Elsevier

NeuroToxicology

Volume 53, March 2016, Pages 314-320
NeuroToxicology

Lactational exposure of mice to low levels of non-dioxin-like polychlorinated biphenyls increases susceptibility to neuronal stress at a mature age

https://doi.org/10.1016/j.neuro.2015.10.003Get rights and content

Highlights

  • We exposed dam mice to Σ6 NDL-PCBs (0 and 10 ng/kg/day) during lactation.

  • 14-Month-old PCB-exposed and -naive offspring mice were subjected to brain injection.

  • Long-term memory deficits were observed in adult PCB-exposed mice.

  • Expression of pre- and post-synaptic proteins was decreased in hippocampus of exposed mice.

  • Early exposure to NDL-PCBs induces late neuronal vulnerability to amyloid stress.

Abstract

Lactational exposure to low levels of the sum of the six indicator polychlorinated biphenyls (Σ6 NDL-PCBs, 10 ng/kg/day) is known to lead to persistent anxious behavior in young and adult offspring mice at postnatal days 40 and 160, respectively. At more advanced life stages, we evaluated the effects on the mouse brain of neuronal stress induced by the synaptotoxic amyloid-beta (Aβ) peptide. Perinatal exposure of lactating mice to Σ6 NDL-PCBs did not affect short-term memory performances of their offspring male mice aged 14 months as compared to control PCB-naive mice. However, following intracerebroventricular injection of soluble Aβ oligomers, significant impairments in long-term memory were detected in the mice that had been lactationally treated with Σ6 NDL-PCBs. In addition, immunoblot analyses of the synaptosomal fraction of hippocampal tissues from treated mice revealed a lower expression of the synaptic proteins synaptophysin and PSD-95. Though preliminary, our findings suggest for the first time that early exposure to low levels of NDL-PCBs induce late neuronal vulnerability to amyloid stress. Additional experiments are needed to confirm whether early environmental influences are involved in the etiology of brain aging and cognitive decline.

Introduction

Early-life exposure to certain natural and synthetic chemicals may increase the risk of neurodegenerative and other diseases later in life (Spencer, 1987, Landrigan et al., 2005, Kisby and Spencer, 2011, Fox et al., 2012). The increase in childhood pathologies, such as hyperactivity or memory alterations, and the occurrence of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases in the elderly, may be due in part to the early chronic exposure of pollutants and their related impacts in early stages of life (Corrigan et al., 2000, Bihaqi et al., 2011, Bihaqi and Zawia, 2013, Bihaqi et al., 2014a, Medehouenou et al., 2011, Medehouenou et al., 2014, Jurewicz et al., 2013, Grandjean and Landrigan, 2014). Fetuses and newborn babies are particularly exposed to chemicals during their development via maternal transfer, when the central nervous system (CNS) is still in maturation. These young individuals are thought to be more susceptible than adults to environmental insults (Weiss and Landrigan, 2000).

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent organic compounds that accumulate in lipid tissues of living organisms (Ogura, 2004, Hornbuckle et al., 2006). Upon ingestion, they can be stored in fatty tissues, including the brain (Dewailly et al., 1999), and it has been shown that during the perinatal stage, these xenobiotics may cross the blood–brain barrier (Kunisue et al., 2007, Montie et al., 2009). Numerous epidemiological investigations have linked PCB levels detected in human biological tissues to neurocognitive and neurobehavioral deficits in older adults (Hatcher-Martin et al., 2012, Medehouenou et al., 2014, Richardson et al., 2014), suggesting potential neurotoxicity in humans (Fonnum and Mariussen, 2009). Experimental animal and human studies have proposed that exposure to PCBs increases the risk of neurodegenerative disease (Caudle et al., 2006, Petersen et al., 2008, Hatcher-Martin et al., 2012).

Exposure to non-dioxin-like (NDL) PCBs has been shown to affect CNS development. We found previously a persistent anxious behavior from postnatal day (PND) 0 up to PND 21 in young and adult mice treated with the sum of six indicator NDL-PCBs through mother's milk during lactation (Elnar et al., 2012). Here, we ask whether such an early exposure could lead to adverse effects in cognition later in adulthood. We provide evidence for increased neuronal susceptibility to amyloid stress induced by intracerebroventricular (icv) injection of neurotoxic soluble oligomers of amyloid-beta (Aβ) peptide.

Section snippets

Lactational exposure to Σ6 NDL-PCBs

Animal studies were performed in accordance with the European Union (Directive 2010/63/EU) and approved by the local research ethics committee (CELMEA-2013-0010).

Animal treatment, as well as composition (PCBs 28, 52, 101, 138, 153 and 180, purity > 99.5%, Sigma–Aldrich) and preparation of the stock solution of Σ6 NDL-PCBs have been detailed previously (Elnar et al., 2012). Briefly, 50 sexually mature female and 40 male Swiss albino mice (OF 1, Charles River, France) aged 9 weeks (30–40 g body

Effects of early PCB exposure on cognitive capacities

These tests were conducted to determine whether early lactational exposure to Σ6 NDL-PCBs at a low level could affect learning and memory capacities at a mature age.

Discussion

Whereas developmental exposure to lead (Pb) is reported to induce cognitive impairments, to increase the expression of the Aβ precursor protein as well as Aβ levels, and to promote neurodegeneration in old age (Wu et al., 2008, Huang et al., 2011, Bihaqi and Zawia, 2013, Bihaqi et al., 2014a, Bihaqi et al., 2014b, Liu et al., 2014), little is known about the effects of early life exposure to PCBs on brain susceptibility to amyloid stress.

The aim of this study was to investigate the long-term

Conclusion

This preliminary study shows that, at maturity, early-life lactational exposure to very low levels of Σ6 NDL-PCBs increases brain susceptibility to amyloid stress and impaired long-term memory.

Conflict of interest statement

The authors have no conflict of interest to declare.

Acknowledgments

Nicolas Fischer is thanked for his skilled technical assistance in brain injection. Financial support was provided by the Agence Nationale de la Recherche (ANR-11-CESA-000) and the Région Lorraine. A. Allouche was supported by thesis fellowships from the University of Damascus, Damascus, Syria.

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    These authors contributed equally to this study.

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