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Developmental neurotoxicity of persistent and non-persistent pollutants: Behavioral and neurochemical assessments of a perfluorinated compound, pesticides and interaction effects
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The focus of this thesis was to investigate developmental neurotoxic effects of different persistent and non-persistent environmental pollutants, alone or in binary mixtures, when exposure occurs during a critical period of brain development, in mice. The compounds investigated included a perfluorinated compound, perfluorohexane sulphonate (PFHxS), and four different pesticides, endosulfan, cypermethrin, chlorpyrifos and carbaryl.

Both persistent and non-persistent pollutants are detected in the environment and in humans, which shows that exposure to these compounds is occurring in real life. Humans can therefore be exposed to various pollutants during their whole lifetime, starting from the gestational period to adulthood. Furthermore, exposure to environmental pollutants is rarely exclusive to a single compound, but rather occurs through combinations of various pollutants present in the environment. Exposure to environmental pollutants during human brain development have been suggested to be a possible cause for neuropsychiatric disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Previous studies have shown that chemicals can induce irreversible disorders in brain function when exposure to these chemicals occurs during a critical defined period of the brain development known as the brain growth spurt (BGS). The BGS is characterized by a rapid growth and development of the immature brain. In humans, and mice, this period also overlaps the lactation period indicating that newborns and toddlers can be exposed via mothers’ milk as well.

This thesis has shown that a single oral exposure to PFHxS, endosulfan, cypermethrin, chlorpyrifos or carbaryl can induce developmental neurotoxic effects in mice, when exposure occurs during a critical period of brain development. These effects are manifested as persistent altered adult spontaneous behavior in a novel home environment, modified habituation, altered susceptibility of the cholinergic system and changed levels of neuroproteins in the mouse brain. Furthermore, a single neonatal co-exposure to a binary mixture of carbaryl/chlorpyrifos or PFHxS/endosulfan can interact and exacerbate the adult behavioral effects. These effects were seen at dosages were the single compound did not elicit a response or induced a much weaker behavioral effect. This indicates that risk assessments conducted on single compounds might underestimate interaction effects of mixtures when co-exposed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1283
Keyword [en]
Brain, Neonatal, Mixtures, Cholinergic system, Organochlorines, Pyrethroids, Organophosphates, Carbamates, Insecticides, PFCs, PFAAs, PFHxS, Endosulfan, Cypermethrin, Chlorpyrifos, Carbaryl
National Category
Natural Sciences
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-261742ISBN: 978-91-554-9326-4 (print)OAI: oai:DiVA.org:uu-261742DiVA: diva2:851609
Public defence
2015-10-23, Zootissalen, EBC, Villavägen 9, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-10-02 Created: 2015-09-03 Last updated: 2015-10-05
List of papers
1. Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose
Open this publication in new window or tab >>Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose
2013 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, 185-191 p.Article in journal (Refereed) Published
Abstract [en]

Perfluoroalkyl acids, including perfluorohexane sulfonate (PFHxS), are fluorinated organic compounds used as surfactants and water and stain repellents in carpets, paper, and textiles, with characteristics to bioaccumulate and biomagnify in the food chain. PFHxS is found in umbilical cord blood, human milk and child serum from all over the world. We have recently reported that neonatal exposure to certain perfluoroalkyl acids, PFOS and PFOA, can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. The present study indicates that a single exposure to PFHxS on postnatal day 10, during a vulnerable period of brain development can alter adult spontaneous behavior and cognitive function in both male and female mice, effects that are both dose-response related and long-lasting/irreversible. PFHxS affected the cholinergic system, manifested as altered nicotine-induced behavior in adult animals. This is also in agreement with earlier studies on neonatal exposure to PFOS and PFOA. The present findings show that PFHxS, a member of the perfluoroalkyl acid group, can act as a developmental neurotoxicant and affect the cholinergic system and cognitive function and the effects show similarities with effects earlier reported after neonatal exposure to other POPs, such as bisphenol A, PBDEs and PCBs.

Keyword
Perfluorohexane sulfonate (PFHxS), Neonatal, Developmental neurotoxicity, Behavior
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-199010 (URN)10.1016/j.tox.2012.12.013 (DOI)000316522300020 ()
Available from: 2013-05-02 Created: 2013-05-02 Last updated: 2017-12-06Bibliographically approved
2. A single neonatal exposure to perfluorohexane sulfonate (PFHxS) affects the levels of important neuroproteins in the developing mouse brain
Open this publication in new window or tab >>A single neonatal exposure to perfluorohexane sulfonate (PFHxS) affects the levels of important neuroproteins in the developing mouse brain
2013 (English)In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 37, 190-196 p.Article in journal (Refereed) Published
Abstract [en]

Perfluorohexane sulfonate (PFHxS) is an industrial chemical and belongs to the group of perfluorinated compounds (PFCs). It has recently been shown to cause developmental neurobehavioral defects in mammals. These compounds are commonly used in products such as surfactant and protective coating due to their ability to repel water- and oil stains. PFCs are globally found in the environment as well as in human umbilical cord blood, serum and breast milk. In a previous study on other well-known PFCs, i.e. PFOS and PFOA, it was shown that neonatal exposure caused altered neuroprotein levels in the hippocampus and cerebral cortex in neonatal male mice. The present study show that neonatal exposure to PFHxS, during the peak of the brain growth spurt, can alter neuroprotein levels, e.g. CaMKII, GAP-43, synaptophysin and tau, which are essential for normal brain development in mice. This was measured for both males and females, in hippocampus and cerebral cortex. The results suggest that PFHxS may act as a developmental neurotoxicant and the effects are similar to that of PFOS and PFOA, but also to other substances such as PCBs, PBDEs and bisphenol A. 

Keyword
Perfluorohexane sulfonate (PFHxS), Neonatal, Developmental neurotoxicity, CaMKII, GAP-43, Synaptophysin, Tau
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-204997 (URN)10.1016/j.neuro.2013.05.007 (DOI)000321413400023 ()
Available from: 2013-08-14 Created: 2013-08-13 Last updated: 2017-12-06Bibliographically approved
3. Developmental neurotoxic effects of two pesticides: behavior and neuroprotein studies on endosulfan and cypermethrin
Open this publication in new window or tab >>Developmental neurotoxic effects of two pesticides: behavior and neuroprotein studies on endosulfan and cypermethrin
Show others...
2015 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 335, 1-10 p.Article in journal (Refereed) Published
Abstract [en]

Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. Exposure to these substances during early development may lead to adverse behavior effects manifested at a later phase of life. Pesticides are a wide group of chemicals which are still actively used and residues are found in the environment and in food products.

The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5 mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-259789 (URN)10.1016/j.tox.2015.06.010 (DOI)000360517600001 ()26143737 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 282957
Available from: 2015-08-12 Created: 2015-08-12 Last updated: 2017-12-04Bibliographically approved
4. Developmental neurotoxic effects of two pesticides: behavior and biomolecular studies on chlorpyrifos and carbaryl
Open this publication in new window or tab >>Developmental neurotoxic effects of two pesticides: behavior and biomolecular studies on chlorpyrifos and carbaryl
Show others...
2015 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 288, no 3, 429-438 p.Article in journal (Refereed) Published
Abstract [en]

In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.

Keyword
Developmental neurotoxicology, Chlorpyrifos, Carbaryl, Acetylcholinesterase, Protein, Behavior
National Category
Other Biological Topics
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-261192 (URN)10.1016/j.taap.2015.08.014 (DOI)000363083600015 ()26314619 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 282957
Available from: 2015-09-03 Created: 2015-08-31 Last updated: 2017-12-04Bibliographically approved

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