# Dioxins do not only bind to AHR but also team up with EGFR at the cell-surface: a novel mode of action of toxicological relevance?

## TL;DR

Dioxins may act by binding to EGFR at the cell surface, not just through AHR, which could explain additional toxic effects like breast cancer and placental damage.

## Contribution

Dioxins and DLCs inhibit EGFR activation by directly binding to its extracellular domain, revealing a novel mode of action.

## Key findings

- Dioxins bind to EGFR's extracellular domain, inhibiting growth factor-induced activation.
- This mechanism may contribute to breast cancer development and placental toxicity.
- Other environmental chemicals may also act via this mode of action.

## Abstract

Dioxins and dioxin-like compounds (DLCs) are highly toxic organic pollutants whose production and use are prohibited by international law. Despite this, these biopersistent and lipophilic chemicals are prevalent in the environment and accumulate in the food chain, posing significant health risks to consumers even at low exposure levels. Acute dioxin intoxication can cause chloracne, while chronic exposure has been associated with a wide range of adverse health effects, including carcinogenicity, reproductive and developmental disorders, immunotoxicity, and endocrine disruption. In the mid-1970s, scientists identified a transcription factor known as the aryl hydrocarbon receptor (AHR), which becomes activated upon binding of dioxins. AHR orchestrates numerous adaptive and maladaptive stress responses and is believed to mediate most, if not all, of the toxic effects triggered by dioxins and DLCs. Recent studies have provided mounting evidence that dioxins and dioxin-like polychlorinated biphenyls can inhibit growth factor-induced activation of the epidermal growth factor receptor (EGFR) by directly binding to its extracellular domain. This interaction prevents the activation of EGFR by polypeptide growth factors and downstream signal transduction. In this article, we explain this newly identified mechanism of action for dioxins and DLCs in detail and discuss its potential toxicological relevance by using two examples, i.e. breast cancer development and placental toxicity. Finally, we briefly refer to other environmental chemicals of global concern that, based on first published data, may act via the same mode of action.

See also the graphical abstract(Fig. 1).