Search Results (418)

Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like C. elegans lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The C. elegans lifecycle is 3 days. The effects of 5FU, HU, and RV on the C. elegans morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in C. elegans may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that C. elegans can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed. Full article

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which VPA promotes the differentiation of satellite glial cells (SGCs) into neurons. We observed sustained intracellular pH elevation during the VPA-induced neural differentiation of SGCs, and the modulation of intracellular pH was shown to influence this differentiation process. Then, we found that VPA regulates intracellular pH through NHE1 (sodium–hydrogen exchanger 1), and that the pharmacological inhibition of NHE1 not only attenuated intracellular pH elevation but also substantially impaired VPA-induced neuronal differentiation. Finally, our results showed that the elevated intracellular pH promoted the neuronal differentiation of SGCs by activating β-catenin signaling. These findings provide novel insights into the mechanisms of VPA-induced neurogenesis, advancing our understanding of its pharmacological profile and informing its potential therapeutic application in neuronal regeneration strategies. Full article

Background: Oral isotretinoin is an effective treatment for refractory and moderate acne unresponsive to conventional therapies, considered the most effective option for such cases. Objective: This study aimed to evaluate the knowledge, concerns, and experiences of acne patients undergoing isotretinoin treatment in Qassim, Saudi Arabia, with a focus on commonly reported adverse effects. Methods: A cross-sectional study was conducted from December 2023 to February 2024 using a self-administered questionnaire. This study targeted male and female acne vulgaris patients from the Qassim region attending the outpatient dermatology clinic at King Saud Hospital (KSH). Results: A total of 131 acne patients participated. Of these, 97.7% had heard of isotretinoin, and 92.4% were aware of its side effects. The most common sources of information were colleagues, friends, or family (37.4%), followed by previous use (26%) and healthcare professionals (24%). The most frequently reported side effect was dryness (51.9%), followed by liver function changes (24.4%) and fetal abnormalities (13%). There was a significant association between educational level and knowledge of isotretinoin’s side effects (p = 0.003) and awareness of specific side effects (p < 0.001). Conclusion: Most acne patients had sufficient knowledge of isotretinoin and its adverse effects, with dryness being the most commonly reported side effect. The primary sources of information were non-medical, highlighting the need for health education to ensure informed and safe isotretinoin use. Full article

Hypoglossia and micrognathia are rare congenital malformations. They are most likely to occur after disruption of blastogenesis during embryonic development and formation of the first pharyngeal arch. They may be associated with other malformations such as otocephaly or hypogenesis syndrome of the oromandibular limb. We present the case of a female infant with hypoglossia, micrognathia, and situs inversus as a very rare triadic combination. This clinical presentation does not correspond to the description of existing syndromes. In the available literature, we were able to find only a small number of described cases that are somewhat similar to ours. The etiology of hypoglossia with micrognathia and situs inversus is unknown and has been attributed to both genetic and teratogenic causes. It is also unclear whether the combination of these three malformations can be classified as its own syndrome or not. Here, we present a child born from a pregnancy exposed to the SARS-CoV-2 virus in the first weeks of embryonic development, whose whole genome sequencing confirmed normality, as a contribution to elucidating the etiology of these congenital malformations. The possible influence of the SARS-CoV-2 virus on the occurrence of these anomalies and the exact mechanism of action should be confirmed in subsequent research. Full article

Background/Objectives: Maternal use of medication during pregnancy may have teratogenic effects, as seen with drugs like thalidomide, valproate, and phenytoin. Despite rigorous testing, both new and established drugs still pose a risk of teratogenesis, particularly if the teratogenic effects are probabilistic and not deterministic. Public health organizations maintain registers to centralize and evaluate adverse drug reactions (ADR). However, underreporting in these registries can obscure the signals of drug-related congenital malformations. This study aims to evaluate potential ADR-associated congenital malformations in Denmark over the past decade; Methods: An observational cross-sectional study was conducted using data from the national Danish Medicines Agency’s pharmacovigilance database, which includes all spontaneous ADR reports submitted to the Danish Medicines Agency from 1 July 2013 to 30 June 2023. Maternal antenatal drug use was identified, and reported ADRs were assessed for congenital malformations; Results: We identified reports of potential ADR-related congenital malformations in 75 children, with 92 diagnoses as classified by ICD-10. Eighty-five different drugs from 58 ATC codes were implicated. Only three diagnoses were reported in five or more children. The reports were generally sporadic, with no new signals detected; Conclusions: Public awareness is crucial when novel threats arise from medications, infections, or technologies, as these may pose risks to unborn children. Ongoing monitoring of potential ADR-related congenital malformations remains a critical component of public health. Given the potential underreporting, we encourage a low threshold for reporting ADRs based on suspicion alone, with final causality assessments made by health authorities. Full article

