Perinatal exposure to polystyrene microplastics induces multigenerational impairment of male reproduction via disrupted steroidogenesis and proteostasis.

T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3’ untranslated region (UTR) of CD3ζ mRNA. We showed that SRSF1 regulates alternative splicing of the 3’UTR of CD3ζ to promote expression of the normal full length 3`UTR over an unstable splice variant in human T cells. In this study we show that SRSF1 regulates transcriptional activation of CD3ζ. Specifically, overexpression and silencing of SRSF1 respectively increases and decreases CD3ζ total mRNA and protein expression in Jurkat and primary T cells. Using promoter-luciferase assays, we show that SRSF1 enhances transcriptional activity of the CD3ζ promoter in a dose dependent manner. Chromatin immunoprecipitation assays show that SRSF1 is recruited to the CD3ζ promoter. These results indicate that SRSF1 contributes to transcriptional activation of CD3ζ. Thus our study identifies a novel mechanism whereby SRSF1 regulates CD3ζ expression in human T cells and may contribute to the T cell defect in SLE.

The splicing factor SRSF1 stabilizes the mRNA of TSLP to enhance acute lung injury

Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8+ T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8+ T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8+ T cells.

Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.

It is suggested that intrauterine environment play a role in the development of PCOS, and that first generation (F1) male offspring of the prenatal androgenized (PNA)-mice model exhibit metabolic dysfunction such as increased body weight and insulin resistance. Whether prenatal androgenisation, with or without diet-induced obesity, cause transgenerational effects on the male offspring through the paternal lineage have not previously been investigated. Therefore, we investigated how maternal high-fat high sucrose (HFHS) diet-induced obesity and in utero exposure to dihydrotestosterone (DHT) during embryonic day (E) 16.5-E18.5 (to create a PNA model) affect the metabolic phenotype of first, second and third (F1 to F3) generation male offspring. F1 and F2 male offspring were mated with females fed control diet (CD) to follow the paternal lineage. We found that F1 males born from mothers exposed to DHT and fed CD have longer anogenital distance (AGD), demonstrating androgen exposure in utero with no effect on F2 and F3 male offspring. F1 males from DHT exposed mothers with diet-induced obesity weigh more compared to F1 males from lean or obese mothers, with no differences in F2 and F3 male offspring. However, the F3 males from DHT exposed great-grand-mothers with diet-induced obesity have higher fat mass compared to other groups indicating a transgenerational effect. Moreover, F1 males from mothers with diet-induced obesity were insulin resistant with increased HOMA-IR and F3 male offspring from the same group exhibited impaired glucose tolerance as measured with oral glucose tolerance test. At night, when mice are more active, had F1 males from DHT exposed mothers fed CD or diet-induced obesity, and from vehicle treated mothers with diet-induced obesity, lower energy expenditure (EE) and respiratory exchange ratio (RER) measurement. Of note, the metabolic phenotype was exaggerated in F3 male offspring, with significantly lower EE, RER and total activity both during day and night time. These results likely reflect the higher body weight and increased fat mass in F1 and F3 male offspring. Taken together, these results demonstrate that diet-induced obesity before and during pregnancy together with androgen exposure cause a transgenerational effect on metabolic features in male offspring following the male germline.

Exposure to polystyrene microplastics with different functional groups: Implications for blood pressure and heart.

Functional and Clinical Relevance of Splicing Factor SRSF1 in Multiple Myeloma (MM)

Lactating exposure to microplastics at the dose of infants ingested during artificial feeding induced reproductive toxicity in female mice and their offspring

Adsorption behavior of triclosan by different microplastics and the impact of water chemistry.

This chapter will delve into the burgeoning concern surrounding microplastics (MPs) exposure and its insidious impact on male reproductive health. MPs, ubiquitous environmental pollutants stemming from the degradation of plastic products, have permeated various ecosystems and consequently found their way into the human body through multiple exposure routes, such as ingestion via food and water, and inhalation of airborne MP particles. The scope of this chapter encompasses an in-depth exploration of the mechanisms through which MPs exert their deleterious effects. It will examine the potential for MPs to induce oxidative stress in male reproductive tissues, leading to damage of sperm cells and disruption of the blood-testis barrier. Furthermore, the endocrine-disrupting properties of MPs will be scrutinized, as these pollutants can interfere with the normal hormonal regulation of the male reproductive system, affecting testosterone production and spermatogenesis. In addition, the chapter will present epidemiological evidence linking MPs exposure to adverse reproductive outcomes in men, such as reduced sperm quality, including decreased sperm count, motility, and morphology, as well as an increased risk of male infertility. Animal studies that have provided crucial insights into the dose-response relationships and the potential for transgenerational effects of MPs on male reproductive health will also be discussed. By synthesizing the existing body of knowledge, this chapter aims to highlight the urgent need for further research and public health interventions to mitigate the potential harm of MPs to male reproductive health.

