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Toxicological Sciences : An Official... Aug 2023Significant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over...
Significant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over 50%. This dramatic decrease in fertility can be attributed in part to our increasing exposure to endocrine disrupting chemicals (EDCs). Diethylstilbestrol (DES) is an estrogenic EDC that was prescribed to millions of pregnant women between 1940 and 1970 and resulted in detrimental reproductive effects in the offspring that were exposed in utero. Women who were exposed to DES in utero experienced higher rates of infertility, pregnancy complications, and reproductive cancers. Alarmingly, there is evidence to suggest that these effects may persist in the grandchildren and great grandchildren of exposed women. To define the transgenerational reproductive impacts in females following exposure to DES, gestating mice were exposed to DES and the effects monitored in the female descendants across 3 generations. There was a trend for reduced pregnancy rate and fertility index seen across the generations and moreover, the anogenital distance (AGD) was significantly reduced up until the third, unexposed generation. The onset of puberty was also significantly affected, with the timing of vaginal opening occurring significantly earlier in DES descendants. These results indicate a transgenerational effect of DES on multiple reproductive parameters including fertility, timing of puberty, and AGD. These data have significant implications for more than 50 million DES descendants worldwide as well as raising concerns for the ongoing health impacts caused by exposures to other estrogenic EDCs which are pervasive in our environment.
Topics: Pregnancy; Female; Male; Humans; Mice; Animals; Diethylstilbestrol; Prenatal Exposure Delayed Effects; Semen; Fertility; Reproduction
PubMed: 37471692
DOI: 10.1093/toxsci/kfad066 -
Accident; Analysis and Prevention Oct 2023Professional driver education and training has traditionally been used to improve the driving skills of young people with the expectation that they will drive more...
Professional driver education and training has traditionally been used to improve the driving skills of young people with the expectation that they will drive more safely and therefore be less likely to crash. Despite this, much research has failed to find such an effect. The Goals for Driver Education (GDE) is a theoretical framework developed to improve the effectiveness of driver education. The GDE seeks to draw attention to a broader array of factors that may influence the driving of young people and hence increase the scope of what is included in driver education and training. Within the GDE, factors affecting driving and driver education are grouped into combinations of four hierarchical levels that represent influences on driving at increasing levels of abstraction (GDE level 1: Vehicle manoeuvring; GDE level 2: Mastery of traffic situations; GDE level 3: Goals and contexts of driving; GDE level 4: Goals for life and skills for living) and three types of individual competencies (Knowledge and skills; Risk-increasing factors; Self-evaluation skills). However, to date there have been few, if any, attempts to operationalise the GDE in a quantitative way. In response, the Perceptions of Driver Education Scale (PDES) was developed to gain an understanding of what two important stakeholder groups in the driver education and training ecosystem perceived to be important to be taught to novice drivers. Understanding these perceptions may lead to greater acceptance of the driver education and training that is designed and make it more effective. Following rigorous scale development procedures, thirty-five items were developed a priori using expert opinion and deployed, via an online survey, to a sample of parents of novice drivers (N = 518) and a separate sample of novice drivers (N = 247), both from Queensland, Australia. Exploratory Factor Analysis was performed on the parent responses and Confirmatory Factor Analysis was performed using the novice driver responses. A 29-item 9 factor solution was judged to be the best fit with the overall scale and each of the factors displaying strong levels of internal consistency. The 9 factors cover most hierarchical level and competency combinations, although removal of items meant that there is no representation concerning perceptions of Self-evaluation skills related to Level 3: Goals and contexts of driving within the PDES. Overall, the PDES is a valid and reliable instrument for investigating the aspects of driver education and training that are perceived as important by novice drivers and parents. The scale may also be applicable for use with other stakeholder groups and could also be used to evaluate pre-existing driver education and training programs.
Topics: Humans; Adolescent; Automobile Driving; Accidents, Traffic; Ecosystem; Goals; Licensure; Parents
PubMed: 37441986
DOI: 10.1016/j.aap.2023.107190 -
Research Square Jun 2023Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought...
Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFβ1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFβ1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-months old Eker rats exposed neonatally to Diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFβ1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFβ1 decreased NER capacity while inhibiting TGFβ signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFβ1, but increased expression in EDC-MMSCs after TGFβ signaling inhibition. Overall, we demonstrated that the overactivation of the TGFβ pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFβ pathway links early-life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.
PubMed: 37333266
DOI: 10.21203/rs.3.rs-3001855/v1 -
Gynecologic Oncology Reports Aug 2023Primary vaginal cancer is rare and comprises 1-2% of female genital tract cancers. Among the types of vaginal cancer, adenocarcinoma accounts for only 10% with the peak...
