Glyphosate induces benign monoclonal gammopathy and promotes multiple myeloma progression in mice

Lei Wang,Zhaojian Gong,Yong Li,Qipan Deng,Hui Hu,Ken H Young,Zhongxin Lu,Ming Liu,Xiaodong Ma,Shanshan Zhang,Zijun Y Xu-Monette

doi:10.1186/s13045-019-0767-9

Abstract

BackgroundGlyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL.MethodsVk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks.ResultsVk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice.ConclusionsThese data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.

Highlights

Glyphosate is the most popular and profitable agrochemical, being registered to use in over 160 countries and accounting for around 25% of the global herbicide market
Chronic glyphosate exposure reduces survival and induces splenomegaly in Vk*MYC mice Eight-week-old Vk*MYC mice and their WT littermates were provided 1.0 g/L glyphosate in drinking water for 72 weeks, and animals were monitored at regular intervals before sacrifice (Fig. 1a)
Glyphosate significantly affected the health of Vk*MYC mice, all of which had to be euthanized by week 72 (Fig. 1b)

Summary

Introduction

Glyphosate is the most popular and profitable agrochemical, being registered to use in over 160 countries and accounting for around 25% of the global herbicide market. It acts via inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the shikimate pathway, which is critical to the growth of most plants but absent in animals. Multiple epidemiological studies have investigated the association of glyphosate exposure and cancer risk using either cohort or case-control designs [5]. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL

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Discussion

Conclusion