Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

Abstract

Humans are exposed to a large number of environmental chemicals in their daily life, many of which are readily detectable in blood or urine. It remains uncertain if these chemicals can cause adverse health effects when present together at low doses. In this study we have tested whether a mixture of 27 chemicals administered orally to juvenile male rats for three months could leave a pathophysiological footprint. The mixture contained metals, perfluorinated compounds, PCB, dioxins, pesticides, heterocyclic amines, phthalate, PAHs and others, with a combined dose of 0.16 (Low dose), 0.47 (Mid dose) or 1.6 (High dose) mg/kg bw/day. The lowest dose was designed with the aim of obtaining plasma or urine concentrations in rats at levels approaching those observed in humans. Some single congeners were administered at doses representative of combined doses for chemical groups. With this baseline, we found effects on weight, histology and gene expression in the liver, as well as changes to the blood plasma metabolome in all exposure groups, including low-dose. Additional adverse effects were observed in the higher dosed groups, including enlarged kidneys and alterations to the metabolome. No significant effects on reproductive parameters were observed.

Metabolomic Markers of Phthalate Exposure in Plasma and Urine of Pregnant Women

“…It may be possible that these hormone levels are related to cholesterol availability which is regulated by SREBP1c and activated by phthalate exposure ( 55 ). The discrepancy in hormone level changes in previous reports and our findings may reflect experimental differences in animal or cell culture models compared to human subjects, or perhaps related to dose effects ( 46 ).…”

“…In animal models, the association of phthalate biomarkers with increased inflammatory response has been clearly demonstrated with detrimental effects on the neonate ( 43 – 45 ). For example, as with our study, rats exposed to phthalate also have increased arachidonate containing phosphatidylcholine ( 46 ). Multiple studies have evaluated phthalate exposure in pregnant women ( 47 – 49 ), and several have also demonstrated relationships with oxidative stress markers across pregnancy ( 11 , 50 ).…”

“…Muczynski et al, showed that phthalates increase the levels of mRNA for LXR α, and SREBP members, possibly up-regulating lipid and cholesterol synthesis in human fetal gonads ( 53 ). Consistent with the up-regulated genes, phospholipids and neutral lipids are increased in rats with phthalate exposure ( 46 ). Our results showing correlations between higher phthalate exposure with products of lipid biosynthesis provides evidence that phthalate-induced disruption of upstream transcription factors (LXR, SREBP1c, SREBP2) may also occur in humans, contributing to increased lipid biosynthesis and obesity.…”

Metabolomics in chemical risk analysis – A review

“…Environmental and dietary exposure levels or NOAELs are usually included as the lowest data point of doseresponse curves when carrying out human health hazard characterization of chemical mixtures by metabolomics approaches [150,152,153]; therefore, it cannot be considered that the effects of low doses of chemical mixtures have been studied by metabolomics in detail. More importantly, when investigating possible effects by metabolomics, it should be relevant to include groups exposed to individual chemicals in order to correctly conclude that the metabolome disruption is a consequence of additive or interactive effects of the mixture rather than an observation resulting from increased sensitivity of the metabolomics approach compared to the toxicity test used for the establishment of the individual NOAELs.…”

Regulatory assessment and risk management of chemical mixtures: challenges and ways forward

“…Silva et al 2002). In addition, combined effects from simultaneous exposure to multiple chemicals at human-relevant levels were demonstrated (Hadrup et al 2016). Moreover, possible combined effects from sequential exposure to multiple chemicals should not be overlooked considering also chemicals with dissimilar effects, for example, if chemicals act on pathways involved in carcinogenesis Weinberg 2000, 2011).…”