Assessment of endocrine-disrupting effects of emerging polyhalogenated carbazoles (PHCZs): In vitro, in silico, and in vivo evidence.

Polyhalogenated carbazoles (PHCZs) are an emerging class of persistent, bioaccumulative compounds that are structurally and chemically related to dioxins. They have been detected widely in sediment, river, and soil samples, but their environmental risks are largely unknown. Therefore, seven common PHCZs were tested for their endocrine disrupting potential in silico, in vitro, and in vivo. A dual-luciferase reporter gene assay was used to detect receptor-mediated (agonist or antagonistic) activity (concentration range: 10-9-10-5 M) against the estrogen receptor α (ERα), glucocorticoid receptor α (GRα), and mineralocorticoid receptor (MR). The alterations in the steroidogenesis pathway were investigated in H295R cells. Antagonistic effects against GRα were observed with five PHCZs, along with an increase in the cortisol levels of H295R cells. The most common effect observed was that of the agonistic activity of ERα, with the molecular docking analysis further indicating that hydrogen bonding and hydrophobic interactions may stabilize the interaction between PHCZs and the estrogen receptor binding pocket. In addition, a seven-day exposure of young female rats to three PHCZs (27-BCZ, 3-BCZ, and 36-BCZ) resulted in changes in serum E2 levels, uterine epithelium cell heights, and relative uterus weights. In conclusion, endocrine-disrupting effects, especially the estrogenic effects, were observed for the tested PHCZs. Such adverse effects of PHCZs on humans and wildlife warrant further thorough investigation.

Metabolomic modulations of HepG2 cells exposed to bisphenol analogues.

Bisphenol analogues including bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol S (BPS) share similar chemical structures and endocrine disrupting effects. Their effects on metabolisms, however, are so far only marginally understood. In this study, NMR-based metabonomic profiles of HepG2 cell culture media and PCR array were used to assess the metabolomics disturbances and gene expression levels of HepG2 in response to four BPs (BPA, BPAF, BPF, and BPS). The results indicated that BP analogues resulted in disturbances in 7-15 metabolites that were classified as amino acid (alanine, glutamine, glutamate), intermediates and end-products in the glycolysis (pyruvate) and the tricarboxylic acid cycle (acetate, lactate). Their rank in order according to the number of metabolites and pathways was BPF > BPA > BPAF > BPS. The common disrupted pathways (pyruvate metabolism; alanine, aspartate, and glutamate metabolism) indicated enhanced glycolysis. The following glucometabolic PCR array analysis suggested that although four BPs shared the capability of disrupting glucose metabolism, they may act through different mechanisms: BPAF has increased the pyruvate kinase (PKLR) expression level, which implied enhanced glycolysis that was agreed with NMR results. The other three BP analogues, however, decreased the expression level of glucokinase (GCK) that indicated glucose sensing impairment. Our results demonstrated the potential for using metabolomic and PCR array to understand the underlying action of mechanisms and identify the potential targets for future targeted risk assessment.

Consumption of drinking water N-Nitrosamines mixture alters gut microbiome and increases the obesity risk in young male rats.

N-nitrosamines (NAs) are an emerging group of disinfection by-products that occur as a mixture in drinking water. Although the potency of the individual NA components in drinking water is negligible, their combined effect is rarely reported. We tested whether multicomponent NAs mixtures at environmentally relevant levels would produce significant effects when each component was combined at extremely low concentrations i.e. a million times lower than its No Observed Effect Concentration (NOEC). Mixture L (the maximum values detected in drinking water) or mixture M (one order of magnitude higher than detected) were fed to male and female Sprague-Dawley (SD) rats since PND 28 for seven days. We found that the body weight gains and the triglyceride (TG) levels increased significantly in mixture M treated male rats. Correspondingly, an obesogenic microbiota profile was obtained in the mixture M treated young male rat: Firmicutes/Bacteroidetes and the obesity-related taxa including Alistipes, Ruminococcus were enriched. Collectively, this is the first in vivo demonstration of NAs mixtures at environmentally relevant levels. Despite the complicated relationship between gut microbiota and obesity, our study has demonstrated that changes in gut microbiota may contribute to the development of obesity after the exposure. Our results highlight that changes in gut microbiota could be a risk factor for obesity, which emphasizes the need to include gut microbiota in the traditional mammalian risk assessment.

Insights into the interactions between tetracycline, its degradation products and bovine serum albumin.

Tetracyclines (TCs) are the most widely used antibiotics in the world. Because antibiotics have low bioavailability and are difficult to completely remove using current sewage treatment facilities, residual TCs and their degradation products in the environment, animal and plant foodstuffs and personal care products may enter the body through the food chain, thus causing unpredictable effects on human health. We studied bovine serum albumin (BSA) (a functional protein) as a target of tetracycline-induced toxicity by examining its interactions with TC, anhydrotetracycline (ATC) and epitetracycline (ETC), based on a fluorescence spectroscopy and molecular docking method under simulated physiological conditions. The interaction mechanism was elucidated at the molecular level. The results show that TC, ATC and ETC bind at site II of BSA and interact mainly through hydrogen bonding interactions and van der Waals interactions. The binding affinities can be ranked in the order ATC > TC > ETC.