Prenatal exposure to glufosinate ammonium disturbs gut microbiome and induces behavioral abnormalities in mice

Highlights

• Prenatal exposure to glufosinate ammonium induces behavioral abnormalities in mice.

• Gut microbiome mediates the toxicity of glufosinate ammonium on neurodevelopment.

• Disturbed gut microbiome caused by glufosinate ammonium is reversible.

Abstract

Glufosinate ammonium (GLA) is a widely used organophosphate herbicide, which could be commonly detected in body fluids of both pregnant women and newborns. Existing evidences indicate that GLA has reproductive toxicity, while data concerning the effects of prenatal GLA exposure on neurodevelopment is rather limited. Here we employed a mouse model exposed to GLA prenatally. Reduced locomotor activity, impaired memory formation and autism-like behaviors were observed in the treatment group. Marked alteration in gut microbiome of the treatment offspring mice could be found at 4th week, and seemed to recover over time. Fecal metabolomics analysis indicated remarkable changes in microbiome-related metabolism in the treatment group, which could be the cause of behavioral abnormality in mice. Present study suggested that prenatal exposure to GLA disturbed gut microbiome and metabolism, and thereby induced behavioral abnormalities in mice.

Introduction

Intellectual disability and behavioral dysfunction, also defined as neurodevelopmental disorders (NDDs), are reported to be induced by environmental exposures during early life (Boivin et al., 2015; Pietropaolo et al., 2017). Mounting evidence has indicated that over 15 % of the US children are suffering from NDDs (Boyle et al., 2011), which results in poor life quality of the patients and also a heavy burden on the society (Wanke et al., 2018). Hence, it is important to identify the etiology of NDDs so that better preventive and control measures can be implemented. Environmental chemicals are important risk factors that are associated with the occurrence of NDDs (Lam et al., 2017) in addition to the genetic abnormalities. However, clarifying the roles of environmental chemicals that interfere with the neurodevelopment is not easy due to the multiplicity and modifiability of the environment (Bennett et al., 2016).

As substances controlling pests and weeds, pesticides include herbicides, insecticides, rodenticides, bactericides, etc., and herbicides account for approximately 40 % of total pesticide use (Grube et al., 2011). Recently, a few epidemiological studies have demonstrated that early life pesticide exposures are associated with child neurodevelopmental defects and mental disorders, including autism spectrum disorder (ASD), lower IQ, cognitive developmental disabilities, etc (Sagiv et al., 2018; Gaspar et al., 2015; Engel et al., 2016; Viel et al., 2015), which are in accordance with the findings that prenatal pesticide treatment could induce behavioral disorders as well as neuroanatomical and functional aberrations in rodents (Guo et al., 2018a; Dhuriya et al., 2017; Lan et al., 2017). Therefore, the effects of prenatal exposure to pesticides on offspring neurodevelopment are an important issue in public health.

Glufosinate ammonium (GLA), a substitute herbicide of paraquat, is widely used with an increasing utilization around the world (Maillet et al., 2016; Cha et al., 2018). A study conducted by Aris and Leblanc (2011) found that the metabolite of GLA, 3-methylphosphinicopropionic acid (MPPA), could be detected in nearly all serum samples from a group of mother-child pairs, which indicates the universal exposure and potential transplacental exposure to GLA. Previous studies have well documented the neurotoxicity of GLA (Cha et al., 2018; Feat-Vetel et al., 2018). Given such data, the health effects of GLA exposure especially for neurodevelopment are a great concern. However, relevant data are rather limited till now (Laugeray et al., 2014). During last decade, the health effects of gut microbiome have been considered even more profound particularly in neurological disorders, such as ASD, schizophrenia and neurodegenerative diseases, etc (Sharon et al., 2016; Carlson et al., 2018). It is well established that gut bacteria are essential for the synthesis of vitamins and amino acids and the detoxification of exogenous toxins (Komaroff, 2017). Environmental exposures during pregnancy are reported to disturb the gut microbiome of the offspring (Buffington et al., 2016; Ba et al., 2017), but the potential for prenatal GLA exposure to disturb host-gut microbiota is poorly understood.

The objectives of the current study are to understand whether prenatal exposure to GLA could induce neurobehavioral abnormalities in offspring and to decipher the role of gut microbiota in these diseases. Therefore, we employed a mouse model prenatally exposed to GLA through drinking water in order to clarify the effects, the mechanisms, and the potential influences of GLA on neurodevelopment.