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

Abstract

BACKGROUND: Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed in vivo via the action of arsenic (+3 oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre-and perinatal effects are unclear. This is particularly important because methylated arsenicals are known to cross the placenta. OBJECTIVES: We tested the effects of early life exposure to inorganic and methylated arsenicals on atherosclerotic plaque formation and its composition in apolipoprotein E knock-out (apoE −= − ) mice and evaluated whether apoE −= − mice lacking As3MT expression were susceptible to this effect. METHODS: We exposed apoE −= − or apoE −= − =As3MT −= − mice to 200 ppb inorganic or methylated arsenic in the drinking water from conception to weaning and assessed atherosclerotic plaques in the offspring at 18 wk of age. Mixed regression models were used to estimate the mean difference in each outcome relative to controls, adjusting for sex and including a random effects term to account for within-litter clustering. RESULTS: Early life exposure to inorganic arsenic, and more profoundly methylated arsenicals, resulted in significantly larger plaques in the aortic arch and sinus in both sexes. Lipid levels in these plaques were higher without a substantial difference in macrophage numbers. Smooth muscle cell content was not altered, but collagen content was lower. Importantly, there were sex-specific differences in these observations, where males had higher lipids and lower collagen in the plaque, but females did not. In mice lacking As3MT, arsenic did not alter the plaque size, although the size was highly variable. In addition, control apoE −= − =As3MT −= − mice had significantly larger plaque size compared with control apoE −= − . CONCLUSION: This study shows that early life exposure to inorganic and methylated arsenicals is pro-atherogenic with sex-specific differences in plaque composition and a potential role for As3MT in mice.

2-Hydroxypropyl-beta-cyclodextrin Treatment Does Not Induce Atherosclerotic Lesion Regression in Western-Type Diet-Fed Apolipoprotein E Knockout Mice

“…Differences have previously been found in the susceptibility of male and female APOE KO mice to atherosclerosis, with a higher predisposition in females [ 10 , 11 ]. This can also explain why the respective atherosclerotic lesion extents were highly similar in our study and that of Kim et al, despite the markedly different combinations of the sex of the mice used and time of atherogenic diet feeding (6 weeks mild atherogenic diet feeding in female mice versus 12 weeks extreme atherogenic diet feeding in male mice, respectively).…”

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease

“…A recent study conducted in the same mouse model used for replication in this work showed that an in utero and early-life arsenic exposure can enhance atherosclerosis later in life in apoE −/− mice. 109 Comparing the DNA methylation data from the livers harvested in that study to the top hits from our population-based study, we observed differential DNA methylation in the genes of interest. The fact that these DMPs and DMRs are validated in a different tissue (blood versus liver) that is equally important to CVD, in particular in the context of cardiometabolic disease, provides supporting evidence of a potential causal relationship between arsenic-induced DNA methylation changes and atherosclerosis.…”

Arsenic Exposure, Blood DNA Methylation and Cardiovascular Disease

“…A recent study conducted in the same mouse model used for replication in this work showed that an in utero and early-life arsenic exposure can enhance atherosclerosis later in life in apoE−/− mice. 113 Comparing the DNA methylation data from the livers harvested in that study to the top hits from our population-based study, we observed differential DNA methylation in the genes of interest. The fact that these DMPs and DMRs are validated in a different tissue (blood vs. liver) that is equally important to CVD, in particular in the context of cardiometabolic disease, provides supporting evidence of a potential causal relationship between arsenic-induced DNA methylation changes and atherosclerosis.…”