In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system.

Antoine M Snijders,Adam B Olshen,Catherine Metayer,Adam J De Smith,Abel Huang,Todd P Whitehead,Scott C Kogan,Briana Fitch,Priyatama Pandey,Aaron Hechmer,Jian-Hua Mao,Mi Zhou,Suzaynn F Schick,Joseph L Wiemels

doi:10.1042/cs20201498

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.

Highlights

Acute lymphoblastic leukemia (ALL) is the most common type of childhood malignancy, with more than 50000 children diagnosed worldwide yearly, and 80% of these leukemias are B lymphoblastic
To determine the effect of thirdhand smoke’ (THS) exposure on leukemia/lymphoma risk, bone marrow (BM) samples from THS-exposed and control Cdkn2a−/− mice were transplanted into BM ablated wildtype recipient mice, which were followed for 1 year
We utilized the Cdkn2a null mouse model of childhood ALL to address in utero and early-life THS exposure effects, from the first day of pregnancy through weaning, on plasma cytokines, body weight, hematologic parameters and leukemia/lymphoma development

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the most common type of childhood malignancy, with more than 50000 children diagnosed worldwide yearly, and 80% of these leukemias are B lymphoblastic. The development of childhood ALL involves genetic and epigenetic processes, but the connection between specific environmental exposures and acquired tumor genetic and epigenetic changes in leukemia cells is inherently difficult to study in human populations. Incidence of childhood leukemia has steadily increased in the last half century, among Latinos [1,4]. This increase is mainly accounted for by one leukemia subtype—common CD10+, CD19+ childhood pre-B cell ALL. The causes for this increase have been hypothesized to include exposures to chemicals (e.g. tobacco smoke, pesticides), dietary factors, fetal growth rates and patterns of infection [5,6]. For the first time, we assessed the effect of exposure to ‘thirdhand smoke’ (THS), the residue left on surfaces after smoking, on the development of ALL

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