BACKGROUND
Primary vaginal cancer is rare and comprises 1-2% of female genital tract cancers. Among the types of vaginal cancer, adenocarcinoma accounts for only 10% with the peak incidence in women less than 20 years old. Clear cell type vaginal adenocarcinoma is most associated with exposure to diethylstilbestrol (DES) in-utero.
CASE
We present a case of an 18-year-old nulliparous woman, DES-exposure naive, who was diagnosed with stage I clear cell vaginal adenocarcinoma during a routine pelvic exam for abnormal vaginal bleeding. She underwent a fertility-preserving radical vaginectomy and pelvic lymphadenectomy with neovagina creation and uterovaginal cervical reconstruction. She has been without disease for 28 months.
CONCLUSION
Although rare, vaginal cancer can be diagnosed on routine women's health exams. Early screening and diagnosis allow for innovative fertility-preserving surgical approaches without compromising oncologic outcomes. To our knowledge, this is the first case of a fertility-preserving radical vaginectomy, neovagina creation using a vertical rectus abdominis myocutaneous (VRAM) flap, and uterocervicovaginal reconstruction to successfully treat early stage clear cell vaginal adenocarcinoma with surgery alone, sparing the patient from adjuvant chemotherapy or radiation.
PubMed: 37325294
DOI: 10.1016/j.gore.2023.101214 -
Cells Jun 2023Cyclic nucleotide phosphodiesterases 2A (PDE2A) and PDE3A play an important role in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine...
Cyclic nucleotide phosphodiesterases 2A (PDE2A) and PDE3A play an important role in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-to-cAMP crosstalk. Each of these PDEs has up to three distinct isoforms. However, their specific contributions to cAMP dynamics are difficult to explore because it has been challenging to generate isoform-specific knock-out mice or cells using conventional methods. Here, we studied whether the CRISPR/Cas9 approach for precise genome editing can be used to knock out and genes and their distinct isoforms using adenoviral gene transfer in neonatal and adult rat cardiomyocytes. Cas9 and several specific gRNA constructs were cloned and introduced into adenoviral vectors. Primary adult and neonatal rat ventricular cardiomyocytes were transduced with different amounts of Cas9 adenovirus in combination with PDE2A or PDE3A gRNA constructs and cultured for up to 6 (adult) or 14 (neonatal) days to analyze PDE expression and live cell cAMP dynamics. A decline in mRNA expression for PDE2A (~80%) and PDE3A (~45%) was detected as soon as 3 days post transduction, with both PDEs being reduced at the protein level by >50-60% in neonatal cardiomyocytes (after 14 days) and >95% in adult cardiomyocytes (after 6 days). This correlated with the abrogated effects of selective PDE inhibitors in the live cell imaging experiments based on using cAMP biosensor measurements. Reverse transcription PCR analysis revealed that only the PDE2A2 isoform was expressed in neonatal myocytes, while adult cardiomyocytes expressed all three PDE2A isoforms (A1, A2, and A3) which contributed to the regulation of cAMP dynamics as detected by live cell imaging. In conclusion, CRISPR/Cas9 is an effective tool for the in vitro knock-out of PDEs and their specific isoforms in primary somatic cells. This novel approach suggests distinct regulation of live cell cAMP dynamics by various PDE2A and PDE3A isoforms in neonatal vs. adult cardiomyocytes.
Topics: Animals; Mice; Rats; CRISPR-Cas Systems; Cyclic AMP; Diethylstilbestrol; Myocytes, Cardiac; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Protein Isoforms
PubMed: 37296663
DOI: 10.3390/cells12111543 -
Best Practice & Research. Clinical... Jul 2023Nutrition plays a major role in the healthy pregnancy and development of the fetus. In addition, nutrition can expose humans to a wide range of potentially hazardous... (Review)
Review
Nutrition plays a major role in the healthy pregnancy and development of the fetus. In addition, nutrition can expose humans to a wide range of potentially hazardous environmental constituents, such as organic pollutants and heavy metals from marine or agricultural food products while processing, producing, and packaging. Humans constantly face these constituents through air, water, soil, food, and domestic products. During pregnancy, the rate of cellular division and differentiation is higher; exposure to any of these environmental toxicants can lead to developmental defects as they cross the placental barrier and, in some cases, can harm the successive generation too, as some contaminants can act on the reproductive cells of the fetus (Diethylstilbestrol). Pregnant women are considered a vulnerable population to food contaminant exposure and require a proper dietary chart and conscious food choices. Food is a source of both essential nutrients and environmental toxicants. Here, we have researched the possible toxicants of the food industry and their influence on the fetus's in-utero development, along with the importance of dietary interventions and the need to balance a healthy diet to overcome the harms. The cumulative exposure to environmental toxicants can influence the mother's prenatal environment and affect the fetus's development.
