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Early Life Exposure to Environmental Contaminants (BDE-47, TBBPA, and BPS) Produced Persistent Alterations in Fecal Microbiome in Adult Male Mice.

ABSTRACT: The gut microbiome is a pivotal player in toxicological responses. We investigated the effects of maternal exposure to 3 human health-relevant toxicants (BDE-47, tetrabromobisphenol [TBBPA], and bisphenol S [BPS]) on the composition and metabolite levels (bile acids [BAs] and short-chain fatty acids [SCFAs]) of the gut microbiome in adult pups. CD-1 mouse dams were orally exposed to vehicle (corn oil, 10 ml/kg), BDE-47 (0.2 mg/kg), TBBPA (0.2 mg/kg), or BPS (0.2 mg/kg) once daily from gestational day 8 to the end of lactation (postnatal day 21). 16S rRNA sequencing and targeted metabolomics were performed in feces of 20-week-old adult male pups (n = 14 - 23/group). Host gene expression and BA levels were quantified in liver. BPS had the most prominent effect on the beta-diversity of the fecal microbiome compared with TBPPA and BDE-47 (QIIME). Seventy-three taxa were persistently altered by at least 1 chemical, and 12 taxa were commonly regulated by all chemicals (most of which were from the Clostridia class and were decreased). The most distinct microbial biomarkers were S24-7 for BDE-47, Rikenellaceae for TBBPA, and Lactobacillus for BPS (LefSe). The community-wide contributions to the shift in microbial pathways were predicted using FishTaco. Consistent with FishTaco predictions, BDE-47 persistently increased fecal and hepatic BAs within the 12α hydroxylation pathway, corresponding to an up-regulation with the hepatic BA-synthetic enzyme Cyp7a1. Fecal BAs were also persistently up-regulated by TBBPA and BPS (liquid chromatography-mass spectrometry). TBBPA increased propionic acid and succinate, whereas BPS decreased acetic acid (gas chromatography-mass spectrometry). There was a general trend in the hepatic down-regulation of proinflammatory cytokines and the oxidative stress sensor target gene (Nqo1), and a decrease in G6Pdx (the deficiency of which leads to dyslipidemia). In conclusion, maternal exposure to these toxicants persistently modified the gut-liver axis, which may produce an immune-suppressive and dyslipidemia-prone signature later in life.

SUBMITTER: Gomez MV

PROVIDER: S-EPMC8456301 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants until the early 2000s, mainly in home furnishings and electronics. The persistence of PBDEs in the environment leads to continued ubiquitous exposure to low levels, with infants and children experiencing higher exposures than adults. Accumulating evidence suggest that low-level exposures during early life stages can affect brain development and lead to long-term behavioral impairments. We investigated the effects of zebrafish exposure to low doses of the two prominent PBDEs; 2,2',4,4',5,-Pentabromodiphenyl ether (BDE-99) and 2,2',4,4',-Tetrabromodiphenyl ether (BDE-47), during embryo-development on short- and long-term behavioral endpoints. We included the organophosphate pesticide chlorpyrifos (CPF) due to its well documented neurotoxicity across species from zebrafish to humans. METHODS:Zebrafish embryos were exposed to the following individual treatments; 0.1% DMSO (vehicle control); 0.3?M CPF; 0.01, 0.03, 0.1, 0.3?M BDE-47; 0.003, 0.03, 0.3, 1, 3, 10, 20?M BDE-99 from 5 until 120h post fertilization (hpf). Low exposure levels were determined as those not causing immediate overt toxicity, and behavior assays were conducted in the low-level range. At 144 hpf the larvae were tested for locomotor activity. At approximately 6 months of age adult zebrafish were tested in a behavioral battery including assays for anxiety-related behavior, sensorimotor response and habituation, social interaction, and predator avoidance. RESULTS:In the short-term, larval locomotor activity was reduced in larvae treated with 0.3?M CPF and 0.1?M BDE-47. BDE-99 treatment caused non-monotonic dose effects, with 0.3?M causing hyperactivity and 1?M or higher causing hypoactivity. In the long-term, adult anxiety-related behavior was reduced in all treatments as measured in both the novel tank dive test and tap test. DISCUSSION:We show that exposure of zebrafish embryos to low concentrations of the brominated flame retardants BDE-47 and BDE-99, and the organophosphate pesticide CPF, caused both short- and long-term behavioral impairments. Interestingly, we also found that at very low exposure concentrations, where there were no visible effects on larval activity, adult behavior was still strongly affected.

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Early Life Exposure to Environmental Contaminants (BDE-47, TBBPA, and BPS) Produced Persistent Alterations in Fecal Microbiome in Adult Male Mice.

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