of Minhang district in Shanghai, China. At delivery, 667 male singletons were born. They were then followed up at birth (n = 439) and at 6 (n = 411) and 12 months (n = 376) of age when anopenile distance (AGDAP) and anoscrotal distance (AGDAS) were measured. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 500 male infants who had both maternal plasma concentrations of PFASs and at least one AGD measurement of at three time points were included in the present study. Multiple linear regression models were used to evaluate the potential linear associations between maternal concentrations of PFASs and AGD. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal plasma concentrations (ln-transformed) of perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA) were inversely associated with AGDAS or AGDAP at birth (AGDAS: per ln unit increase in PFAS concentrations: ß (95% CI): -0.65 (-1.27 to -0.02) mm for PFOS; -0.58 (-1.11 to -0.06) mm for PFDA; and -0.57 (-1.09 to -0.06) mm for PFUdA; AGDAP: per ln unit increase in PFAS concentrations: ß (95% CI): -0.63 (-1.24 to -0.01) mm for PFDA and - 0.76 (-1.36 to -0.16) mm for PFUdA). At 6 months of age, per unit increase in maternal ln concentrations of PFOS and perfluorotridecanoic acid (PFTrDA), AGDAS decreased on average by -2.21 (95% CI: -4.28 to -0.14) and -1.11 (95% CI: -2.17 to -0.06) mm, respectively. Additionally, ln-transformed perfluorooctanoic acid (PFOA) showed nonsignificant but inverse associations with both AGDAS and AGDAP at 6 months of age. We found no significant associations between ln-transformed maternal concentrations of PFASs and either AGDAS or AGDAP at 12 months of age. However, significantly inverse association of ln-transformed PFOA with AGDAP was observed in male infants who never or shortly breastfed (<3 months) at 12 months of age. LIMITATIONS, REASONS FOR CAUTION: AGD measurements were performed by different examiners at each follow-up visit, and the intra-examiner variation was not assessed, which might cause intra-rater and inter-rater measurement errors. Additionally, our study may have selection bias since a considerable number of participants withdrew from the cohort although the differences in demographic characteristics were not statistically significant between included mother-infant pairs and those excluded. No statistical correction was made for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may have important implications for the early development of genital health in male infants since PFASs can be detected in almost all pregnant women and infants worldwide. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development program of China (2018YFC1002801 and 2016YFC1000505), the Science and Technology Commission of Shanghai Municipality (16ZR1430100), the National Natural Science Foundation of China (81428011), and the Innovation-Oriented Science and Technology Grant from National Health Commission Key Laboratory of Reproduction Regulation (CX2017-06). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effects of androgen and oestrogen on IGF pathways controlling phallus growth.

The development of the mammalian phallus involves hormone-dependent mesenchymal-epithelial signalling mechanisms that contribute to urethral closure and regulation of phallus elongation and growth. In marsupials, most differentiation and growth of the phallus occurs post-natally, making them amenable to direct hormone treatment. Expression of IGFs, FGFs, EFNB2, MAFB, DLX5 and AP-1 mRNAs in the phallus at day 50 post-partum (pp) were altered after treatment of tammar wallaby young from day 20 to 40 pp with androgen, oestrogen or after castration at day 25 pp. However, the most interesting changes occurred in the IGF pathway genes. Androgen treatment upregulated IGF1 in female phalluses and oestrogen treatment upregulated IGF1 in male phalluses, but it was downregulated by castration. IGFBP3 was higher in female phalluses and downregulated by androgen. IGF1 expression was higher in all untreated male than in female phalluses from day 50 to 150 pp, but IGFBP3 had the reverse pattern. At day 90 pp, when urethral closure in males is progressing and male phallus growth is accelerating. IGF1 and PCNA protein were only detected in the male urorectal septum, suggesting for the first time that closure and elongation may involve IGF1 activation of cell proliferation specifically in male phalluses. These effects of sex steroids on gene expression and on the IGF1 signalling pathway in particular, suggest that the developing phallus may be especially susceptible to perturbation by exogenous hormones.

Low dose of flurochloridone affected reproductive system of male rats but not fertility and early embryonic development.

