Arsenic exposure induces a bimodal toxicity response in zebrafish

AbstractChronic arsenic exposure causes skin cancer, although the underlying molecular mechanisms are not well defined. Altered microRNA and mRNA expression likely play a pivotal role in carcinogenesis. Changes in genome-wide differential expression of miRNA and mRNA at 3 strategic time points upon chronic sodium arsenite (As3+) exposure were investigated in a well-validated HaCaT cell line model of arsenic-induced cutaneous squamous cell carcinoma (cSCC). Quadruplicate independent HaCaT cell cultures were exposed to 0 or 100 nM As3+ for up to 28-weeks (wk). Cell growth was monitored throughout the course of exposure and epithelial-mesenchymal transition (EMT) was examined employing immunoblot. Differentially expressed miRNA and mRNA profiles were generated at 7, 19, and 28-wk by RNA-seq, followed by identification of differentially expressed mRNA targets of differentially expressed miRNAs through expression pairing at each time point. Pathway analyses were performed for total differentially expressed mRNAs and for the miRNA targeted mRNAs at each time point. RNA-seq predictions were validated by immunoblot of selected target proteins. While the As3+-exposed cells grew slower initially, growth was equal to that of unexposed cells by 19-wk (transformation initiation), and exposed cells subsequently grew faster than passage-matched unexposed cells. As3+-exposed cells had undergone EMT at 28-wk. Pathway analyses demonstrate dysregulation of carcinogenesis-related pathways and networks in a complex coordinated manner at each time point. Immunoblot data largely corroborate RNA-seq predictions in the endoplasmic reticulum stress (ER stress) pathway. This study provides a detailed molecular picture of changes occurring during the arsenic-induced transformation of human keratinocytes.

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Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres

International Journal of Toxicology ◽

10.1177/10915818211009844 ◽

2021 ◽

Vol 40 (3) ◽

pp. 211-217

Author(s):

Brayden Whitlock

Keyword(s):

Animal Models ◽

Telomere Length ◽

Mouse Models ◽

Arsenic Exposure ◽

Tumor Formation ◽

The Body ◽

Cancer Resistance ◽

Selective Pressures ◽

Toxicity Monitoring ◽

In Captivity

Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.

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Drinking Water Arsenic and Adverse Reproductive Outcomes in Men and Women: A Systematic PRISMA Review

Water ◽

10.3390/w13141885 ◽

2021 ◽

Vol 13 (14) ◽

pp. 1885

Author(s):

Ida M. Barsøe ◽

Ninna H. Ebdrup ◽

Hannah S. Clausen ◽

Julie Lyngsø ◽

Jörg Schullehner ◽

...

Keyword(s):

Drinking Water ◽

Spontaneous Abortion ◽

Semen Quality ◽

Arsenic Exposure ◽

Quality Characteristics ◽

Reproductive Outcomes ◽

Case Control Studies ◽

Time To Pregnancy ◽

Cross Sectional ◽

Men And Women

Infertility is a worldwide health issue, but mechanisms of both male and female reproductive toxicity remain to be elucidated. So far, a limited focus has been on potentially harmful environmental factors such as arsenic, which is naturally occurring in groundwater. The objective of this review was to systematically investigate the association between arsenic in drinking water and adverse reproductive outcomes in men and women of fertile age. We conducted a systematic literature search and included case-control studies and cohort studies reporting on decreased semen quality characteristics, increased time to pregnancy, infertility, or spontaneous abortion. In total, 433 articles were screened and ultimately, eight studies were included. Included literature was quality assessed with the Newcastle-Ottawa Scale. Findings were reported in a narrative synthesis. Only one study investigated male fertility. An association between increasing arsenic exposure and decreasing semen quality characteristics was found, as well as an indication of arsenic accumulation in seminal plasma. These findings are, however, at high arsenic levels (>1000 µg/L). No consistent evidence was found to support the hypothesis that arsenic exposure from drinking water is a cause of longer waiting time to pregnancy or spontaneous abortion, being the only endpoints investigated in the included literature. In conclusion; the evidence is sparse and of varying quality, however, it does warrant attention, as it conflicts with existing evidence, mainly from cross-sectional or ecologic studies.

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