Genome-wide transcriptome analysis reveals that Bisphenol A activates immune responses in skeletal muscle.

Cumulative human exposure to the environmental toxin, bisphenol A (BPA), has raised important health concerns in recent decades. However, the direct genomic regulation of BPA in skeletal muscles and its clinical significance are poorly understood. Therefore, we conducted a genome-wide transcriptome analysis after daily oral administration of BPA at the lowest observed adverse-effect level (LOAEL, 50 mg/kg) in male mice for six weeks to explore the gene-expression regulations in skeletal muscle induced by BPA. The primary Gene Ontology terms linked to BPA-dependent, differentially expressed genes at LOAEL comprised adaptive-immune response, positive regulation of T cell activation, and immune system process. The gene-set enrichment analysis disclosed increased complement-associated genes [complement components 3 (C3) and 4B, complement factor D, complement receptor 2, and immunoglobulin lambda constant 2] in the group administered with BPA, with a false-discovery rate of <0.05. Subsequent validation analysis conducted in BPA-fed animal skeletal muscle tissue and in vitro experiments confirmed that BPA induced immune activation, as evidenced by increased levels of C3 and C4α proteins in mice, C2C12 myoblasts, and mouse skeletal muscle cells. In addition, BPA markedly upregulated the transcription of tumor necrosis factor-α (Tnfα) in C2C12 myoblasts and mouse skeletal muscle cells, which was substantially inhibited by 5z-7-oxozeanol and parthenolide, providing further evidence of BPA-induced inflammation in muscle cells. Our bioinformatics and subsequent animal and in vitro validations demonstrate that BPA can activate inflammation in skeletal muscle, which could be a risk factor underlying chronic muscle weakness and wastage.

Variations in biophysical characteristics of mangroves along retreating and advancing shorelines.

Mangrove shoreline retreat or advance is a natural process in a mangrove delta. However, due to various natural and anthropogenic stressors, mangrove shoreline retreat is the second largest cause of mangrove loss globally. It is important to understand the scale at which mangrove shoreline changes are causing biophysical changes along the mangrove shorelines and, in turn, understand if certain biophysical characteristics can explain the changes along the shoreline. This will help identify the response of mangroves to shoreline changes. Videography and spatial mapping were used to study temporarily and permanently changing mangrove shorelines in the Sundarbans, the largest mangrove forest in the world (~10,000 km2), located in India and Bangladesh. Data was collected along a ~ 239 km shoreline at 54 sites. 36.4 % of all the studied shorelines were experiencing major retreat, 63.8 % and 27.2 % of all (major and minor) retreating areas had 1-25 % and > 25 % dead trees. The biophysical characteristics statistically (P < 0.0001) associated with retreating mangrove shorelines were - cliff-type shoreline profiles, number of dead trees, and absence of stream and grass, with shoreline profiles as the strongest predictor of shoreline retreat. Moreover, 68.7 % and 73 % of historically retreating shorelines had a cliff-type shoreline profile and Excoecaria agallocha as the dominating species, respectively. Moreover, due to the strong correlation between historical changes and current shoreline types, it was concluded that characteristics along the shoreline are partly a product of historical shoreline transitions. Thus, the present status of the shoreline can not only predict the history of the shoreline but can also give insights into the future biophysical changes in the mangrove forests.

Bisphenol-A disturbs hormonal levels and testis mitochondrial activity, reducing male fertility.

