2022 - New Science: PFOS alters systemic TH levels without affecting TSH

There are over 9000 perfluorinated compounds manufactured today...
Post Reply
pfpcnews
Posts: 812
Joined: Mon Apr 03, 2006 5:50 am

2022 - New Science: PFOS alters systemic TH levels without affecting TSH

Post by pfpcnews »

Davidsen N, Ramhøj L, Lykkebo CA, Kugathas I, Poulsen R, Rosenmai AK, Evrard B, Darde TA, Axelstad M, Bahl MI, Hansen M, Chalmel F, Licht TR, Svingen T - "PFOS-induced thyroid hormone system disrupted rats display organ-specific changes in their transcriptomes" Environ Pollut 305:119340 (2022)
https://pubmed.ncbi.nlm.nih.gov/35460815/
https://www.sciencedirect.com/science/a ... via%3Dihub

Abstract
Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans and animals. In adults, thyroid hormones (THs) are regulated by the hypothalamic-pituitary-thyroid (HPT) axis, but also by organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore disrupt the TH system at various locations and through different mechanisms. To start addressing this, we exposed adult male rats to 3 mg PFOS/kg/day for 7 days and analysed effects on multiple organs and pathways simultaneously by transcriptomics. This included four primary organs involved in TH regulation, namely hypothalamus, pituitary, thyroid, and liver. To investigate a potential role of the gut microbiota in thyroid hormone regulation, two additional groups of animals were dosed with the antibiotic vancomycin (8 mg/kg/day), either with or without PFOS. PFOS exposure decreased thyroxine (T4) and triiodothyronine (T3) without affecting thyroid stimulating hormone (TSH), resembling a state of hypothyroxinemia. PFOS exposure resulted in 50 differentially expressed genes (DEGs) in the hypothalamus, 68 DEGs in the pituitary, 71 DEGs in the thyroid, and 181 DEGs in the liver. A concomitant compromised gut microbiota did not significantly change effects of PFOS exposure. Organ-specific DEGs did not align with TH regulating genes; however, genes associated with vesicle transport and neuronal signaling were affected in the hypothalamus, and phase I and phase II metabolism in the liver. This suggests that a decrease in systemic TH levels may activate the expression of factors altering trafficking, metabolism and excretion of TH. At the transcriptional level, little evidence suggests that the pituitary or thyroid gland is involved in PFOS-induced TH system disruption.

EXCERPTS:

"Another point to consider with respect to PFOS exposure is the gut microbiota. The intestinal microbiota can affect TH metabolism by interfering with iodine uptake, as well as degradation and enterohepatic cycling of TH (Fröhlich and Wahl, 2019). In rats, an altered microbiota can lead to changes in serum TH levels, as well as TH excretion (de Herder et al., 1989). The microbiota also plays a role in the intestinal cycling of TH destined for excretion (de Herder et al., 1989; van der Spek et al., 2017) and PFASs are known to go through enterohepatic cycling in both humans and rats (Johnson et al., 1984; Zhao et al., 2017). Therefore, the composition of the gut microbiota could potentially impact how PFOS exposure disrupts the TH system."

SEE: Gut Dysbiosis
viewtopic.php?f=7&t=1850

"PFASs are known to affect Wnt signaling (Yang et al., 2020), so we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway resource implemented into the pathview tool (Luo and Brouwer, 2013) to display potential DEGs relevant to Wnt signaling. Irrespective of GO functional terms, it revealed that some genes of the Wnt signaling pathway were affected by PFOS exposure when combining DEGs from all organs, for instance the G protein-coupled receptor Frizzled (Fig. 5). Similarly, some of the DEGs identified in the animals exposed to PFOS are known to be involved in MAPK, calcium, or PPAR signaling pathways (Figure S4-S6, S2_Supplementary_Figures)."

SEE: Wnt
viewtopic.php?f=75&t=2579

"We also found that the TH metabolites rT3 and T1Ac were reduced, which indicates that the PFOS effect profile extends beyond T3 and T4. Finally, we saw no changes to TSH levels in serum, nor changes to thyroid gland weights, supporting the fact that TSH is not elevated in response to the pronounced drop in serum T4 and T3."

"...This suggests that PFOS exposure affects the hypothalamus in a way that could impact TRH regulation. However, the HPT axis is still functional in PFOS-exposed male rats (Chang et al., 2008). Nevertheless, our results suggest that PFOS could affect TRH regulation directly, albeit our study design precludes the possibility to address this specifically. Importantly, however, it is still difficult to discriminate between effects that may be caused directly by PFOS exposure and those that potentially are caused by a lack of TH in the hypothalamus or the brain. Further studies are needed to understand the extent of effects on neuronal function in the hypothalamus, as well as effects on TRH release."

"Although our thyroid hormone system-disrupted rats did not reveal obvious enrichments or DEGs that are known to be central players in thyroid signaling, KEGG analysis did reveal potential disruptions to other important regulatory pathways. For instance, Wnt signaling, which is affected by PFOS in vitro (Yang et al., 2020), showed some signs of disruption in all of the four organs. In addition, DEGs did associate with calcium, MAPK and PPAR signaling pathways. Importantly, multiple genes of the PPAR signaling pathway were dysregulated in the liver, showing that PPAR is a likely target for PFOS. It should be noted, however, that this study has analysed transcriptional changes in the adult rat. In adult animals, the impact of dysregulation to key regulatory pathways may not be as consequential as they would be if exposure occurs during development, for example with Wnt signaling that is crucial for guiding numerous developmental processes. A second point is that these transcriptional changes are just as likely not a consequence of reduced TH levels, but a direct effect of PFOS on target tissues. Our study design cannot distinguish between what effects are caused directly by PFOS or secondary to TH system disruption, or a mixture of the two."
Post Reply