Topics: Female; Pregnancy; Humans; Placenta; Hazardous Substances; Environmental Pollutants; Fetal Development
PubMed: 37295316
DOI: 10.1016/j.bpobgyn.2023.102351 -
Bulletin of Mathematical Biology Jun 2023A multiscale mathematical model describing the metals biosorption on algal-bacterial photogranules within a sequencing batch reactor (SBR) is presented. The model is...
A multiscale mathematical model describing the metals biosorption on algal-bacterial photogranules within a sequencing batch reactor (SBR) is presented. The model is based on systems of partial differential equations (PDEs) derived from mass conservation principles on a spherical free boundary domain with radial symmetry. Hyperbolic PDEs account for the dynamics of sessile species and their free sorption sites, where metals are adsorbed. Parabolic PDEs govern the diffusion, conversion and adsorption of nutrients and metals. The dual effect of metals on photogranule ecology is also modelled: metal stimulates the production of EPS by sessile species and negatively affects the metabolic activities of microbial species. Accordingly, a stimulation term for EPS production and an inhibition term for metal are included in all microbial kinetics. The formation and evolution of the granule domain are governed by an ordinary differential equation with a vanishing initial value, accounting for microbial growth, attachment and detachment phenomena. The model is completed with systems of impulsive differential equations describing the evolution of dissolved substrates, metals, and planktonic and detached biomasses within the granular-based SBR. The model is integrated numerically to examine the role of the microbial species and EPS in the adsorption process, and the effect of metal concentration and adsorption properties of biofilm components on the metal removal. Numerical results show an accurate description of the photogranules evolution and ecology and confirm the applicability of algal-bacterial photogranule technology for metal-rich wastewater treatment.
Topics: Models, Biological; Mathematical Concepts; Metals; Biofilms; Bacteria
PubMed: 37269488
DOI: 10.1007/s11538-023-01168-x -
Reproductive Toxicology (Elmsford, N.Y.) Aug 2023Female reproductive toxicity assessments rely on histological evaluation of ovaries by hematoxylin & eosin (H&E)-stained cross-sections. This is time-consuming,...
Female reproductive toxicity assessments rely on histological evaluation of ovaries by hematoxylin & eosin (H&E)-stained cross-sections. This is time-consuming, labor-intensive and costly, thus alternative methods for ovarian toxicity assessment could be valuable. Here, we report on an improved method based on quantification of antral follicles (AF) and corpora lutea (CL) using ovarian surface photographs, called 'surface photo counting' (SPC). To validate a potential utility for the method to detect effects on folliculogenesis in toxicity studies, we investigated ovaries from rats exposed to two well-known endocrine disrupting chemicals (EDCs), diethylstilbestrol (DES) and ketoconazole (KTZ). Animals were exposed to DES (0.003, 0.012, 0.048 mg/kg body weight (bw)/day) or KTZ (3, 12, 48 mg/kg bw/day) during puberty or adulthood. At the end of the exposure, ovaries were photographed under stereomicroscope and subsequently processed for histological assessments to allow for direct comparison between the two methods by quantifying AF and CL. There was a significant correlation between the SPC and histology methods, albeit CL counts correlated better than AF counts, potentially due to their larger size. Effects of DES and KTZ were found by both methods, suggesting applicability of the SPC method to chemical hazard and risk assessment. Based on our study, we propose that SPC can be employed as a fast and cheap tool for assessment of ovarian toxicity in in vivo studies to prioritize chemical exposure groups for further histological assessment.
Topics: Rats; Animals; Female; Ovary; Sexual Maturation; Ovulation; Corpus Luteum; Ovarian Follicle
PubMed: 37268149
DOI: 10.1016/j.reprotox.2023.108416 -
European Review For Medical and... May 2023Epilepsy, a neurodegenerative disorder, continues to throw challenges in the therapeutic management. The current study sought to ascertain if the therapeutic...
Therapeutic enhancing potential of piracetam with diethylstilbestrol in prevention of grand-mal seizures in rats: inhibition of PI3K/Akt/mTOR signaling pathway and IL-1β, IL-6, TNF-α cytokines levels.
OBJECTIVE
Epilepsy, a neurodegenerative disorder, continues to throw challenges in the therapeutic management. The current study sought to ascertain if the therapeutic interactions between piracetam and diethylstilbestrol may prevent grand-mal seizures in rats.
