In vitro human cell-based TTR-TRβ CALUX assay indicates thyroid hormone transport disruption of short-chain, medium-chain, and long-chain chlorinated paraffins

Abstract

Over the last decades, short-chain chlorinated paraffins (SCCPs), medium-chain chlorinated paraffins (MCCPs), and long-chain chlorinated paraffins (LCCPs) have become the most heavily produced monomeric organohalogen compound class of environmental concern. However, knowledge about their toxicology is still scarce, although SCCPs were shown to have effects on the thyroid hormone system. The lack of data in the case of MCCPs and LCCPs and the structural similarity with perfluoroalkyl substances (PFAS) prompted us to test CPs in the novel TTR-TR CALUX assay for their thyroid hormone transport disrupting potential. Four self-synthesized and additionally purified single chain length CP mixtures (C10-CPs, C11-CPs, C14-CPs and C16-CPs) and two each of industrial MCCP and LCCP products were tested in parallel with PFOA. All CP mixtures influenced the TTR binding of T4, giving activities of 1,300 to 17,000 µg/g PFOA equivalents and lowest observable effect concentrations (LOELs) of 0.95 to 0.029 mM/L incubate. Highest activities and lowest LOELs were observed for C16-CPs (48.3% Cl content, activity 17,000, LOEL 0.047 mM/L) and a LCCP mixture (71.7% Cl content; activity 10,000; LOEL 0.029 mM/L). A trend of higher activities and lower LOELs towards longer chains and higher chlorination degrees was implied, but could not be statistically confirmed. Irrespectively, the less well examined and current-use LCCPs showed the highest response in the TTR-TRβ CALUX assay.

Long-Chain Chlorinated Paraffins Have Reached the Arctic

“…The current study found that LCCPs as well as other CP classes have been present in Arctic biota for decades. LCCPs have recently shown stronger suppressive effects on membrane transport of amino acids in a cytotoxic study and higher thyroid hormone transport disrupting potential based on the TTR-TRβ CALUX assay, compared to SCCPs and MCCPs . The cumulative effect of exposure to many organohalogen compounds could also result in lower effect levels of complex mixtures relative to single compounds for marine mammal immunity .…”

“…LCCPs have recently shown stronger suppressive effects on membrane transport of amino acids in a cytotoxic study 53 and higher thyroid hormone transport disrupting potential based on the TTR-TRβ CALUX assay, compared to SCCPs and MCCPs. 54 The cumulative effect of exposure to many organohalogen compounds 6 could also result in lower effect levels of complex mixtures relative to single compounds for marine mammal immunity. 4 In addition, aquatic invertebrates are sensitive to CP toxicity, and fish may be sensitive to CPs following prolonged exposure to low concentrations.…”

Substances of emerging concern in Baltic Sea water: Review on methodological advances for the environmental assessment and proposal for future monitoring

“…In vitro bioassays that measure estrogenic effects would, thus, target substances such as EE2, E2, and E1, but also weaker estrogens such as nonylphenols. Correspondingly, in vitro bioassays measuring thyroid-transthyretin disruption (TTR-TRβ CALUX) would target several PFAS compounds, but also chlorinated paraffins (Sprengel et al 2021 ).…”

Temporal Trends and Age-Dependent Sex Differences in Chlorinated Paraffin Accumulation in Moose

“…The dose makes the poison . The dramatic age-dependent increase of CP concentrations in adult male moose indicates elevated risks of adverse effects including carcinogenic and endocrine-disrupting effects . In particular, the significant age-dependent accumulation tendency of SCCPs in male moose is perhaps of high concern.…”

“…40 The dramatic age-dependent increase of CP concentrations in adult male moose indicates elevated risks of adverse effects including carcinogenic 19 and endocrine-disrupting effects. 16 In particular, the significant age-dependent accumulation tendency of SCCPs in male moose is perhaps of high concern. Recent studies revealed oxidative stress effects of SCCPs, 17 and SCCPs showed activation of NRF2 with cross-model comparison of transcriptomic dose−response.…”