An acute dose of glyphosate alters novel object exploration and hippocampal cFos expression in a sex-dependent manner in wildtype mice.

Glyphosate (GLY) is the active ingredient in most herbicides, including off-the-shelf weed killers such as Roundup®. GLY crosses the blood-brain barrier, increases oxidative stress and genotoxicity, and impacts reproduction, but the extent of its effects remains unclear. Previous research reports conflicting evidence on sex-specific susceptibility to GLY's effects, and very few investigate the effects of a single, acute dose on learning, memory, and neuronal activation. In vitro studies have found GLY interferes with gene expression and is uniquely capable of inducing DNA double strand breaks (DSBs) compared to other herbicides. DSBs can induce expression of immediate early genes (IEGs), which are important for synaptic plasticity, learning, and memory. However, a clear connection between GLY, IEGs, and learning and memory has yet to be made. To explore this, we tested male and female wildtype mice in novel object recognition after they received an acute, oral dose of 0, 250, or 500 mg/kg of GLY and assessed hippocampal DSB and IEG levels. We hypothesized that a single dose of GLY would impair memory by disrupting IEG expression and would affect males more than females. We did not find robust evidence that GLY impaired memory, though females that received 500 mg/kg did not explore the novel object more than the familiar. Hippocampal DSBs were decreased following 500 mg/kg in both sexes, yet hippocampal IEG immunoreactivity was decreased in GLY-exposed males only, revealing a complex sex-dependent relationship. These data add to the literature that GLY is potentially detrimental, highlighting the need for further investigations.