Health Effects Associated With Pre- and Perinatal Exposure to Arsenic

Abstract

Inorganic arsenic is a well-established human carcinogen, able to induce genetic and epigenetic alterations. More than 200 million people worldwide are exposed to arsenic concentrations in drinking water exceeding the recommended WHO threshold (10μg/l). Additionally, chronic exposure to levels below this threshold is known to result in long-term health effects in humans. The arsenic-related health effects in humans are associated with its biotransformation process, whereby the resulting metabolites can induce molecular damage that accumulates over time. The effects derived from these alterations include genomic instability associated with oxidative damage, alteration of gene expression (including coding and non-coding RNAs), global and localized epigenetic reprogramming, and histone posttranslational modifications. These alterations directly affect molecular pathways involved in the onset and progression of many conditions that can arise even decades after the exposure occurs. Importantly, arsenic metabolites generated during its biotransformation can also pass through the placental barrier, resulting in fetal exposure to this carcinogen at similar levels to those of the mother. As such, more immediate effects of the arsenic-induced molecular damage can be observed as detrimental effects on fetal development, pregnancy, and birth outcomes. In this review, we focus on the genetic and epigenetic damage associated with exposure to low levels of arsenic, particularly those affecting early developmental stages. We also present how these alterations occurring during early life can impact the development of certain diseases in adult life.

Keywords: DNA methylation; arsenic; epigenetics; fetal development; genetics; in utero exposure.

Figure 1

Health effects derived from gestational exposure to arsenic in drinking water. Arsenic ingested by the mother can cross the placental barrier. Gestational exposure to arsenic has been associated with effects at pre-and perinatal stages, as well as during childhood. These effects include adverse pregnancy outcomes and alterations to the cardiovascular, respiratory, and immune system. Moreover, in utero exposure has been correlated with an increased risk of developing cancer and other types of diseases during the adult life. Created with BioRender.com.

Figure 2

Arsenic biotransformation as mechanisms for molecular damage. Arsenic dissolved in drinking water (mainly as arsenate, in its oxidation state +5, As[V]) is readily absorbed by the gastrointestinal tract. Biotransformation of arsenic occurs in the liver, where arsenite (As[III]) and As[V] goes through a series of redox reactions, resulting in the generation of mono and dimethylated arsenic intermediaries: Monomethylarsonous acid (MMA[III]), monomethylarsonic acid (MMA[V]), dimethylarsinous acid (DMA[III]), and dimethylarsinic acid (DMA[V]). S-adenosylmethionine (SAM) is the methyl donor during arsenic biotransformation to both oxidation state III and oxidation state V arsenic species. The transfer of a methyl group from SAM to trivalent arsenicals is catalyzed by the arsenic6 (+3 oxidation state) methyltransferase (AS3MT), producing methylated and dimethylated arsenicals. Epigenetic alterations, including global and local DNA methylation changes, alteration of miRNA expression, and changes in the histone modification pattern, are associated with this process. On the other hand, the redox reactions involved in arsenic biotransformation lead to ROS-mediated disruption of the mitochondrial electron transport chain, which subsequently results in DNA damage such as double- and single-strand breaks, and specific mutational patterns. Created with BioRender.com.