STUDY QUESTION: How does bisphenol-A (BPA) influence male fertility, and which mechanisms are activated following BPA exposure? SUMMARY ANSWER: BPA exposure causes hormonal disruption and alters mitochondrial dynamics and activity, ultimately leading to decreased male fertility. WHAT IS KNOWN ALREADY: As public health concerns following BPA exposure are rising globally, there is a need to understand the exact mechanisms of BPA on various diseases. BPA exposure causes hormonal imbalances and affects male fertility by binding the estrogen receptors (ERs), but the mechanism of how it mediates the hormonal dysregulation is yet to be studied. STUDY DESIGN SIZE DURATION: This study consisted of a comparative study using mice that were separated into a control group and a group exposed to the lowest observed adverse effect level (LOAEL) (n = 20 mice/group) after a week of acclimatization to the environment. For this study, the LOAEL established by the US Environmental Protection Agency of 50 mg/kg body weight (BW)/day of BPA was used. The control mice were given corn oil orally. Based on the daily variations in BW, both groups were gavaged every day from 6 to 11 weeks (6-week exposure). Before sampling, mice were stabilized for a week. Then, the testes and spermatozoa of each mouse were collected to investigate the effects of BPA on male fertility. IVF was carried out using the cumulus-oocyte complexes from female hybrid B6D2F1/CrljOri mice (n = 3) between the ages of eight and twelve weeks. PARTICIPANTS/MATERIALS SETTING METHODS: Signaling pathways, apoptosis, and mitochondrial activity/dynamics-related proteins were evaluated by western blotting. ELISA was performed to determine the levels of sex hormones (FSH, LH, and testosterone) in serum. Hematoxylin and eosin staining was used to determine the effects of BPA on histological morphology and stage VII/VIII testicular seminiferous epithelium. Blastocyst formation and cleavage development rate were evaluated using IVF. MAIN RESULTS AND THE ROLE OF CHANCE: BPA acted by binding to ERs and G protein-coupled receptors and activating the protein kinase A and mitogen-activated protein kinase signaling pathways, leading to aberrant hormone levels and effects on the respiratory chain complex, ATP synthase and protein-related apoptotic pathways in testis mitochondria (P < 0.05). Subsequently, embryo cleavage and blastocyst formation were reduced after the use of affected sperm, and abnormal morphology of seminiferous tubules and stage VII and VIII seminiferous epithelial cells (P < 0.05) was observed. It is noteworthy that histopathological lesions were detected in the testes at the LOAEL dose, even though the mice remained generally healthy and did not exhibit significant changes in BW following BPA exposure. These observations suggest that testicular toxicity is more than a secondary outcome of compromised overall health in the mice due to systemic effects. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: Since the protein expression levels in the testes were validated, in vitro studies in each testicular cell type (Leydig cells, Sertoli cells, and spermatogonial stem cells) would be required to shed further light on the exact mechanism resulting from BPA exposure. Furthermore, the BPA doses employed in this study significantly exceed the typical human exposure levels in real-life scenarios. Consequently, it is imperative to conduct experiments focusing on the effects of BPA concentrations more in line with daily human exposures to comprehensively assess their impact on testicular toxicity and mitochondrial activity. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate that BPA exposure impacts male fertility by disrupting mitochondrial dynamics and activities in the testes and provides a solid foundation for subsequent investigations into the effects on male reproductive function and fertility following BPA exposure, and the underlying mechanisms responsible for these effects. In addition, these findings suggest that the LOAEL concentration of BPA demonstrates exceptional toxicity, especially when considering its specific impact on the testes and its adverse consequences for male fertility by impairing mitochondrial activity. Therefore, it is plausible to suggest that BPA elicits distinct toxicological responses and mechanistic endpoints based on the particular concentration levels for each target organ. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1A6A1A03025159). No competing interests are declared.

Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics.

Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying an epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in controlling epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation, with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis and resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.

Boar fertility is controlled through systematic changes of mitochondrial protein expression during sperm capacitation.

Vigorous activation of mitochondria in spermatozoa during capacitation induces the biological and morphological changes of spermatozoa to acquire fertilizing ability. To in-depth understand the dynamic roles of mitochondrial and male fertility, this study was to identify how the mitochondrial proteins are changed during sperm capacitation and regulate male fertility using boar spermatozoa. The mitochondrial proteins were differentially changed during sperm capacitation according to fertility status, i.e., superior litter size (SL) and normal litter size (NL). Following sperm capacitation, ubiquitin-cytochrome c reductase core protein (UQCRC1) and ATP synthase F1 (ATP5F1) increased in NL, while cytochrome c oxidase subunit 5B (COX5B), and cytochrome c1 (CYC1) proteins decreased. In contrast, only and ubiquinone oxidoreductase core subunit 8 (NDUFS8) protein was increased in SL following capacitation. The protein expression difference value of CYC1, COX5B, and NDUFS8 following sperm capacitation was lower in NL than SL boars. Based on these complicated changes during sperm capacitation, the accuracy for predicting male fertility of NDUFS8 was increased to 87 %. Overall, considering the systematic orchestration of mitochondrial protein expression according to sperm capacitation status, it will be possible to better understand male fertility.

Environmentally relevant doses of endocrine disrupting chemicals affect male fertility by interfering with sertoli cell glucose metabolism in mice.

