Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice.

Rodent alveolar/bronchiolar carcinomas (ABC) that arise either spontaneously or due to chemical exposure are similar to a subtype of lung adenocarcinomas in humans. B6C3F1/N mice and F344/NTac rats exposed to cobalt metal dust (CMD) by inhalation developed ABCs in a dose dependent manner. In CMD-exposed mice, the incidence of Kras mutations in ABCs was 67% with 80% of those being G to T transversions on codon 12 suggesting a role of oxidative stress in the pathogenesis. In vitro studies, such as DMPO (5,5-dimethyl-1-pyrroline N-oxide) immune-spin trapping assay, and dihydroethidium (DHE) fluorescence assay on A549 and BEAS-2B cells demonstrated increased oxidative stress due to cobalt exposure. In addition, significantly increased 8-oxo-dG adducts were demonstrated by immunohistochemistry in lungs from mice exposed to CMD for 90 days. Furthermore, transcriptomic analysis on ABCs arising spontaneously or due to chronic CMD-exposure demonstrated significant alterations in canonical pathways related to MAPK signaling (IL-8, ErbB, Integrin, and PAK pathway) and oxidative stress (PI3K/AKT and Melatonin pathway) in ABCs from CMD-exposed mice. Oxidative stress can stimulate PI3K/AKT and MAPK signaling pathways. Nox4 was significantly upregulated only in CMD-exposed ABCs and NOX4 activation of PI3K/AKT can lead to increased ROS levels in human cancer cells. The gene encoding Ereg was markedly up-regulated in CMD-exposed mice. Oncogenic KRAS mutations have been shown to induce EREG overexpression. Collectively, all these data suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents and these findings may also be relevant in the context of human lung cancers.

Impairment in Working Memory and Executive Function Associated with Mercury Exposure in Indigenous Populations in Upper Amazonian Peru.

The Matsigenka people living traditional lifestyles in remote areas of the Amazon rely on a fish-based diet that exposes them to methylmercury (MeHg) at levels that have been associated with decreased IQ scores. In this study, the association between Hg levels and working memory was explored using the framework of the Multicomponent Model. Working memory tasks were modified to fit the culture and language of the Matsigenka when needed and included measures for verbal storage (Word Span) visuospatial storage (Corsi Block Task) and a measure of executive functions, the Self-Ordered Pointing Task (SOPT). An innovation of the Trail Making Tests A & B (TMT A & B) was pilot tested as another potential measure of executive functions. The mean hair Hg levels of 30 participants, ages 12 to 55 years, from three different communities (Maizal, Cacaotal and Yomibato) was 7.0 ppm (sd = 2.40), well above the World Health Organization (WHO) limit for hair of 2.0 ppm and ranged from 1.8 to 14.2 ppm, with 98% of a broader sample of 152 individuals exceeding the WHO limit. Hair Hg levels showed significant associations with cognitive performance, but the degree varied in magnitude according to the type of task. Hg levels were negatively associated with executive functioning performance (SOPT errors), while Hg levels and years of education predicted visuospatial performance (Corsi Block accuracy). Education was the only predictor of Word Span accuracy. The results show that Hg exposure is negatively associated with working memory performance when there is an increased reliance on executive functioning. Based on our findings and the review of the experimental research, we suggest that the SOPT and the Corsi Block have the potential to be alternatives to general intelligence tests when studying remote groups with extensive cultural differences.