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Antibiotics are among the most commonly used group of pharmaceuticals in human medicine. They can therefore reach surface and groundwater bodies through different routes, such as wastewater treatment plant effluents, surface runoff, or infiltration of water used for agricultural purposes. It is well known that antibiotics pose a significant risk to environmental and human health, even at low concentrations. The aim of the present study was to evaluate the presence of aminoglycosides and phenicol antibiotics in municipal wastewaters, sea water and pharmaceutical effluents in Tunisia. All analysed water samples contained detectable levels of aminoglycoside and phenicol antibiotics. The highest concentrations in wastewater influents were observed for neomycin and kanamycin B (16.4ng mL−1 and 7.5 ng mL−1, respectively). Chloramphenicol was found in wastewater influents up to 3 ng mL−1. It was observed that the waste water treatment plants were not efficient in completely removing these antibiotics. Chloramphenicol and florfenicol were found in sea water samples near aquaculture sites at levels up to, respectively, 15.6 ng mL−1 and 18.4 ng mL−1. Also aminoglycoside antibiotics were found near aquaculture sites with the highest concentration of 3.4 ng mL−1 for streptomycin. In pharmaceutical effluents, only gentamycin was found at concentrations up to 19 ng mL−1 over a sampling period of four months.

Background Obesity is associated with varying degrees of metabolic dysfunction. In this study, we aimed to discover markers of the severity of metabolic impairment in men with obesity via a multiomics approach. Methods Thirty-two morbidly men with obesity who were candidates for Roux-en-Y gastric bypass (RYGB) surgery were prospectively followed. Nine healthy adults served as controls. Deep phenotyping, including targeted metabolomics, transcriptomics, and brain magnetic resonance imaging (MRI), was performed. Results Testosterone emerged as a key contributor to phenotypic variability via principal component analysis and was therefore used to further categorize obese patients as having or not having hypogonadotropic hypogonadism (HH). Despite having comparable body mass indices, obese individuals with HH presented with worse metabolic defects than obese individuals without HH, including higher insulin resistance, as well as MRI signs of hypothalamic inflammation and a specific blood transcriptomics signature. The upregulated genes were involved mainly in inflammation, mitochondrial function, and protein translation. Integration of gene expression and clinical data revealed high FGF21 and low cortisol levels as the top markers correlated with the transcriptomic signature of metabolic risk. Following RYGB-induced substantial weight loss, testosterone levels markedly increased in both obese individuals with and without HH, challenging the current definition of hypogonadism. A longitudinal study in a subset of men with obesity following bariatric surgery revealed a unique FGF21 trajectory with a sharp peak at one month post-RYGB that correlated with metabolic and reproductive improvements. Conclusions Combining clinical, biochemical, and molecular markers allows adequate stratification of metabolic risk in men with obesity and provides novel tools for personalized care.

Abstract Context Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease. Objective Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease. Design, Setting, and Participants Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years. Main outcome measures Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT). Results Baseline age was 34 ± 6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P < 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P < 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P < 0.001). Conclusion Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.

In the following study, we came up with and validated a prompt, sensitive and precise method for the simultaneous determination of 56 antimicrobial drugs (tetracyclines, sulfonamides, β-lactams, macrolides and quinolones) using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This method was implemented with success to determine antibiotics in samples collected from four wastewater treatment plants and five coasts in Tunisia. Results showed the presence of high concentrations of antibiotics that ranged from 0.1 to 646 ng mL−1, which can induce many negative impacts on health and the environment. For this reason, we have opted to evaluate toxicity of wastewater samples using a battery of biotests. In fact, genotoxicity was assessed using three tests: Vitotox, comet and micronucleus assays. The input and output of wastewater treatment plants induced a strongly genotoxic effect on the Salmonella typhimurium TA104 prokaryotic Vitotox assay. This result was confirmed using the comet and the micronucleus assays performed on the human liver hepatocellular carcinoma cells. The genotoxic power of the tested wastewater treatment plants' samples could be attributed to the presence of the higher quantities of antibiotics that are detected in these samples and to the antibiotic and organic compound cocktails.

BackgroundInitiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy. MethodsTransgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry. ResultsAfter 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, −19.4 to −17.4, P < 0.001 [ie, −97.1%]), 383 pmol/L (95% CI, −405 to −362, P < 0.001 [ie, −98.3%]), and 1.2 nmol/L (95% CI, −1.4 to −1.0, P < 0.001 [ie, −36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, −9.7 to −5.1 [ie, −28.0%]) and 1.8 µmol/L (95% CI, −2.2 to −1.4 [ie, −20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy. ConclusionsOur findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.