The growing global deterioration in several aspects of human health has been partly attributed to hazardous effects of endocrine-disrupting chemicals (EDCs) exposure. Therefore, experts and government regulatory agencies have consistently advocated for studies on the combined effects of EDCs that model human exposure to multiple environmental chemicals in real life. Here, we investigated how low concentrations of bisphenol A (BPA), and phthalates compounds affect the Sertoli cell glucose uptake/lactate production in the testis and male fertility. An EDC mixture containing a detected amount of each chemical compound in humans, called daily exposure (DE), and DE increased in magnitude by 25 (DE25), 250 (DE250), and 2500 (DE2500), and corn oil (control) were administered for six weeks to male mice. We found that DE activated estrogen receptor beta (Erß) and glucose-regulated protein 78 (Grp 78) and disrupted the estradiol (E2) balance. In addition, DE25, DE250, and DE2500 doses of the EDC mixture via binding with Sertoli cells' estrogen receptors (ERs) inhibited the glucose uptake and lactate production processes by downregulating glucose transporters (GLUTs) and glycolytic enzymes. As a result, endoplasmic reticulum stress (ERS), marked by unfolded protein response (UPR) activation, was induced. The accompanying upregulation of activating transcription factor 4 (ATF4), inositol requiring enzyme-1 (IRE1), C/EBP homologous protein (CHOP), and mitogen-activated protein kinase (MAPK) signaling promoted antioxidant depletion, testicular cell apoptosis, abnormal regulation of the blood-testis barrier, and decreased sperm count. Therefore, these findings suggest that human and wildlife exposure to multiple environmental chemicals can produce a wide range of reproductive health complications in male mammals.

Recent Update and Drug Target in Molecular and Pharmacological Insights into Autophagy Modulation in Cancer Treatment and Future Progress.

Recent evidence suggests that autophagy is a governed catabolic framework enabling the recycling of nutrients from injured organelles and other cellular constituents via a lysosomal breakdown. This mechanism has been associated with the development of various pathologic conditions, including cancer and neurological disorders; however, recently updated studies have indicated that autophagy plays a dual role in cancer, acting as a cytoprotective or cytotoxic mechanism. Numerous preclinical and clinical investigations have shown that inhibiting autophagy enhances an anticancer medicine's effectiveness in various malignancies. Autophagy antagonists, including chloroquine and hydroxychloroquine, have previously been authorized in clinical trials, encouraging the development of medication-combination therapies targeting the autophagic processes for cancer. In this review, we provide an update on the recent research examining the anticancer efficacy of combining drugs that activate cytoprotective autophagy with autophagy inhibitors. Additionally, we highlight the difficulties and progress toward using cytoprotective autophagy targeting as a cancer treatment strategy. Importantly, we must enable the use of suitable autophagy inhibitors and coadministration delivery systems in conjunction with anticancer agents. Therefore, this review briefly summarizes the general molecular process behind autophagy and its bifunctional role that is important in cancer suppression and in encouraging tumor growth and resistance to chemotherapy and metastasis regulation. We then emphasize how autophagy and cancer cells interacting with one another is a promising therapeutic target in cancer treatment.

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms.

Autophagy is an evolutionarily conserved cellular system crucial for cellular homeostasis that protects cells from a broad range of internal and extracellular stresses. Autophagy decreases metabolic load and toxicity by removing damaged cellular components. Environmental contaminants, particularly industrial substances, can influence autophagic flux by enhancing it as a protective response, preventing it, or converting its protective function into a pro-cell death mechanism. Environmental toxic materials are also notorious for their tendency to bioaccumulate and induce pathophysiological vulnerability. Many environmental pollutants have been found to influence stress which increases autophagy. Increasing autophagy was recently shown to improve stress resistance and reduce genetic damage. Moreover, suppressing autophagy or depleting its resources either increases or decreases toxicity, depending on the circumstances. The essential process of selective autophagy is utilized by mammalian cells in order to eliminate particulate matter, nanoparticles, toxic metals, and smoke exposure without inflicting damage on cytosolic components. Moreover, cigarette smoke and aging are the chief causes of chronic obstructive pulmonary disease (COPD)-emphysema; however, the disease's molecular mechanism is poorly known. Therefore, understanding the impacts of environmental exposure via autophagy offers new approaches for risk assessment, protection, and preventative actions which will counter the harmful effects of environmental contaminants on human and animal health.

