Interactions of Environmental Chemicals and Natural Products With ABC and SLC Transporters in the Digestive System of Aquatic Organisms

An organism’s diet is a major route of exposure to both beneficial nutrients and toxic environmental chemicals and natural products. The uptake of dietary xenobiotics in the intestine is prevented by transporters of the Solute Carrier (SLC) and ATP Binding Cassette (ABC) family. Several environmental chemicals and natural toxins have been identified to induce expression of these defense transporters in fish and aquatic invertebrates, indicating that they are substrates and can be eliminated. However, certain environmental chemicals, termed Transporter-Interfering Chemicals or TICs, have recently been shown to bind to and inhibit fish and mammalian P-glycoprotein (ABCB1), thereby sensitizing cells to toxic chemical accumulation. If and to what extent other xenobiotic defense or nutrient uptake transporters can also be inhibited by dietary TICs is still unknown. To date, most chemical-transporter interaction studies in aquatic organisms have focused on ABC-type transporters, while molecular interactions of xenobiotics with SLC-type transporters are poorly understood. In this perspective, we summarize current advances in the identification, localization, and functional analysis of protective MXR transporters and nutrient uptake systems in the digestive system of fish and aquatic invertebrates. We collate the existing literature data on chemically induced transporter gene expression and summarize the molecular interactions of xenobiotics with these transport systems. Our review emphasizes the need for standardized assays in a broader panel of commercially important fish and seafood species to better evaluate the effects of TIC and other xenobiotic interactions with physiological substrates and MXR transporters across the aquatic ecosystem and predict possible transfer to humans through consumption.

Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

Obituary: Dr Gordon Charles Hard (1931-2021)

Dr Gordon Hard, of Tairua, New Zealand, a preeminent international toxicology thought leader and international consultant in toxicologic pathology of the kidney, passed on November 22, 2021. He was a key player in shaping and developing the global field of toxicologic pathology and the role of toxicologic pathology in risk assessment of environmental chemicals and pharmaceuticals.

Profile of Environmental Chemicals in the Korean Population—Results of the Korean National Environmental Health Survey (KoNEHS) Cycle 3, 2015–2017

The Korean National Environmental Health Survey (KoNEHS) program provides useful information on chemical exposure, serves as the basis for environmental health policies, and suggests appropriate measures to protect public health. Initiated on a three-year cycle in 2009, it reports the concentrations of major environmental chemicals among the representative Korean population. KoNEHS Cycle 3 introduced children and adolescents into the analysis, where the blood and urine samples of 6167 participants were measured for major metals, phthalates, phenolics, and other organic compounds. Lead, mercury, cadmium, metabolites of DEHP and DnBP, and 3-phenoxybenzoic acid levels of the Korean adult population tended to decrease compared to previous survey cycles but remained higher than those observed in the US or Canada. Both bisphenol A (BPA) and trans,trans-muconic acid concentrations have increased over time. Heavy metal concentrations (blood lead, and cadmium) in children and adolescents were approximately half that of adults, while some organic substances (e.g., phthalates and BPA) were high. BPA showed higher levels than in the US or Canada, whereas BPF and BPS showed lower detection rates in this cycle; however, as these are increasingly used as a substitute for BPA, further research is necessary. As environmental chemicals may affect childhood health and development, additional analyses should assess exposure sources and routes through continuous observations.

Ovine fetal testis stage-specific sensitivity to environmental chemical mixtures

Exposure of the fetal testis to numerous individual environmental chemicals is frequently associated with dysregulated development, leading to impaired adult reproductive competence. However, ‘real-life’ exposure involves complex mixtures of environmental chemicals (ECs). Here we test the consequences, for the male fetus, of exposing pregnant ewes to EC mixtures derived from pastures treated with biosolids fertiliser (processed human sewage). Fetal testes from continuously exposed ewes were either unaffected at Day 80 or exhibited a reduced area of testis immunostained for CYP17A1 protein at Day 140. Fetal testes from Day 140 pregnant ewes exposed transiently for 80 day periods during early (0-80 days), mid (30-110 days) or late (60-140 days) pregnancy, had fewer Sertoli cells and reduced testicular area stained for CYP17A1. Male fetuses from ewes exposed during late pregnancy also exhibited reduced fetal body, adrenal and testis mass, anogenital distance and lowered testosterone: collectively indicative of an anti-androgenic effect. Exposure limited to early gestation induced more testis transcriptome changes than observed for continuously exposed Day 140 fetuses. These data suggest that a short period of EC exposure does not allow sufficient time for the testis to adapt. Consequently, testicular transcriptomic changes induced during the first 80 days of gestation may equate with phenotypic effects observed at Day 140. In contrast, relatively fewer changes in the testis transcriptome in fetuses exposed continuously to ECs throughout gestation is associated with less severe consequences. Unless corrected by or during puberty, these differential effects would predictably have adverse outcomes for adult testicular function and fertility.