BACKGROUND: Fluorochloridone (FLC) is a widely used herbicide, and its target organs are testes and epididymides. The Globally Harmonized System of Classification and Labelling of Chemicals classified FLC as Level 2-possibly cause fertility or fetal damage (no relevant data support). The maximum residue levels of FLC in processed crops have been reviewed in the latest European Food Safety Authority (EFSA) report in 2018. However, the toxic effect of FLC on fertility and early embryonic development is limited, and the health risk assessment of FLC needs further consideration. This study investigated the potential effects of FLC on fertility and early embryonic development in rats. METHODS: One hundred rats of each sex were divided into four groups including three FLC-treated groups at doses of 2 mg/kg, 5 mg/kg and 15 mg/kg, and a vehicle control group (0.5% (w/v) sodium carboxymethyl cellulose). Male and female rats were dosed for 9 and 2 consecutive weeks, intragastrically, prior to cohabitation and lasted throughout the mating period for males and continued until Gestation Day 7 (GD7) for females. Parameters such as weights and coefficients of reproductive organs, epididymal sperm number and motility, indexes of copulation, fecundity and fertility indexes, mating period, estrous cycle, corporalutea number, implantations, live, dead and resorbed fetuses, preimplantation loss rate, and postimplantation loss rate were observed in this study. RESULTS: Obvious toxicity of male reproductive system was found at the dose of 15 mg/kg including decreases in testicular and epididymal weight, also in sperm motility rate. Whereas the increase in sperm abnormality rate was observed. However, no significant effects of FLC were found on lutea count, implantations count, fetuses count and weight, live fetuses count (rate), dead fetuses count (rate), resorbed fetuses count (rate), placentas weight, fetuses gender, preimplantation loss (rate) and postimplantation loss (rate). Furthermore, FLC had no adverse effects on fertility and early embryonic development in rats. CONCLUSION: The no-observable-adverse-effect level (NOAEL) of FLC on fertility and early embryonic development in rats was considered to be 5 mg/kg/day.

Prenatal exposure to an environmentally relevant phthalate mixture disrupts testicular steroidogenesis in adult male mice.

Endocrine disrupting chemicals (EDCs) in the environment are considered to be a contributing factor to the decline in the sperm quality. With growing evidence of the harmful effects of EDCs on the male reproductive system, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects reproductive outcomes and androgen synthesis. In this study, an environmentally relevant composition of phthalates (15% DiNP, 21% DEHP, 36% DEP, 15% DBP, 8% DiBP, and 5% BBzP) that were detected in urine samples of pregnant women in Illinois, United States, was used. Pregnant CD-1 mice (F0) were orally dosed with a vehicle or the phthalate mixtures (20 µg/kg/day, 200 µg/kg/day, 200 mg/kg/day, or 500 mg/kg/day) from gestational day 10.5 to the day of birth. Then, the indices of the reproductive function of the F1 males born to these dams were assessed. Those male mice prenatally exposed to the phthalate mixture had smaller gonads, prostates and seminal vesicles, especially in the 20 µg/kg/day and 500 mg/kg/day phthalate mixture groups, compared to the controls. Importantly, at the age of 12 months, those prenatally exposed mice had significantly lower serum testosterone concentrations accompanied by the decreased mRNA expression of testicular steroidogenic genes (StAR, Cyp11, and Cyp17) and impaired spermatogenesis. Taken together, this study found that prenatal exposure to environmentally relevant doses of a phthalate mixture caused a life-long impact on the reproduction in male mice.

The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system.

BACKGROUND: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats. METHODS: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups. RESULTS: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure. CONCLUSIONS: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.

Uroplakin expression in the male reproductive tract of rat.

Uroplakins (UPKs) play an important role in the normal and pathophysiology of the urothelium. They protect the urothelium and play a crucial role during urothelial infections by Uropathogenic E. coli. However, their functions beyond this organ system remain unexplored. A wide variety of proteins secreted in the male reproductive tract tissues contribute to spermatogenesis, sperm maturation, fertilization and innate immunity. However, the presence of UPKs and their possible contribution to the male reproductive tract physiology is not yet reported. Hence, in this study, we characterized UPKs in the male reproductive tract of rats. To the best of our knowledge, for the first time, we report the expression of UPKs in the male reproductive system. Upk1a, Upk1b, Upk2 and Upk3b mRNA and their corresponding proteins were abundantly expressed in the caput, cauda, testis, seminal vesicles and the prostate. Their expression was not developmentally regulated. UPK protein expression was also localized on the spermatozoa, suggesting a role for these proteins in sperm function. To study the role of UPKs in innate immunity, Upk mRNA expression in response to endotoxin challenge was evaluated in vitro and in vivo. In the rat testicular and epididymal cell lines, Upk mRNA levels increased in response to lipopolysaccharide challenge. However, in the caput, cauda, testes, seminal vesicle and prostate obtained from LPS treated rats, Upk mRNA expression was significantly reduced. Results of this study indicate a role for UPKs in male reproductive physiology and innate immune responses.

Surgical management of retained needle in a transgender woman's phallus.

Intracavernosal self-injection (ICI) is an effective treatment for erectile dysfunction. A rare but serious complication is needle breakage. We report an unusual case of a 51-year-old transgender female patient who did not desire gender-affirming surgery, and used ICI to treat her longstanding erectile dysfunction. She presented to the emergency department 2 months after needle breakage during ICI, and was subsequently successfully treated with intraoperative fluoroscopy and needle fragment extraction. It is important to recognize transgender patients may desire to preserve sexual function, and for providers to engage in discussion surrounding sexual health throughout treatment for gender dysphoria.