Table 1.

The key pathways and their relevance to both mercury exposure and TC

Pathway	Hg relevance	TC relevance	Mechanism
RAS/MAPK/PI3K	Hg – > RAS activation	H-RAS, N-RAS, K-RAS activating mutation in TC	RAS activation– > MAPK and PI3K activation downstream
MAPK/ERK	Hg – > MAPK activation	RET/PTC fusion, RET activating mutation, BRAF mutations in TC	MAPK activation– > ERK phosphorylation
PTEN/Akt/CREB	Hg – > PTEN inhibition	PTEN inhibiting mutations, AKT1 activating mutation in TC	Akt/CREB activation
Endocrine/HPA axis	Hg – > Low T3/T4; Elevated TSH	High TSH– > thyroid cell proliferation in TC	Cell proliferation stimulated by TSH
ROS/Nrf2	Hg – > ROS production– > Nrf2 activation	Nrf2 signaling – > PTC	Nrf2 signaling– > Apoptosis inhibition
ROS/ oxidative stress	Hg – > ROS production– > DNA damage	Oxidative stress– > DNA damage– > carcinogenesis	DNA damage
DNA repair	Hg – > Inhibition of DNA repair proteins (PARP-1, DNA ligase III-alpha, XRCC1)	Inability to repair DNA damage– > carcinogenesis	DNA damage

Hg = mercury; RAS/MAPK/PI3K = cell signaling cascades; ERK = extracellular signal-regulated kinase; RET = a relevant receptor tyrosine kinase; PTEN = phosphatase and tensin homolog; Akt/CREB = signaling cascade in cell survival; HPA = hypothalamic–pituitary–adrenal axis; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; TC = thyroid cancer; ROS = reactive oxygen species; Nrf2 = Nuclear factor erythroid 2-related factor 2 (Prete et al. 2020; Hao et al. 2009; Maggisano et al. 2020; Unoki et al. 2016; Steinhaus et al. 2021; Marotta et al. 2020; Fiore et al. 2009; Boelaert 2009; Mohammadi-Bardbori and Rannug 2014; Buha et al. 2021; Tinkov et al. 2021; Ziros et al. 2013; Skalny et al. 2022; Wyatt et al. 2017; Pieper et al. 2014; Cebulska-Wasilewska et al. 2005)