Melatonin ameliorates renal dysfunction in glyphosate- and hard water-treated mice.

Chronic interstitial nephritis in agricultural communities (CINAC) is a severe and widespread disease that has been associated with environmental and occupational exposure to glyphosate and hard water. However, the potential underlying mechanisms remain incompletely understood. Melatonin is reported to exert protective effects on the kidney, but whether melatonin can attenuate renal tubular injury in mice exposed to glyphosate combined with hard water is unclear. Here, mice were treated with high doses and environmentally relevant doses of glyphosate (100 mg/kg·bw and 0.7 mg/L, respectively) and/or hard water (2500 mg/L CaCO3 and 250 mg/L Ca2+, respectively) via their drinking water for 12 weeks. We found that high-dose glyphosate or hard water treatment significantly increased the levels of biomarkers of renal damage, including ß2-microglobulin, neutrophil gelatinase-associated lipid carrier protein, and/or albumin, in the urine; these increased biomarker levels were correlated with obvious morphological changes, and all of these changes were also observed in animals exposed to environmentally relevant doses of glyphosate and/or high Ca2+ water. Melatonin (10 mg/kg·bw, intraperitoneal injection, daily for 12 weeks) administered concomitantly with high doses of glyphosate and hard water inhibited the glyphosate- and hard water-induced increases in the levels of kidney injury biomarkers and changes in morphology; this result was intriguing. Additionally, glyphosate combined with hard water at both high and environmentally relevant doses significantly upregulated the expression of the endoplasmic reticulum (ER) stress marker proteins Bip, ATF6, and PERK as well as the pyroptosis-related proteins (NLRP3 and caspase 1 signaling proteins) in renal tissues. Similarly, melatonin significantly attenuated the increased ER stress and pyroptosis induced by high doses of glyphosate and hard water. In summary, we conclude that exposure to glyphosate and hard water at both high doses and environmentally relevant doses causes renal dysfunction in mice, and this dysfunction can be attenuated by melatonin, possibly through the inhibition of ER stress and pyroptosis. Our results support the notion that melatonin may have therapeutic potential for the treatment of chronic kidney diseases.

Habitual use of fish oil supplements, genetic predisposition, and risk of fractures: a large population-based study.

BACKGROUND: Epidemiologic studies have suggested an inverse association between circulating concentrations of long-chain ω-3 PUFAs and fracture risk. However, whether supplementation of long-chain ω-3 PUFA (i.e. fish oil) is associated with fracture risk, and whether the association is modified by genetic predisposition to fracture risk remain unclear. OBJECTIVES: To evaluate the associations of habitual fish oil supplement use with fracture risk, and to explore the potential effect modification by genetic predisposition. METHODS: This study included 492,713 participants from the UK Biobank who completed a questionnaire on habitual fish oil supplement use between 2006 and 2010. HRs and 95% CIs for fractures were estimated from multivariable Cox proportional hazards models. A weighted fracture-genetic risk score (GRS) was derived from 14 validated single nucleotide polymorphisms. RESULTS: During a median follow-up of 8.1 y, 12,070 incident fractures occurred among participants free of fracture at baseline (n = 441,756). Compared with nonuse, habitual use of fish oil supplements was associated with a lower risk of total fractures (HR = 0.93; 95% CI: 0.89, 0.97), hip fractures (HR = 0.83; 95% CI: 0.75, 0.92), and vertebrae fractures (HR = 0.85; 95% CI: 0.72, 0.99). The inverse association for total fractures was more pronounced among participants having a higher fracture-GRS than among those with a lower fracture-GRS (P-interaction <0.001). Among participants with a history of fracture at baseline (n = 50,957), fish oil use was associated with a lower risk of total recurrent fractures (HR = 0.88; 95% CI: 0.82, 0.96) and vertebrae recurrent fractures (HR = 0.64; 95% CI: 0.46, 0.88) but not with hip fracture recurrence. CONCLUSIONS: Our findings suggest that habitual fish oil supplement use is associated with lower risks of both incident and recurrent fractures. The inverse associations of fish oil use with total fractures appeared to be more pronounced among individuals at higher genetic risk of fractures than those with lower genetic risk.

Involvement of mitochondrial fission in renal tubular pyroptosis in mice exposed to high and environmental levels of glyphosate combined with hard water.