Multiple Chemical Sensitivity

Multiple Chemical Sensitivity (MCS), a condition also known as Chemical Sensitivity (CS), Chemical Intolerance (CI), Idiopathic Environmental Illness (IEI) and Toxicant Induced Loss of Tolerance (TILT), is an acquired multifactorial syndrome characterized by a recurrent set of debilitating symptoms. The symptoms of this controversial disorder are reported to be induced by environmental chemicals at doses far below those usually harmful to most persons. They involve a large spectrum of organ systems and typically disappear when the environmental chemicals are removed. However, no clear link has emerged among self-reported MCS symptoms and widely accepted objective measures of physiological dysfunction, and no clear dose-response relationship between exposure and symptom reactions has been observed. In addition, the underlying etiology and pathogenic processes of the disorder remain unknown and disputed, although biologic and psychologic hypotheses abound. It is currently debated whether MCS should be considered a clinical entity at all. Nevertheless, in the last few decades MCS has received considerable scientific and governmental attention in light of the many persons reporting this illness. In this review, we provide a general overview of the history, definition, demographics, prevalence, and etiologic challenges in defining and understanding MCS.

From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study

Hazard assessment strategies are often supported by extrapolation of damage probabilities, regarding chemical action and species susceptibilities. Yet, growing evidence suggests that an adequate sampling of physiological responses across a representative taxonomic scope is of paramount importance. This is particularly relevant for Nuclear Receptors (NR), a family of transcription factors, often triggered by ligands and thus, commonly exploited by environmental chemicals. Within NRs, the ligand-induced Ecdysone Receptor (EcR) provides a remarkable example. Long regarded as arthropod specific, this receptor has been extensively targeted by pesticides, seemingly innocuous to non-target organisms. Yet, current evidence clearly suggests a wider presence of EcR orthologues across metazoan lineages, with unknown physiological consequences. Here, we address the state-of-the-art regarding the phylogenetic distribution and functional characterization of metazoan EcRs and provide a critical analysis of the potential disruption of such EcRs by environmental chemical exposure. Using EcR as a case study, hazard assessment strategies are also discussed in view of the development of a novel “precision hazard assessment paradigm.

Reduction of Environmental Chemicals, Toxicity and Particulate Matter in Wet Scrubber Device to Achieve Zero Emissions

When fine particles generated by the foundry industry are present in the atmosphere, they have an impact on the climate because of their influence on atmospheric radioactive phenomena. As a result of this scenario, there is a rising amount of legislation restricting the emission of pollutants from foundry industries and related businesses. In response to this situation, many researchers have concentrated on end-of-pipe technologies, one of which is the wet scrubber, which is a device that is primarily used in foundries to control pollution and is one of the devices that has been incorporated. The disadvantage of using this wet scrubber, on the other hand, is that it contributes to secondary pollution when it is used. In order to combat secondary pollution, a model of an enhanced wet scrubber system that incorporates a multi-sand filtering technology was developed. The performance of this redesigned wet scrubber system was evaluated with the use of computational fluid dynamics software. Because of the introduction of the filtration tank's computation, it was discovered that successful filtration was accomplished using sand filters, meaning that environmental chemicals and particles were totally filtered from 0.17 kg at the entrance to zero kg of particles at the outflow.

Targeted Metabolomics to Assess Exposure to Environmental Chemicals of Concern in Japanese Quail at Two Life Stages

This proof-of-concept study characterizes the Japanese quail (Coturnix japonica) hepatic metabolome following exposure to benzo[a]pyrene, chlorpyrifos, ethinylestradiol, fluoxetine hydrochloride, hexabromocyclododecane, lead(II)nitrate, seleno-L-methionine, and trenbolone in embryos and adults. The analysis revealed effects on lipid metabolism following exposure to several chemicals at both life stages. The most pronounced effects were observed in embryos exposed to 41.1 μg/g chlorpyrifos. This work highlighted challenges and the need for further avian metabolomics studies.