Abnormal histone replacement following BPA exposure affects spermatogenesis and fertility sequentially.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely distributed in the environment. Its exposure has been linked to male infertility in animals and humans due to its ability to induce epigenetic modification. Despite extensive research confirming the impact of BPA on epigenetic regulation, fundamental concerns about how BPA causes epigenetic changes and the underlying mechanism of BPA on the male reproductive system remain unresolved. Therefore, we sought to investigate the effects of BPA on epigenetic regulation and the histone-to-protamine (PRM) transition, which is fundamental process for male fertility in testes and spermatozoa by exposing male mice to BPA for 6 weeks while giving the mice in the control group corn oil by oral gavage. Our results demonstrated that the mRNA levels of the histone family and PRMs were significantly altered by BPA exposure in testes and spermatozoa. Subsequently, core histone proteins, the PRM1/PRM2 ratio, directly linked to male fertility, and transition proteins were significantly reduced. Furthermore, we discovered that BPA significantly caused abnormal histone-to-protamine replacement during spermiogenesis by increased histone variants-related to histone-to-PRM transition. The levels of histone H3 modification in the testes and DNA methylation in spermatozoa were significantly increased. Consequently, sperm concentration/motility/hyperactivation, fertilization, and early embryonic development were adversely affected as a consequence of altered signaling proteins following BPA exposure. To our knowledge, this is the first study to indicate that BPA exposure influences the histone-to-PRM transition via altering epigenetic modification and eventually causing reduced male fertility.

Establishment of a male fertility prediction model with sperm RNA markers in pigs as a translational animal model.

BACKGROUND: Male infertility is an important issue that causes low production in the animal industry. To solve the male fertility crisis in the animal industry, the prediction of sperm quality is the most important step. Sperm RNA is the potential marker for male fertility prediction. We hypothesized that the expression of functional genes related to fertilization will be the best target for male fertility prediction markers. To investigate optimum male fertility prediction marker, we compared target genes expression level and a wide range of field data acquired from artificial insemination of boar semen. RESULTS: Among the genes related to acrosomal vesicle exocytosis and sperm-oocyte fusion, equatorin (EQTN), zona pellucida sperm-binding protein 4 (ZP4), and sperm acrosome membrane-associated protein 3 exhibited high accuracy (70%, 90%, and 70%, respectively) as markers to evaluate male fertility. Combinations of EQTN-ZP4, ZP4-protein unc-13 homolog B, and ZP4-regulating synaptic membrane exocytosis protein 1 (RIMS1) showed the highest prediction value, and all these markers are involved in the acrosome reaction. CONCLUSION: The EQTN-ZP4 model was efficient in clustering the high-fertility group and may be useful for selection of animal that has superior fertility in the livestock industry. Compared to the EQTN-ZP4 model, the ZP4-RIMS1 model was more efficient in clustering the low-fertility group and may be useful in the diagnosis of male infertility in humans and other animals. The appointed translational animal model and established biomarker combination can be widely used in various scientific fields such as biomedical science.

Hepatic consequences of a mixture of endocrine-disrupting chemicals in male mice.

The global epidemic of metabolic syndrome has been partially linked to ubiquitous exposure to endocrine-disrupting chemicals (EDCs). Although the impacts of exposure to single EDCs have been thoroughly studied, the consequences of simultaneous uncontrolled exposure to multiple EDCs require further investigations. Therefore, in this study, we evaluated how exposure to mixtures containing bisphenol A and seven phthalates impacts liver functions and metabolic homeostasis. Male mice were gavaged with either EDCs at four different dose combinations or corn oil (control) for six weeks. The results showed that exposure to EDCs at the human daily exposure limit had a negligible impact on liver function. However, EDC at ≥ 25 orders of magnitude of human-relevant doses had detrimental impacts on overall liver function, leading to metabolic abnormalities, steatohepatitis, and hepatic fibrosis via the activation of both genomic and non-genomic pathways. The metabolic phenotype was linked to alterations in key genes involved in hepatic lipid and glucose metabolism. In contrast, alterations in cytokine expression, oxidative stress, and apoptosis impacted steatohepatitis and fibrosis. Because EDC exposure does not occur independently, the findings of the combined effects of exposure to multiple EDCs have significant relevance for public health.

Systematic multi-omics reveals the overactivation of T cell receptor signaling in immune system following bisphenol A exposure.