Background and Objectives: The use of antiseizure medications (ASMs) during pregnancy is critical to seizure control in women with epilepsy but raises concerns regarding the use of these drugs and their possible effect on the maternal serum biochemical markers used for second-trimester prenatal screening. The aim of this study was to assess the effect of ASMs on the levels of maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) assessed in the serum biomarker analyses part of second-trimester prenatal screening. Materials and Methods: This retrospective cohort study included 43 pregnant women in the ASM-exposed group (levetiracetam, lamotrigine, carbamazepine, or combined therapy) and 43 matched controls without medication use. Groups were matched based on maternal age, gravidity, parity, abortion history, gestational age at testing, body mass index, and smoking status with propensity score matching. Serum AFP, uE3, and hCG levels measured at 15–20 weeks of gestation were compared between groups. The incidence of fetal congenital anomalies or aneuploidies was also compared between groups. Results: Pregnant women in the ASM-exposed group had significantly higher maternal serum AFP (1.34 ± 0.42 vs. 1.01 ± 0.31 MoM; p < 0.001) and uE3 (1.28 ± 0.39 vs. 1.05 ± 0.34 MoM; p = 0.004) than the controls. However, hCG did not differ significantly between the groups (1.07 ± 0.46 vs. 1.01 ± 0.42 MoM; p = 0.523). Regarding the ASM subgroups (levetiracetam, lamotrigine, and carbamazepine), there were no significant differences in the serum biomarkers (p > 0.05). There was no significant difference between the ASM-exposed and control groups in terms of the incidence of congenital anomalies or aneuploidies (2.3% in the ASM-exposed group vs. 2.3% in the control group; p = 1.000). Conclusions: The use of ASMs during pregnancy significantly alters second-trimester maternal serum biochemical markers, including our primary concerns, AFP and uE3, which could cause inaccurate interpretations of second-trimester prenatal screening. Clinicians should carefully consider maternal medication exposure when interpreting these biochemical markers in pregnant women with epilepsy to prevent the misclassification of fetal risks and avoid unnecessary invasive procedures. Full article

Medium chain triglycerides (MCTs) are regarded as an important ingredient for functional foods and nutraceuticals. Cinnamomum camphora seed kernel oil (CCSKO) contains more than 95% medium chain fatty acids (MCFAs), which is a significantly higher level than palm kernel oil (62%) and coconut oil (55%). However, the safety assessment of CCSKO, as the only natural MCT oil rich in capric acid and lauric acid found so far in the world, has not been fully verified. The study aimed to investigate the 90-day sub-chronic oral toxicity and teratogenicity of CCSKO. In the sub-chronic oral toxicity study, no clinically significant adverse events occurred in male or female Sprague–Dawley (SD) rats with CCSKO daily administration for 13 weeks. Moreover, there were no dose–response relationships between CCSKO and body-weight gain, food intake and food utilization in male or female SD rats. No significant differences (p > 0.05) were found in the hematological properties or organ weights between the male and female SD rats. In the teratogenicity test, no toxicological signs were observed in either Wister pregnant rats or fetuses. The no-observed-adverse-effect level of CCSKO was determined to be more than 4 mL/kg body weight. These results suggested that CCSKO may be an excellent edible oil with high oral safety. Full article

Neural crest cells (NCCs) play a significant role in the development of ventricular outflow tracts (OFTs), and cardiac neural crest cells (cNCCs) are involved in the development of the embryonic conus, suggesting that these cell lineages may be a teratogenic target for the development of cardiopathies in offspring conceived under a hyperglycemic environment. We evaluate the effect of the hyperglycemic intrauterine environment on the morphological and anatomical changes in the conal ridges along with the alterations in the spatiotemporal expression of AP2α in offspring hearts at 13, 15, and 17 DPC. The anatomical and histological analysis of the hearts in the experimental group presented smaller dimensions compared to the control group in the offspring at the three ages studied. Consequently, this resulted in a hyperglycemic environment that altered the immunostaining of AP2α in the hearts of the offspring at the three ages studied. Thus, the hyperglycemic intrauterine environment in offspring caused important morphological alterations in the development of conal ridges and promoted the generation of conotruncal heart defects in which the double outlet of the right ventricle, the atrioventricular (AV) canal, predominated. Therefore, knowing that exposing the offspring to more glucose potentially can lead to complications during organogenesis of the circulatory and central nervous systems. Full article