Abstract Disclosure: J. Walravens: None. T. Reyns: None. M. Cools: None. T. Fiers: None. B. Lapauw: None. Introduction: 11-oxygenated androgens are implicated in several disorders of androgen excess such as premature adrenarche, PCOS and CAH. These steroids may be more useful markers than traditional androgens to follow disease progression and treatment in such disorders. However, most research focusses on 11-oxygenated androgen levels in adult life. Little is known about 11-oxygenated androgen levels in childhood and adolescence. Furthermore, no widely accepted reference ranges exist for these steroids, limiting their clinical use. To overcome some of these issues, we report 11-keto testosterone (11KT) levels throughout life with their reference ranges. Objective: To determine the changes in 11KT serum levels in men and women throughout life and establish corresponding reference ranges. Methods: Steroid levels were determined in 13600 in- and outpatients using the steroid panel at Ghent University Hospital. This steroid panel includes 15 steroids, among which testosterone, androstenedione, pregnenolone (preg), DHEA, cortisol and 11KT. Data were stratified according to sex and age category: per 3 years in individuals from 0 to 18 years and per decade in adults. Extreme outliers for testosterone, androstenedione, DHEA and cortisol were removed per age and sex category. Afterwards, 11KT 90% reference ranges were established for apparently healthy individuals using the refineR-package for RStudio. DHEA and preg were included in the analysis as adrenal steroid controls. Finally, reference ranges were LOESS-smoothed across age categories to reduce effects of varying sample sizes. Results: In men, 11KT levels increase linearly from 0-2 years from a median of 8.0 (90% reference range: 1.2-48.2) ng/dL in early life to a peak of 36.5 (14.0–91.3) ng/dL at 15-18 years. Afterwards, 11KT levels decrease at 5% per 10 years to 24.2 (6.9-53.7) ng/dL in the age category of 70-79. In women, 11KT levels increase from 19.0 (2.3-45.1) ng/dL from 0-2 years to 29.1 (11.0-75.1) ng/dL at 15 to 18 years. Afterwards, 11KT levels remain constant until 60 to 69 years where 11KT levels quickly decrease to 21.6 (8.8-46.8) ng/dL at ages 70 to 79.In both men and women, DHEA and preg reached peak concentrations later than 11KT at ages of 20 to 29, after which concentrations decreased faster per 10 years (DHEA: 25%, preg: 16%). Conclusion: Our results show differences between the course of 11KT levels and other steroids. Compared to DHEA and preg, 11KT levels peak earlier in life, between 15 and 18 years, as compared to around 20-29 years and decrease at a slower rate. Additionally, 11KT levels peak earlier than total testosterone levels (15-18 vs ±30 years) and decline at a slower pace (5%/10 years vs. 10-20%/10 years). This larger difference compared to testosterone can likely be attributed to the adrenal synthesis of 11KT, as opposed to the gonadal synthesis of testosterone, supporting its potential as a marker of adrenal disorders in men. Presentation: 6/3/2024

Genetic variation in SHBG structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean, 34.5) years. Genotyping using microarray (Illumina) for single-nucleotide polymorphism (SNPs) suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; P < .05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all P < .05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all P < .05). No clear effects on measured free T were found, except for a trend toward higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; P < .05) in the larger global study population. In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

