Exposure to p,p'-DDE Induces Morphological Changes and Activation of the PKCα-p38-C/EBPβ Pathway in Human Promyelocytic HL-60 Cells.

Nallely A Torres-Avilés,Ana L Luna,Monica Moreno-Galván,Mariana Salgado-Bustamante,Emma S Calderón-Aranda,Diana Patricia Portales-Pérez,Damaris Albores-García

doi:10.1155/2016/1375606

Abstract

Dichlorodiphenyldichloroethylene (p,p′-DDE), the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT), is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p′-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p′-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p′-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p′-DDE effect on [Ca2+]i, C/EBPβ protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 μg/mL of p,p′-DDE increased [Ca2+]i, PKCα, p38, and C/EBPβ protein levels; the increase of nuclear C/EBPβ protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p′-DDE-induced oxidative stress. p38 phosphorylation induced by p,p′-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p′-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p′-DDE on the development of bone marrow disorders in humans, these effects deserve further study.

Highlights

Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant that was used until the end of the twentieth century as a pesticide and to control vectors of dengue and malaria worldwide [1]
Because results did not show an effect of 1.9 μg/mL p,p󸀠DDE on proliferation at 96 h, we considered that the effect observed in MTT assays at this time is a consequence of a temporal decrease of metabolic capability of cells to reduce of MTT instead of cell death
Our work suggests that p,p󸀠-DDE exposure at the concentrations found in bone marrow of humans can induce intracellular molecular pathways (ROS, PKCα, p38, and CCAAT/enhancer binding protein β (C/EBPβ)) that are involved in the myeloid differentiation and, induce morphological differentiation of this human myeloid cell line

Summary

Introduction

Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant that was used until the end of the twentieth century as a pesticide and to control vectors of dengue and malaria worldwide [1]. Pesticide exposure alters cell differentiation in bone marrow resulting in noncompetent cells or haematological disorders [8,9,10,11,12]. DDT and p,p󸀠-DDE exposure are associated with a risk of developing bone marrow disorders such as aplastic anaemia, acute myeloid leukaemia (AML), and non-Hodgkin lymphoma [13,14,15,16,17,18,19]. Epidemiological data has associated home pesticide exposure during a child’s early years with acute lymphoblastic leukaemia (ALL) and exposure before birth with AML [20]. Epidemiological studies demonstrate the adverse effects of DDT on haematological or immunological parameters [21,22,23,24,25], currently there are no data available on the association between p,p󸀠-DDE exposure

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