Persistent β-Hexachlorocyclohexane Exposure Impacts Cellular Metabolism with a Specific Signature in Normal Human Melanocytes

Abstract

Background: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of β-hexachlorocyclohexane (β-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. Methods: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. Results: We demonstrated that β-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/β-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. Conclusions: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.

STAT3 Pathways Contribute to β-HCH Interference with Anticancer Tyrosine Kinase Inhibitors

“…These byproducts are predominantly still deposited in unregulated landfills at numerous sites across the globe. Our previous studies [ 20 , 21 , 22 ] and those by Papaccio et al [ 26 ] on the molecular and cellular mechanisms of β-HCH have described its activity as an endocrine disruptor, activator of the aryl hydrocarbon receptor, activator of signal transducer and activator of transcription 3 (STAT3) signaling pathways, modulator of energy metabolism, inducing the Warburg effect, ROS species booster, and promoter of all three stages of carcinogenesis.…”