Chronic arsenic exposure of ovarian surface and fallopian tube cultures induces giant and/or multinucleated cells with phagocytosis-like properties and an inflammatory phenotype

Abstract

Chronic exposure to arsenic, a toxic metalloid frequently found in groundwater and food, represents a significant environmental health risk and has been implicated in the etiology of several cancers, including ovarian cancer. However, the precise pathways through which arsenic exerts its toxic impact on the ovary are not fully understood. This study investigates the impact of chronic arsenic exposure at environmentally relevant concentrations (75 ppb or μg/L) on primary human ovarian surface (OCE1) and fallopian tube (FNE1) cultures derived from the same donor. These heterogeneous cultures provide a unique, human-relevant platform to investigate how chronic arsenic exposure influences distinct cell types within a shared microenvironment. Prolonged arsenic exposure induced significant cytotoxicity and promoted the formation of giant and/or multinucleated cells in both cultures. These cells exhibited phagocytosis-like properties, actively engulfing apoptotic debris. Transcriptomic analyses and pathway enrichment revealed robust activation of pro-inflammatory signaling, notably the canonical NF-κB pathway. This was marked by nuclear translocation of the NF-κB p65 subunit and elevated expression and secretion of pro-inflammatory cytokines, including TNFα, IL-6, and IL-8, driving a sustained inflammatory response. Moreover, arsenic-exposed cells displayed persistent DNA damage, as indicated by increased γ-H2AX foci, accompanied by nuclear structural alterations and elevated expression of cancer stem cell markers, including OCT2, CD133, and ALDH1. These findings suggest that arsenic-induced inflammation and genomic instability converge to promote a tumor-supportive microenvironment, highlighting the potential role of chronic arsenic exposure in ovarian carcinogenesis, particularly in the context of inflammation-driven carcinogenesis.

Keywords: Arsenic; Carcinogenesis; Chronic exposure; Chronic inflammation; DNA damage; Giant cells; Human primary cultures; Multinucleated cells; NF-kB pathway; Ovary.