Chronic interstitial nephritis in agricultural communities (CINAC) has reached epidemic proportions. The combination of glyphosate and hard water has been postulated to play a potent aetiological role in CINAC. Therefore, dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission and subsequent activation of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (Nlrp3)/caspase1 pathway may be involved in the pathogenesis of nephropathy. In the present study, mice were sub-chronically exposed to high doses and environmental levels of glyphosate (100 mg/kg body weight (mg/kg·bw) glyphosate in Roundup and 0.7 mg/L pure glyphosate, respectively) and hard water (2500 mg/L CaCO3 and 250 mg/L Ca2+, respectively) in drinking water. Moreover, Mdivi-1 (Md-1, 10 mg/kg·bw) was intraperitoneally injected to inhibit Drp1 on the basis of the high-dose experiment. Histopathological examination, biochemical analysis, ELISA, western blotting and fluorescent staining were used to analyse renal structure, renal tubular pyroptosis and mitochondrial fission/fusion alterations. The results showed dramatic proximal tubular injury, particularly in the combined groups. Moreover, significant increases in the protein expression levels of calmodulin (CaM), calmodulin-dependent protein kinase II (CaMKII), Drp1/p-Drp1-Ser616 and the Txnip/Nlrp3/caspase1 signalling pathway, and alterations in oxidative stress were observed in the combined groups, and these effects were attenuated by the Drp1 inhibitor Md-1. Intriguingly, there may be a synergistic effect of glyphosate and hard water on renal injury. Taken together, these results suggest that the combination of glyphosate and hard water, even at environmental exposure levels, enhances pyroptosis and ongoing tubulointerstitial inflammation through excessive Drp1-mediated mitochondrial fission.

Potential Interference of Oil Vehicles on Genital Tubercle Development during the Fetal Period in ICR Mice.

Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development.

Ubiquitous occurrence of chlorinated byproducts of bisphenol A and nonylphenol in bleached food contacting papers and their implications for human exposure.

The occurrence of bisphenol A (BPA), nonylphenol (NP), and their six chlorinated byproducts were investigated in 74 food contacting papers (FCPs) from China, the U.S.A., Japan, and Europe using a sensitive dansylation LC-MS/MS method. BPA (

Occurrences and behaviors of naphthenic acids in a petroleum refinery wastewater treatment plant.

Naphthenic acids (NAs) are one class of compounds in wastewaters from petroleum industries that are known to cause toxic effects, and their removal from oilfield wastewater is an important challenge for remediation of large volumes of petrochemical effluents. The present study investigated occurrences and behaviors of total NAs and aromatic NAs in a refinery wastewater treatment plant, located in north China, which combined physicochemical and biological processes. Concentrations of total NAs were semiquantified to be 113-392 µg/L in wastewater from all the treatment units, and the percentages of aromatic NAs in total NAs was estimated to be 2.1-8.8%. The mass reduction for total NAs and aromatic NAs was 15±16% and 7.5±24% after the physicochemical treatment, respectively. Great mass reduction (total NAs: 65±11%, aromatic NAs: 86±5%) was observed in the biological treatment units, and antiestrogenic activities observed in wastewater from physicochemical treatment units disappeared in the effluent of the activated sludge system. The distributions of mass fractions of NAs demonstrated that biodegradation via activated sludge was the major mechanism for removing alicyclic NAs, aromatic NAs, and related toxicities in the plant, and the polycyclic NA congener classes were relatively recalcitrant to biodegradation, which is a complete contrast to the preferential adsorption of NAs with higher cyclicity (low Z value). Removal efficiencies of total NAs were 73±17% in summer, which were higher than those in winter (53±15%), and the seasonal variation was possibly due to the relatively high microbial biotransformation activities in the activated sludge system in summer (indexed by O3-NAs/NAs). The results of the investigations indicated that biotransformation of NA mixtures by the activated sludge system were largely affected by temperature, and employing an efficient adsorbent together with biodegradation processes would help cost-effectively remove NAs in petroleum effluents.

Antibiotic-resistance profile in environmental bacteria isolated from penicillin production wastewater treatment plant and the receiving river.

