Sex-dependent and non-monotonic enhancement and unmasking of methylmercury neurotoxicity by prenatal stress

Abstract

Methylmercury (MeHg) and prenatal stress (PS) are risk factors for neurotoxicity that may co-occur in human populations. Because they also share biological substrates and can produce common behavioral deficits, this study examined their joint effects on behavioral and neurochemical effects in male and female rats. Dams had access to 0, 0.5 or 2.5ppm MeHg chloride drinking water from two weeks prior to breeding through weaning. Half of the dams in each of these treatment groups also underwent PS on gestational days 16–17. This yielded 6 groups/gender: 0-NS, 0-PS, 0.5-NS, 0.5-PS, 2.5-NS, and 2.5-PS. Behavioral testing began in young adulthood and included Fixed Interval (FI) schedule-controlled behavior, novel object recognition (NOR) and locomotor activity, behaviors previously demonstrated to be sensitive to MeHg and/or mediated by brain mesocorticolimbic dopamine glutamate systems targeted by both MeHg and PS. Behavioral deficits were more pronounced in females and included impaired NOR recognition memory only under conditions of combined MeHg and PS, while non-monotonic reductions in FI response rates occurred, with greatest effects at the 0.5ppm concentration; the less reduced 2.5ppm FI response rates were further reduced under conditions of PS (2.5-PS). Correspondingly, many neurochemical changes produced by MeHg were only seen under conditions of PS, particularly in striatum in males and in hippocampus and nucleus accumbens in females, regions of significance to the mediation of FI and NOR performance. Collectively these findings demonstrate sex-dependent and non-monotonic effects of developmental MeHg exposure that can be unmasked or enhanced by PS, particularly for behavioral outcomes in females but for both sexes in neurochemical changes, that were observed at MeHg exposure concentrations that did not influence either reproductive outcomes or maternal behavior. Thus, assessment of risks associated with MeHg may be underestimated in the absence of other extant risk factors with which it may share common substrates and effects.

Canadian Arctic Contaminants and Their Effects on the Maternal Brain and Behaviour: A Scoping Review of the Animal Literature

“…The authors did not report the amount of water consumed in each experimental group, making it difficult to deduce the actual dose consumed. Changes in maternal behaviour attributed to MeHg exposure alone were limited, with no significant group differences [64]. As such, this study suggests a limited effect of MeHg on maternal rodent behaviour.…”

“…In one study, Weston et al (2014) used rats to monitor maternal behaviours, including passive nursing, arched back nursing, blanket nursing, pup licking and grooming, pup licking, no contact and no contact resting following the administration of MeHg [64]. Mothers (dams) were separated into treatment groups exposed to 0, 0.5, or 2.5 ppm MeHg drinking water.…”

Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals

“…Post hoc testing was conducted contingent on ANOVA outcomes using Tukey-Kramer HSD to correct for multiple comparisons for one-way ANOVAs and contrast tests for repeated measures ANOVAs. Given that the two sexes characteristically maintain different hormone profiles and show sex-specific behavioral responses to EDC exposures (Bigsby et al, 1999, Gioiosa et al, 2007, Jašarević et al, 2013), and that our previous data indicates robust sex specific differences during these behavioral tests (Allen et al, 2014, Weston et al, 2014), all analyses were conducted separately by sex. Statistical analyses were conducted using JMP Pro 9.0 (SAS Institute Inc., Cary, N.C.).…”

Effects of early life stress on biochemical indicators of the dopaminergic system: a 3 level meta-analysis of rodent studies

“…Ling et al 2004; Z. Ling et al 2009; Liu et al 2016; Lovic et al 2013; Luchicchi et al 2016; Madruga et al 2006; Matthews et al 2001; Meyer, Nyffeler, Schwendener, et al 2008; Meyer, Nyffeler, Yee, et al 2008; Novak et al 2013; Ognibene et al 2008; Oreland et al 2011; Ozawa et al 2006; Pallarés et al 2013; Panagiotaropoulos et al 2004; Pang et al 2015; Papaioannou et al 2002; Ploj, Roman, and Nylander 2003; Rentesi et al 2013; Reynaert et al 2016; Reznikov and Nosenko 1995; Romano-López et al 2015; Eva Romero et al 2007; E Romero et al 2010; Rossi-George et al 2011; Rots et al 1996; Sasagawa et al 2017; Silvagni et al 2008; Silveira et al 2010; Son et al 2007; Tien et al 2013; Vazquez et al 2007; Vuillermot et al 2012; Wang et al 2009; Weston, Sobolewski, et al 2014; Weston, Weston, et al 2014; Winter et al 2009; Womersley et al 2011; Zager, Mennecier, and Palermo-Neto 2012; Zavitsanou et al 2013; Y. Zhang et al 2015; X.…”