Retinol and retinol-related compounds are essential for human health, particularly in cellular protection, skin health, and the management of medical conditions. Retinol—a vital form of vitamin A—is obtained through the diet as preformed vitamin A or provitamin A carotenoids, retinyl esters. These compounds are indispensable for vision, immune function, and skin health. While retinoic acid has important known biological roles, its presence is limited in the body as it is rapidly metabolized rather than stored, emphasizing the need for sufficient dietary intake. This paper is divided into chapters that highlight important aspects of retinol and retinoid-related compounds, such as their sufficient intake through food sources. The nutritional value of carotenoids is influenced by the balance between trans- and cis-isomers in food, with food processing affecting their bioactivity. Next, it is metabolism in the digestive tract. The bioavailability and efficacy of retinoids are further influenced by gut microbiota, which can modulate immune function and the expression of the genes involved in retinoid metabolism. A third important property greatly influencing their biological function is their structure, predisposing them to certain biological activities. Both retinoids and carotenoids exert key antioxidant functions by protecting cells from oxidative damage, quenching singlet oxygen, and stabilizing free radicals. However, the oxidation of carotenoids can result in various metabolites, such as epoxides and hydroxyketones, that further create a higher demand for antioxidant defenses. Additionally, carotenoids interact with lipoxygenases (LOXs), thus influencing oxidative stress, although this interaction may reduce their antioxidant efficacy. First- and second-generation retinoids regulate gene expression related to skin cell function and oncological diseases. Despite their therapeutic benefits, long-term use carries risks, such as teratogenicity. Ongoing research should aim to enhance the safety, precision, and effectiveness of retinoid therapies, expanding their therapeutic potential. Full article

Background: Isotretinoin is a highly effective treatment for moderate-to-severe acne, but strict contraceptive measures are required because of its teratogenicity. The European Pregnancy Prevention Programme (PPP) aims to minimise foetal exposure through structured protocols. However, real-world data on patient compliance and treatment outcomes are limited. Methods: This retrospective study included 569 female patients aged 14–25 years treated with isotretinoin in Poland (2021–2022). Patients were assigned to three groups based on PPP compliance: full (Group I), partial (Group IIA), and minimal (Group IIB). Data on contraception, cumulative dose, treatment duration, adverse events, laboratory monitoring, and therapy discontinuation were analysed using non-parametric statistical tests (p < 0.05). Results: No pregnancies occurred during treatment. Overall compliance with PPP requirements was high: 100% of the patients used contraception or declared abstinence. The majority (92.79%) used condoms, 1.93% used oral contraceptives, and 7.21% reported abstinence. Significant differences in cumulative isotretinoin dose were observed between the groups (Kruskal–Wallis H = 19.89, p < 0.001), with Group I receiving a lower mean dose than those in Groups IIA (p < 0.001) and IIB (p < 0.01). Notably, all therapy discontinuations (4.75%) occurred in Group I (full compliance), which may reflect stricter monitoring and an earlier identification of adverse effects or patient concerns. These discontinuations were associated with lower cumulative dosing (Mann–Whitney Z = 7.81, p < 0.001) than that seen in the other groups. An inverse correlation between age and cumulative dose was also found (H = 13.09, p = 0.0004), with younger patients (≤17 years) more likely to reach therapeutic targets. Conclusions: Isotretinoin therapy under structured PPP protocols is safe and effective, with no pregnancies reported and excellent contraceptive compliance. Significant differences in dosing and adherence patterns highlight the need for flexible patient-centred approaches to optimise safety and outcomes. Full article

Breast cancer (BC) is the most prevalent malignancy among women worldwide, with a rising incidence in young, premenopausal patients. For those diagnosed with hormone receptor-positive (HR+) BC, tamoxifen is a cornerstone of adjuvant endocrine therapy, significantly reducing recurrence risk and improving long-term survival. However, its prolonged use poses challenges for women desiring pregnancy, prompting interest in temporary treatment interruption as a strategy to achieve reproductive goals while maintaining oncological safety. This systematic review evaluates the impact of tamoxifen on fertility, the feasibility of treatment interruption, and associated reproductive and oncological outcomes. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search across major databases, identifying three relevant studies, including one randomized controlled trial (RCT) and two observational cohort studies. The findings suggest that temporary tamoxifen interruption allows for successful pregnancies without significantly increasing short-term recurrence rates. Notably, the POSITIVE trial demonstrated a pregnancy achievement rate of 74% and a live birth rate of 63.8%, with comparable three-year disease-free survival between patients who interrupted tamoxifen and those who continued therapy. However, concerns remain regarding tamoxifen’s teratogenic risks, emphasizing the need for strict contraceptive measures and preconception counseling. Despite emerging evidence supporting this approach, long-term safety data are limited. Further research is warranted to refine clinical recommendations and optimize reproductive counseling for young BC survivors. Full article