We previously reported a 40-transcripts signature marking the normal mucosa to colorectal adenocarcinoma transition. Eight of these mRNAs also showed splicing alterations, including a specific intron 3 retention in tissue metalloprotease inhibitor I (TIMP1), which decreased during the early steps of colorectal cancer progression. To decipher the mechanism of intron 3 retention/splicing, we first searched for putative RNA binding protein binding sites onto the TIMP1 sequence. We identified potential serine arginine rich splicing factor 1 (SRSF1) and heterogeneous nuclear RiboNucleoProtein A1 (hnRNPA1) binding sites at the end of intron 3 and the beginning of exon 4, respectively. RNA immunoprecipitation showed that hnRNPA1, but not SRSF1 could bind to the corresponding region in TIMP1 pre-mRNA in live cells. Furthermore, using a TIMP1-based ex vivo minigene approach, together with a plasmon resonance in vitro RNA binding assay, we confirmed that hnRNPA1 could indeed bind to wild type TIMP1 exon 4 pre-mRNA and control TMP1 intron 3 splicing, the interaction being abolished in presence of a mutant sequence that disrupted this site. These results indicated that hnRNPA1, upon binding to TIMP1 exon 4, was a positive regulator of intron 3 splicing. We propose that this TIMP1-intron 3 + transcript belongs to the class of nuclear transcripts with "detained" introns, an abundant molecular class, including in cancer.

Effect of nonbiodegradable microplastics on soil respiration and enzyme activity: A meta-analysis

Aging process does not necessarily enhance the toxicity of polystyrene microplastics to Microcystis aeruginosa

T cells from patients with systemic lupus erythematosus (SLE) are poor producers of the vital cytokine interleukin (IL)-2. We recently showed that SLE T cells express lower levels of the serine arginine- rich splicing factor 1 (SRSF1), more so in patients with active disease. Forced expression of SRSF1 restores IL-2 production, indicating that SRSF1 is important in T cell function, and its reduced expression is a potential molecular defect in SLE T cells. The goal of this study was to determine the mechanism/s regulating SRSF1 expression in human T cells and in SLE patients. T cell activation increased mRNA expression of SRSF1 by 3- to 4-fold within 24 hours, while protein expression did not alter much. This discrepancy between mRNA and protein expression was not due to reduced RNA stability. Activating T cells in presence of specific proteolysis inhibitors revealed that proteasome- but not lysosome-mediated mechanisms contribute to reduced SRSF1 expression. Accordingly, immunoprecipitation (IP) studies showed increased ubiquitination of SRSF1 in activated T cells compared with resting cells. More interestingly, SRSF1 showed increased ubiquitination in SLE patients compared to healthy controls and rheumatoid arthritis patients. Our results identify a novel mechanism of SRSF1 protein regulation in human T cells and suggest that increased ubiquitination and proteasome degradation represent a molecular mechanism that contributes to reduced SRSF1 expression in SLE T cells.

There is a paucity of studies on the multigenerational reproductive toxicity of fine particle matter (PM2.5) exposure during pregnancy on male offspring and the underlying mechanisms. This study explored the effects of PM2.5 exposure during pregnancy on the spermatogenesis of three consecutive generations of male mouse offspring. We randomized pregnant C57BL/6 mice into the control group, the Quartz Fiber Membrane control group, and two experimental groups exposed to different concentrations of PM2.5 (4.8 and 43.2 mg/kg B.Wt.). Pregnant mice from experimental groups received intratracheal instillation of PM2.5 of different doses on a three-day basis until birth. F1 mature male offspring from PM2.5-exposed pregnant mice were mated with normal female C57BL/6 mice. Likewise, their F2 mature male followed the same to produce the F3 generation. The results showed that PM2.5 exposure during pregnancy led to decreased body and tail length, body weight, and survival rates, decreased sperm concentration and sperm motility, and increased sperm abnormality rates significantly in F1 male offspring. We barely observed significant impacts of PM2.5 on the birth number, survival rates, and index of testes in the F2 and F3 offspring. Further exploration showed that PM2.5 exposure during pregnancy caused the morphological abnormality of Sertoli cells, downregulated androgen receptor (AR) and connexin43, upregulated anti-Müllerian hormone (AMH), cytokeratin-18 (CK-18), caspase-3, and cleaved caspase-3, decreased thyroid-stimulating hormone (TSH) and testosterone (T), and increased triiodothyronine (T3) in F1 male mouse offspring. Overall, we hypothesize that PM2.5 exposure during pregnancy mainly negatively impacts spermatogenesis in the F1 offspring. The possible mechanism could be that PM2.5 exposure during pregnancy disrupts endocrine hormone release in the F1 generation, thereby influencing the maturation and proliferation of their Sertoli cells and hindering spermatogenesis. This study for the first time investigates the role of Sertoli cells in the reproductive toxicity of PM2.5 on offspring.