The antibiotic-resistance characteristics of bacterial strains in antibiotic production wastewater treatment plants (WWTP) that contain high concentrations of antibiotics are unknown, as are the environmental effects of the discharge of wastewater from such facilities. In this study, 417 strains were individually isolated from the effluent of a WWTP that treated penicillin G production wastewater, as well as from downstream and upstream areas of the receiving river. The minimum inhibition concentrations (MICs) of 18 antibiotics representing seven classes were then determined for each of these strains. Relatively high similarity in the bacterial composition existed between the wastewater and downstream river samples when compared with the upstream sample. High resistance ratios and MIC values were observed for almost all antibiotics in wastewater isolates, followed by strains from downstream river, of which the resistance ratios and levels were still significantly higher than those of upstream strains. The resistance ratios and levels also significantly differed among strains belonged to different species in the penicillin production wastewater effluent and downstream river. In both samples, the resistances to beta-lactam antibiotics were more frequent, with much higher levels, than the other class antibiotics. Then five clinically important resistant genes mainly coding for extended-spectrum beta-lactamases (ESBLs) were determined for all strains, only bla(TEM-1) which did not belong to ESBL was detected in 17.3% and 11.0% of strains isolated from wastewater and downstream river respectively. Class I integrons were detected in 14% of wastewater isolates and 9.1% of downstream isolates, and primarily contained gene cassettes conferring resistance to aminoglycoside antibiotics. The unexpectedly high levels of multiple antibiotic resistance in strains from wastewater and downstream river were speculated to be mainly due to multidrug efflux systems.

Evaluation of wastewater reclamation technologies based on in vitro and in vivo bioassays.

When municipal secondary effluent is used as the main supplementation water source for surface water bodies, its potential adverse ecological effects should not be neglected. The objective of this work was to investigate the effectiveness of several technologies, i.e. combination of coagulation and sand filtration (CSF), ultraviolet (UV) irradiation, chlorination, ozonation, ultrafiltration (UF) and reverse osmosis filtration (RO), on the removal of acute ecotoxicity, genotoxicity and retinoic acid receptor (RAR) agonist activity from the municipal secondary effluent. The effects of treated effluents on the development of Japanese medaka (Oryzias latipes) embryos were also evaluated. The secondary effluent exhibited a mutagenic effect on Salmonella typhimurium strain TA 1535/pSK1002, acute invertebrate toxicity to Daphnia magna, and weak RAR alpha activity. RO and ozonation demonstrated remarkable removals of the genotoxic effect, acute toxicity and RAR activity from secondary effluent, while chlorination could elevate both genotoxicity and acute toxicity. CSF, UV, UF, chlorination as well as RO could decrease the 4-day mortality of medaka embryos and accordingly increase the hatching success rate, comparing with the secondary effluent. Ozonation at 4 mg/l and higher doses, however, elicited significantly higher 4-day mortality, leading to the reduction of the hatching success rate.

Quantitative structure-activity relationships for estrogen receptor binding affinity of phenolic chemicals.

The estrogen receptor (ER) binding affinities of 25 compounds including 15 industrial phenolic chemicals, two phytoestrogens, three natural steroids and one man-made steroid were detected by a binding competition assay. The 17 industrial phenolic chemicals were selected as objective compounds because they are possibly released from epoxy and polyester-styrene resins used in lacquer coatings of concrete tank and lining of steel pipe in water supply system. A quantitative structure-activity relationship (QSAR) for structurally diverse phenols, nine alkylphenols with only one alkyl group, four hydroxyl biphenyls, bisphenol A and four natural and man-made estrogens was established by applying a quantum chemical modeling method. Logarithm of octanol-water coefficient (logPow), molecular volume (V(m)), and energies of the highest occupied molecular orbital ( epsilon (HOMO)) and lowest unoccupied molecular orbital ( epsilon (LUMO)) were selected as hydrophobic, steric (V(m)), and electronic chemical descriptors, respectively. Chemicals capable of ER binding had large V(m) and high epsilon (HOMO), while the effects of logPow and epsilon (LUMO) on the binding affinity could not be identified. The QSAR made successful predictions for the three phytoestrogens. Also, the successful prediction of ER-binding affinity for biochanin A, another phytoestrogen, two indicators of pH (phenolphthalin and phenolphthalein) and one alkylphenolic chemical with three alkyl groups (4-methyl-2,6-di-butyl-phenol), by amending the V(m) in the above-mentioned QSAR according to the electron-density distribution (or HOMO density) is an additional step in the elucidation of chemical steric and electronic parameters for predicting the binding affinities of phenolic compounds.