Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption

Abstract

Metals, including lead (Pb), methylmercury (MeHg) and arsenic (As), are long-known developmental neurotoxicants. More recently, environmental context has been recognized to modulate metals toxicity, including nutritional state and stress exposure. Modulation of metal toxicity by stress exposure can occur through shared targeting of endocrine systems, such as the hypothalamic-pituitary-adrenal axis (HPA). Our previous rodent research has identified that prenatal stress (PS) modulates neurotoxicity of two endocrine active metals (EAMs), Pb and MeHg, by altering HPA and CNS systems disrupting behavior. Here, we review this research and further test the hypothesis that prenatal stress modulates metals neurotoxicity by expanding to test the effect of developmental As ± PS exposure. Serum corticosterone and behavior was assessed in offspring of dams exposed to As ± PS. PS increased female offspring serum corticosterone at birth, while developmental As exposure decreased adult serum corticosterone in both sexes. As + PS induced reductions in locomotor activity in females and reduced response rates on a Fixed Interval schedule of reinforcement in males, with the latter suggesting unique learning deficits only in the combined exposure. As-exposed males showed increased time in the open arms of an elevated plus maze and decreased novel object recognition whereas females did not. These data further confirm the hypothesis that combined exposure to chemical (EAMs) and non-chemical (PS) stressors results in enhanced neurobehavioral toxicity. Given that humans are exposed to multiple environmental risk factors that alter endocrine function in development, such models are critical for risk assessment and public health protection, particularly for children.

Prenatal metal mixtures and sex-specific infant negative affectivity

“…In healthy mice, subchronic As exposure has been shown to enhance “anxiety-like” behaviors, 79 although other research has shown prenatal As to be associated with reduced fear in male, but not female, mice. 80 Similar research conducted in rats has shown prenatal exposure to low levels of Pb and Cd is associated with increased displays of anxious behavior. 81 In humans, higher exposure to Cd, 82 Pb, 83 , 84 and mercury 85 has been positively associated with depression.…”

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice

“…These consequences can even persist across the life span (Needleman et al 1990;Schwabe et al 2012). Furthermore, in combination, Pb and PS can result in enhanced neurotoxicity as has been seen in both human studies (Tamayo y Ortiz et al 2017) and animal models (Rossi-George et al 2011;Sobolewski et al 2018aSobolewski et al , 2018bVirgolini et al 2006;Weston et al 2014), an outcome likely attributable to the shared biological targets of these two factors, that is, the hypothalamic-pituitary-adrenal (HPA) axis, as well as the brain mesocorticolimbic (MESO) system, a network that includes the frontal cortex, nucleus accumbens, and hippocampus (Barros et al 2004;Berger et al 2002;Jung et al 2019;Martínez-Telléz et al 2009;Rossi-George et al 2011;Virgolini et al 2008b). The potential for combined effects of Pb and PS may be further augmented by the fact that HPA axis and brain MESO neurotransmitter circuits have significant interactions critical to the mediation of executive functions and operant behaviors (Bahari et al 2018;Hernaus et al 2018).…”

Methods for Evaluating the Combined Effects of Chemical and Nonchemical Exposures for Cumulative Environmental Health Risk Assessment

“…Findings from the Rochester studies to date indicate that combined exposures to metals and stressors that share biological substrates (here, the HPA axis and brain MESO circuitry) and that produce common adverse effects (e.g., cognitive deficits) can produce enhanced toxicity, or unmask effects of chemical exposures, providing support for the hypothesis of biological interactions consistent with cumulative risk (Figure 1). The enhanced toxicity related to chronic stress is not specific to Pb exposures [47,48,49,51,53,54,55,56,57,58,59], but has been shown for other metals (e.g., MeHg, arsenic (As)) [52,60], suggesting some generalizability. Furthermore, neurotoxicity of developmental exposures to Pb and MeHg can also be enhanced postnatally under conditions of stress to the offspring, for example by early exposure to adversity vs. early positive experience [54].…”

“…HPA axis and brain mesocorticolombic systems have extensive interactions important to mediation of behaviors, including cognition and attention. Modified from Sobolewski et al, 2018 [60].…”