Bisphenol A (BPA) is pervasive in the environment, and exposure to BPA may increase the incidence of noncommunicable diseases like autoimmune diseases and cancer. Although BPA causes immunological problems at the cellular level, no system-level research has been conducted on this. Hence, in this study, we aimed to gain a better understanding of the biological response to BPA exposure and its association with immunological disorders. For that, we explored the transcriptome and the proteomic modifications at the systems and cellular levels following BPA exposure. Our integrated multi-omics data showed the alteration of the T cell receptor (TCR) signaling pathway at both levels. The proportion of enlarged T cells increased with upregulation of CD69, a surface marker of early T cell activation, even though the number of T cells reduced after BPA exposure. Additionally, on BPA exposure, the levels of pLCK and pSRC increased in T cells, while that of pLAT decreased. Following BPA exposure, we investigated cytokine profiles and discovered that chitinase 3 Like 1 and matrix metalloproteinase 9 were enriched in T cells. These results indicated that T cells were hyperactivated by CD69 stimulation, and phosphorylation of SRC accelerated on BPA exposure. Hence, alteration in the TCR signaling pathway during development and differentiation due to BPA exposure could lead to insufficient and hasty activation of TCR signaling in T cells, which could modify cytokine profiles, leading to increased environmental susceptibility to chronic inflammation or diseases, increasing the chance of autoimmune diseases and cancer. This study enhances our understanding of the effects of environmental perturbations on immunosuppression at molecular, cellular, and systematic levels following pubertal BPA exposure, and may help develop better predictive, preventative, and therapeutic techniques.

Heat shock protein family D member 1 in boar spermatozoa is strongly related to the litter size of inseminated sows.

BACKGROUND: Sperm quality evaluation is the logical first step in increasing field fertility. Spermatozoa contain cytoplasmic organelles and biomolecules known as sperm-intrinsic factors, which play key roles in sperm maturation, sperm-oocyte fusion, and embryo development. In particular, sperm membrane proteins [e.g., arginine vasopressin receptor 2, beta-actin, prohibitin, and heat shock protein family D member 1 (HSPD1)] and RNA could be used as functional indicators of male fertility. We sought to clarify the effects of differential mRNA expression of selected genes on several fertilisation parameters, including sperm motility, motion kinematics, capacitation, and litter size, in a porcine model. RESULTS: Our results demonstrated that HSPD1 expression was significantly correlated with male fertility, as measured by the litter size of inseminated sows. The expression of HSPD1 mRNA was linked to sperm motility and other motion kinematic characteristics. Furthermore, HSPD1 had a 66.7% overall accuracy in detecting male fertility, and the high-litter size group which was selected with the HSPD1 marker had a 1.34 greater litter size than the low-litter size group. CONCLUSIONS: Our findings indicate that HSPD1 might be a helpful biomarker for superior boar selection for artificial insemination, which could boost field fertility.

Low Sperm Motility Is Determined by Abnormal Protein Modification during Epididymal Maturation.

PURPOSE: During epididymal sperm maturation, spermatozoa acquire progressive motility through dynamic protein modifications. However, the relationship between sequential protein modifications during epididymal sperm maturation and sperm motility and fertility has not yet been investigated. This study investigated whether sequential changes in fertility-related protein expression including that of enolase 1 (ENO1), ubiquinol-cytochrome c reductase core protein 1 and 2 (UQCRC1 and UQCRC2), and voltage-dependent anion channel 2 (VDAC2) in spermatozoa during epididymal maturation are related to bovine sperm motility. Moreover, we found that mitochondrial metabolism is closely related to fertility-related proteins. Therefore, we investigated how the sequential modification of mitochondrial proteins during epididymal maturation regulates sperm motility. MATERIALS AND METHODS: To determine the differential protein expression in caput and cauda epididymal spermatozoa from low and high motility bulls, western blot analysis was performed. Moreover, signaling pathways were identified to understand the mechanisms of regulation of sperm motility through the differential protein expression associated with fertility-related proteins. RESULTS: We found that ENO1 was substantially higher in the caput spermatozoa from low motility bulls than the caput and cauda spermatozoa from high motility bulls. However, ENO1 expression in low motility bull spermatozoa was downregulated to a level comparable to that in the high motility bull spermatozoa during epididymal maturation. Moreover, there was a lack of modification of mitochondrial proteins, including glutathione peroxidase 4 and NADH:Ubiquinone Oxidoreductase Core Subunit S8, in low motility bull spermatozoa during epididymal maturation, whereas active changes were detected in high motility bull spermatozoa. CONCLUSIONS: Irregular modifications of mitochondrial proteins during epididymal sperm maturation may increase excessive ROS production and premature activation of spermatozoa during epididymal maturation. Consequently, spermatozoa may lose their motility by the earlier consumption of their energy source and may be damaged by ROS during epididymal maturation, resulting in a decline in sperm motility and bull fertility.

Bisphenol A damages testicular junctional proteins transgenerationally in mice.