MATERIALS AND METHODS
Piracetam (PIR; 10 and 20 mg/kg) and diethylstilbestrol (DES; 10 and 20 mg/kg) alone as a low-dose combination were administered to rats for 14 days. The electroshock (MES; 180 mA, 220 V for 0.20 s) was delivered via auricular electrodes on the last day of treatment and rats were monitored for convulsive behavior. To elucidate the mechanism, hippocampal mechanistic target of rapamycin (mTOR) and interleukin (IL)-1β, IL-6 and tumor necrotic factor-alpha (TNF-α) levels were quantified. Hippocampal histopathology was conducted to study the neuroprotective effect of drug/s. In vitro studies and in silico studies were conducted in parallel.
RESULTS
To our surprise, the low dose of the combination regimen of PIR (10 mg/kg) and DES (10 mg/kg) unfolded synergistic anti-seizure potential, with brimming neuroprotective properties. The mechanism could be related to a significant reduction in the levels of hippocampal mTOR and proinflammatory cytokines. The docking scores revealed higher affinities for phosphatidylinositol 3-kinase (PI3K) in co-bound complex, and when docking DES first, while better affinities for protein kinase B (Akt) were revealed when docking PIR first (both drugs bind cooperatively as well). This indicated that the entire PI3K/Akt/mTOR signaling pathway is intercepted by the said combination. In addition, the % of cell viability of HEK-293 cells [pre-exposed to pentylenetetrazol (PTZ)] was increased by 327.29% compared to PTZ-treated cells (toxic control; 85.16%).
CONCLUSIONS
We are the first to report the promising efficacy of the combination (PIR 10 mg/kg + DES 10 mg/kg) to restrain seizures and epileptogenic changes induced by electroshock by a novel mechanism involving inhibiting the PI3K/Akt/mTOR signaling.
Topics: Animals; Humans; Rats; Cytokines; Diethylstilbestrol; HEK293 Cells; Interleukin-6; Pentylenetetrazole; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Piracetam; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha
PubMed: 37259757
DOI: 10.26355/eurrev_202305_32485 -
Microbiology Spectrum Jun 2023The second messenger cyclic dimeric GMP (c-di-GMP) plays a central role in controlling decision-making processes that are vitally important for the environmental...
The second messenger cyclic dimeric GMP (c-di-GMP) plays a central role in controlling decision-making processes that are vitally important for the environmental survival of the human pathogen Vibrio parahaemolyticus. The mechanisms by which c-di-GMP levels and biofilm formation are dynamically controlled in V. parahaemolyticus are poorly understood. Here, we report the involvement of OpaR in controlling c-di-GMP metabolism and its effects on the expression of the trigger phosphodiesterase (PDE) TpdA and the biofilm-matrix related gene . Our results revealed that OpaR negatively modulates the expression of by maintaining a baseline level of c-di-GMP. The OpaR-regulated PDEs ScrC, ScrG, and VP0117 enable the upregulation of , to different degrees, in the absence of OpaR. We also found that TpdA plays the dominant role in c-di-GMP degradation under planktonic conditions compared to the other OpaR-regulated PDEs. In cells growing on solid medium, we observed that the role of the dominant c-di-GMP degrader alternates between ScrC and TpdA. We also report contrasting effects of the absence of OpaR on expression in cells growing on solid media compared to cells forming biofilms over glass. These results suggest that OpaR can act as a double-edged sword to control expression and perhaps biofilm development in response to poorly understood environmental factors. Finally, using an analysis, we indicate outlets of the OpaR regulatory module that can impact decision making during the motile-to-sessile transition in V. parahaemolyticus. The second messenger c-di-GMP is extensively used by bacterial cells to control crucial social adaptations such as biofilm formation. Here, we explore the role of the quorum-sensing regulator OpaR, from the human pathogen V. parahaemolyticus, on the dynamic control of c-di-GMP signaling and biofilm-matrix production. We found that OpaR is crucial to c-di-GMP homeostasis in cells growing on Lysogeny Broth agar and that the OpaR-regulated PDEs TpdA and ScrC alternate in the dominant role over time. Furthermore, OpaR plays contrasting roles in controlling the expression of the biofilm-related gene on different surfaces and growth conditions. This dual role has not been reported for orthologues of OpaR, such as HapR from Vibrio cholerae. It is important to investigate the origins and consequences of the differences in c-di-GMP signaling between closely and distantly related pathogens to better understand pathogenic bacterial behavior and its evolution.
Topics: Humans; Vibrio parahaemolyticus; Phosphoric Diester Hydrolases; Bacterial Proteins; Cyclic GMP; Biofilms; Homeostasis; Gene Expression Regulation, Bacterial
PubMed: 37199626
DOI: 10.1128/spectrum.00872-23