As a mycotoxin, aflatoxin B₁ (AFB₁) has attracted increasing attention due to its highly toxic effects, such as teratogen, carcinogen, and mutagen. AFB₁-producing fungi have been found in both terrestrial and marine sources. Over the last two years, the marine-derived bacteria Kocuria rosea has shown the ability to degrade AFB₁. However, no studies have yet explored the aflatoxin degradation potential in the genus Kocuria, and the molecular basis of aflatoxin metabolisms by strain has not yet been investigated. In this study, we first compared and analyzed the genomic features of 13 bacteria of the genus Kocuria by comparative genomic analysis and investigated the evolutionary patterns (evolutionary selection pressure analysis and gene family expansion analysis) and pan and core genomes of Kocuria strains. It was found that Kocuria genus strains showed high potential in the bioremediation of aromatic compounds and aflatoxin degradation. In addition, this study revealed 1421 differentially expressed genes and 752 upregulated genes between the aflatoxin group and the control group through transcriptome analysis and conducted functional annotation and analysis of functional enrichment. According to the expression and functional analysis of upregulated genes, the enzymes and genes (cytochrome P450, oxidoreductase, intradiol ring-cleavage dioxygenase, hydrolase, and monooxygenase) involved in the aflatoxin degradation of Kocuria rosea were screened. These findings indicate the potential of Kocuria rosea in the remediation of aflatoxin contamination and provide a foundation and direction for the further excavation of novel degradation genes, exploration of degradation mechanisms, and genomic modification. Full article

The prevention of human infectious diseases associated with waterborne pathogens is reliant on the effective disinfection of water supplies by drinking water treatment plants and adequately maintained distribution networks. For decades, the chlorination of water has safeguarded public health, where chlorine is broadly applied in both water disinfection and food production facilities, including the dairy industry, from farm to fork. The identification of chlorine disinfection byproducts in water supplies and dairy food produce is of great concern, however, due to their cytotoxic, genotoxic, mutagenic, teratogenic, and potential endocrine-disrupting activity. The association between the trihalomethanes (THMs) and haloacetic acids (HAAs) and tumour formation is documented and has led to the implementation of maximum contaminant levels enforced by the European Union. Furthermore, chlorine resistance in bacterial species is associated with multidrug resistance in clinically relevant pathogens, where antibiotic- and biocidal-resistant genes are also environmental pollutants. Increasing the concentration of chlorine to surmount this resistance will ultimately lead to increasing concentrations of byproducts in both water and food products, exceeding the EU requirements. This article provides insight into chlorine DBPs as a toxicological public health risk and the relationship between chlorine resistance and antibiotic resistance in microbes relevant to dairy food production. Full article

Cleft palate is a common birth defect worldwide and is caused by both genetic and environmental factors. Intrauterine drug exposure is one of the environmental factors that can induce cleft palate. Mycophenolate mofetil (MPM) is an immunosuppressant drug with teratogenic effects, including cleft palate. However, the research on MPM-induced cleft palate remains limited. Sasa veitchii extract (SE), a medical plant extract, is commercially available in Asia and has been reported to show effectiveness against oral diseases. The purpose of the present study is to evaluate whether SE protects against MPM-induced immunosuppression in human embryonic palatal mesenchymal (HEPM) cells. Cell viability and G1 phase-related cell cycle markers were assessed by co-treatment with MPM and SE. Furthermore, we quantified cleft palate-associated miRNA levels and the expression of its downstream genes. MPM treatment reduced cell viability in a concentration-dependent manner. Co-treatment with SE alleviated MPM-induced inhibition of HEPM cell proliferation. Additionally, SE reduced MPM-induced miR-4680-3p upregulation and the downregulation of its downstream genes (ERBB2 and JADE1). These results suggest that SE alleviated MPM-induced cell proliferation inhibition through modulating miR-4680-3p expression. Full article

Orthobunyaviruses are a diverse group of segmented RNA viruses with significant but underexplored public and veterinary health implications. This study provides a genomic, phylogenetic, and ecological analysis of neglected Orthobunyaviruses using next-generation sequencing and computational predictions. We identified unique phylogenetic relationships, with Tanga virus forming a distinct lineage linked to zoonotic, human-associated, or non-vertebrate viruses across segments. GC content analysis revealed segment-specific patterns: higher GC content in the S segment suggests genomic stability and immune evasion, while lower GC content in the L segment reflects host-vector adaptation. Phylogenetic ties to well-characterized pathogenic viruses, such as Ilesha virus with Cache Valley virus and Bwamba virus with California encephalitis virus, indicate potential neurotropism. Ingwavuma virus clustered with Oropouche virus, suggesting risks of systemic febrile illnesses. Within the Simbu serogroup, Sango and Sabo viruses show teratogenic risks to livestock. Vector and host predictions implicate rodents, artiodactyls, and primates in Orthobunyavirus transmission, emphasizing complex ecological dynamics and zoonotic potential. These findings advance the understanding of Orthobunyavirus diversity, linking genomic features to pathogenicity and ecological adaptation, while providing a foundation for future surveillance and intervention strategies targeting these neglected viruses. Full article