In utero arsenic exposure in mice and early life susceptibility to cancer

Abstract

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

Response to Druwe and Burgoon

“…The key reasons for our position are: (1) lack of consistency and reproducibility (Garry et al 2015); (2) not taking into account the high variability in incidences of lung tumors in control CD-1 mice, including the variability in two studies reported by the Waalkes' group (Tokar et al 2011;Waalkes et al 2014); (3) lack of information regarding historical controls; (4) the statistical criterion of significance used by Waalkes et al does not follow the criterion of Haseman et al (1986); and (5) the biologic implausibility of the dose response being suggested. When evaluating the incidence of common tumors (background incidence ≥1 %, which the background incidence of lung tumors in CD-1 mice clearly meets), Haseman et al (1986) from the National Toxicology Program (NTP) recommended a p value <0.01 be utilized for statistical significance, not p < 0.05 as used by Waalkes et al (2014).…”

Sex-Specific Effects of Prenatal and Early Life Inorganic and Methylated Arsenic Exposure on Atherosclerotic Plaque Development and Composition in Adult ApoE−/− Mice

“…Importantly, these methylated arsenicals appear to be as pro-atherogenic as the parent compounds, indicating that the differences in methylation efficiency conferred by As3MT polymorphisms may not be relevant in this exposure scenario. One criticism of previous murine transplacental models to show intergenerational effects was that high concentrations (42,500-200,000 ppb arsenic) were employed (Garry et al 2015). The groundbreaking studies observing cancer outcomes following in utero exposure to arsenic in mice used 42,500 and 85,000 ppb arsenic (Waalkes et al 2003).…”

Lipid Metabolism Alterations in a Rat Model of Chronic and Intergenerational Exposure to Arsenic

“…To our knowledge, although several studies have focussed on the reproductive and carcinogenic effects of transplacental As exposure [61–63], scarce data are available about the intergenerational effects of arsenic on lipid metabolism in animal models. States and colleagues demonstrated that transplacental arsenic exposure in mice alters developmental programming in the foetal liver, leading to an enduring stress and proinflammatory response postnatally, which may contribute to early onset of atherosclerosis [64].…”