Testicular junctions are pivotal to male fertility and regulated by constituent proteins. Increasing evidence suggests that environmental chemicals, including bisphenol A (BPA), may impact these proteins, but whether the impacts persist for generations is not yet known. Here, we investigate the effect of BPA (a ubiquitous endocrine-disrupting chemical) on testis and sperm functions and whether the effects are transferred to subsequent generations. Male mice (F0) were exposed to corn oil (Control) or 5 or 50 mg BPA/kg body weight/day from 6 to 12 weeks of age. The F0 were mated with wild-type females to produce the first filial (F1) generation. F2 and F3 were produced using similar procedures. Our results showed that BPA doses decreased the levels of some junctional proteins partly via binding with estrogen receptors (ERα and Erß), upregulation of p-ERK1/2, P85, p-JNK and activation of p38 mitogen-activated protein kinase signaling. Consequently, testicular histological abnormalities, disrupted spermatogenesis, decreased sperm count, and inability to fertilize eggs were observed in mice exposed to BPA. These effects were transferred to successive generations (F2), partly through DNA methylation, but mostly alleviated in F3 males. Our findings suggest that paternal exposure to chemicals promoting alteration of testicular junctional proteins and its transgenerational inheritance is a key component of the origin of male reproductive health problems.

Short-term storage of semen samples in acidic extender increases the proportion of females in pigs.

BACKGROUND: Sex preselection is a desired goal of the animal industry to improve production efficiency, depending on industry demand. In the porcine industry, there is a general preference for pork from female and surgically castrated male pigs. Therefore, the birth of more females than males in a litter leads to economic benefits and improved animal welfare in the pig production industry. Our previous study suggested that the porcine semen extender (BTS) adjusted to pH 6.2 maximises the differences in viability between X-chromosome-bearing (X) spermatozoa and Y-chromosome-bearing (Y) spermatozoa without affecting sperm's functional parameters. In this study we aimed to evaluate whether the pH 6.2 extender is applicable at the farm level for increasing the number of female piglets without a decline in spermatozoa fertility. Artificial insemination (AI) was carried out with spermatozoa stored at pH 6.2 and pH 7.2 (original BTS) at day 1 and day 2 of storage. Next, the functional parameters of the spermatozoa, litter size, farrowing rate, and female-to-male ratio of offspring were determined. RESULTS: Although sperm motility decreased significantly after 2 d of storage, the viability of spermatozoa was preserved at pH 6.2 for 3 d. There was no significant difference in the farrowing rate and average litter size between the group inseminated with the spermatozoa stored in (pH 7.2) and that inseminated with spermatozoa stored in acidic BTS. The percentage of female piglets was approximately 1.5-fold higher in sows inseminated on day 1 in the pH 6.2 than in the pH 7.2 group. Furthermore, although there was no significant difference in the female-to-male ratio, the percentage of female piglets born was slightly higher in the pH 6.2 group than in the pH 7.2 group on day 2. CONCLUSIONS: The method optimised in our study is simple, economical, and may enhance the number of female births without any decline in spermatozoa fertility.

Exposure to Environmental Arsenic and Emerging Risk of Alzheimer's Disease: Perspective Mechanisms, Management Strategy, and Future Directions.

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid ß (Aß) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth's crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.

Role of Insulin in Health and Disease: An Update.

Insulin is a polypeptide hormone mainly secreted by ß cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.

Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety.

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

Drivers of owning more BPA.

Bisphenol A (BPA) is a ubiquitous environmental toxin worldwide. Despite the many studies documenting the toxicity of this substance, it remains a popular choice for consumer products. The internet, magazine articles, and newspaper reports are replete with tips on how to avoid BPA exposure, which mostly spread contradictory and often unscientific information. Therefore, based on a comprehensive search of the available biomedical literature, we summarized several confounding factors that may be directly or indirectly related to human BPA exposure. We found that the unique properties of BPA materials (i.e. low cost, light-weight, resistance to corrosion, and water/air-tightness), lack of personal health and hygiene education, fear of BPA-substitutes (with yet unknown risks), inappropriate production, processing, and marketing of materials containing BPA, as well as the state of regulatory guidance are influencing the increased exposure to BPA. Besides, we detailed the disparities between scientifically derived safe dosages of BPA and those designated as "safe" by government regulatory agencies. Therefore, in addition to providing a current assessment of the states of academic research, government policies, and consumer behaviors, we make several reasonable and actionable recommendations for limiting human exposure to BPA through improved labeling, science-based dosage limits, and public awareness campaigns.