•The prevalence of psychoactive drugs in the blood of Italian drivers was studied.•The highest prevalence was found for alcohol (17.3%), followed by medications (13.6%).•The prevalence of Benzodiazepines (7.3%) was much higher than in previous studies.•Antidepressants/antipsychotics and medical opioids had a prevalence of 7.2% and 3.1%.•Medications were mostly found in females and in drivers older than 60-year-old. Psychoactive medicines, such as benzodiazepines and Z-drugs (BdZ), antidepressants and antipsychotics (AA) and medical opioids (MO), have an impairing effect on driving ability. In previous epidemiological studies performed on impaired and/or injured drivers, not all relevant psychoactive substances were included in the toxicological assessment, and their prevalence may be underestimated. This study aims to assess the prevalence of a large set of psychoactive substances (n=53) in Italian drivers involved in a road traffic crash and in predefined population subgroups. The toxicological analyses were performed on the whole blood of 1026 drivers involved in a road traffic crash in the area of Bologna, Italy, from January 2017 to March 2018. Analyses were performed using GC-FID (alcohol), GCMS (illicit drugs) and LC/HRMS (psychoactive drugs). The population was divided into subgroups according to gender, age and crash time. Descriptive statistics were used in order to assess differences among sub-groups. The highest prevalence was found for alcohol (17.3%), followed by medicinal drugs (13.6%) and illicit drugs (5.5%). The prevalence of BdZ, AA and MO were 7.3%, 7.2% and 3.1%, respectively. The frequency of BDZ and AA was significantly higher in female drivers and showed higher prevalence at increasing age. The presence of medicinal drugs was significantly higher during the week and in crashes occurring during the day. Results for alcohol and illicit drugs partially overlap with those reported in previous European and Italian studies, but the prevalence of BdZ was much higher. We also found a high prevalence of AA, which are rarely investigated in epidemiological studies performed on drivers, but may cause impairment of the ability to drive, especially when taken in combination with alcohol or other drugs. The pattern of medication use differs from that involving drugs of abuse, since it is mainly observed in female subjects and older drivers and does not follow the same weekly trend observed for alcohol and other illicit drugs.

Environmental pollution by pharmaceutical residues has become a major problem in many countries worldwide. However, little is known about the concentrations of pharmaceuticals in water sources in Tunisia. Residues in the natural environment have been of increasing concern due to their impact on bacteria resistance development and toxicity to natural communities and ultimately to public health. In this work, we collected the wastewater sample from a pharmaceutical industry, which specializes in the antibiotics manufacture, during the years 2014–2015. Generally, this effluent is discharged into the marine environment and causes environmental problems. The Mediterranean mussel Mytilus galloprovincialis was commonly used as a model organism for its peculiar morphofunctional properties which also make it an excellent marine environmental biomonitoring species. The histological sections of mussel, which are exposed at different dilutions of pharmaceutical wastewater (PW), indicate a large pathological power revealed on the gills. On the other hand, genotoxicity of the studied effluent was evaluated using comet assay for quantification of DNA fragmentation in gill cells. Results show that PW exhibited a statistically significant ( p  < 0.001) genotoxic effect in a dose-dependent manner. However, the toxic effects of PW decreased significantly after its treatment with Bacillus atrophaeus . Toxicities can be imputed to the presence of antibiotics. In fact, chemical analysis of the gills of mussel M. galloprovincialis using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed the presence of some antibiotic residues. These concentrations decrease to half in mussels treated with PW biodegraded by B. atrophaeus .

Today, processed and packaged foods are considered as among the major sources of human exposure to plasticizers and bisphenol which migrate from plastic packing. In the present study, a wide range of food products sold on the Tunisian market such as grain and grain products, milk and dairy products, fats and oil, drink, fish, and sweets have been analyzed firstly in order to identify the presence of phthalates and bisphenol. Then, the identified chemical molecules were studied for their environmental fate and tested in vivo for its toxicity in mice models. The food products analyzed using GC-MS/MS indicated the presence of the benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DiDP), diisononyl phthalate (DiNP), and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINC) and which using UPLC-MS/MS demonstrated the presence of bisphenol A of all food products. However, compared to other phthalates, BBP was found at high concentrations in the puff pastry (123 mg/kg), milk (2.59 mg/kg), butter (1.5 mg/kg), yogurt (2.23 mg/kg), oil (6.94 mg/kg), water (0.57 mg/kg), candy 1 (2.35 mg/kg), candy 2 (0.81 mg/kg), orange juice (1.25 mg/kg), peach juice (1.26 mg/kg), fruit juices (0.4 mg/kg), and chocolate (0.884 mg/kg). The obtained data in vivo clearly showed that the acute administration of BBP caused hepatic and renal damage as demonstrated by an increase in biochemical parameters as well as the activities of plasma marker enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, glucose, urea, creatinine, and uric acid when compared to the control group. By the same occurrence, the histopathological study revealed that BBP strongly modified the structure of hepatic and renal tissues. In addition, the plasticizers and BBP will therefore discharge via wastewater treatment plants in aquatic system and could reach marine organisms such as fish. We have followed the fate of BBP in bream Sparus aurata . In fact, chemical analysis showed the contamination of wild S. aurata by BBP from Sousse Coast (1.5 mg/kg) and wild S. aurata from Monastir Coast (0.33 mg/kg).