Low-dose endosulfan inhibits proliferation and induces senescence and pro-inflammatory cytokine production in human lymphocytes, preferentially impacting cytotoxic cells

Abstract

Endosulfan is a DDT-era organochlorine pesticide. Due to past and current environmental contamination, investigation of endosulfan exposure is of current importance. Acute high dose exposure precipitates neural/endocrine system damage, but the effects on the immune system and of lower doses are not well-characterized. Two relatively low concentrations of endosulfan (i.e. 0.1 and 17 µM ENDO) were investigated in an in vitro study using human peripheral blood mononuclear cells (PBMC) to understand effects of relatively low doses (0.1–25.0 µM [≈0.04–10 ppm/40–10,000 ppb]) of ENDO upon normal human T- and B-lymphocytes and NK cells. The study here found that 17 µM ENDO inhibited phytohemagglutinin-M (PHA)-induced human PBMC proliferation. It was also seen that senescence and apoptosis among non-stimulated cells was increased, specifically within CD8 and NK populations, and that CD4:CD8 ratios also were increased. Treatment of non-stimulated PBMC with ENDO led to overall increases in production of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, -4, and -6, and decreased production of anti-inflammatory IL-10, suggesting an immunosenescence secretory phenotype. Interestingly, when the cells were pre-stimulated with mitogen (PHA), ENDO became inhibitory against the mitogen-induced proliferation and cytokine formation – with the exception of that of TNFα and IL-6, suggesting differential effects of ENDO on activated cells. Thus, at the organismal level, ENDO might also display differential effects during states of autoimmune disease or chronic viral infection in the exposed host.

Keywords:

• Endosulfan
• organochlorine pesticide
• NK cells
• cytotoxic cells
• senescence
• interferon
• PBMC
• Immunosenescence

Acknowledgements

The Authors gratefully acknowledge Miguel Enrique Magaña Virgen (MS) for the invaluable professional assistance, Maria Fernanda Rios Perez, (BS) for participation in the proliferation and cytometry studies, and Galina Petrovna Zaitseva (PhD) for the critical reading of this manuscript, and long leadership in this field and our research group.

Disclosure statement

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this paper.

Additional information

Funding

This study was supported by the P3e funding of the Universidad de Guadalajara, grant number 234401 and P3E2018 240296.