Perfluorinated chemicals (PFOA) can, by interacting with highly brominated diphenyl ethers (PBDE 209) during a defined period of neonatal brain development, exacerbate neurobehavioural defects.

Perfluorinated compounds (PFCs) and polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent environmental compounds, present in humans and at higher levels in infants/children than in adults. This study shows that co-exposure to pentadecafluorooctanoic acid (PFOA) and 2,2',3,3',4,4',5,5',6,6'-decaBDE (PBDE 209) can significantly exacerbate developmental neurobehavioural defects. Neonatal male NMRI mice, 3 and 10 days old, were exposed perorally to PBDE 209 (1.4 or 8.0 µmol/kg bw), PFOA (1.4 or 14 µmol/kg bw), co-exposed to PBDE 209 and PFOA (at the given doses), or a vehicle (20% fat emulsion) and observed for spontaneous behaviour in a novel home environment when 2 and 4 months old. The behavioural defects observed included hyperactivity and reduced habituation indicating cognitive defects. This interaction appears most likely dependent on the presence of PBDE 209 and/or its metabolites together with PFOA, during a defined critical period of neonatal brain development, corresponding to the perinatal and newborn period in humans.

Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10.

Acetaminophen (AAP; or paracetamol) is a widely used nonprescription drug with antipyretic and analgesic properties. Alarmingly, there is an increasing body of evidence showing that developmental exposure to AAP is associated with adverse behavioural outcomes later in life. We have previously shown that relevant doses of AAP in 10-day-old mice affected memory, learning and locomotor activity in the adult animals. Interestingly, the neurons of the dentate gyrus (DG) have a relatively late time of origin as they are generated during the first two weeks of postnatal life in rodents. Since the generation of these cells, which are important for memory processing, coincides with our AAP exposure, we aim to investigate if the cytoarchitecture of the DG is affected by postnatal day 10 AAP treatment. In addition, we investigate if markers for differentiation and migration in the hippocampus were affected by the same treatment. We did not observe any visual effects in adult DG cytoarchitecture, nor any changes of markers for differentiation/migration in the hippocampus in 24 hr after exposure. Even though a large effect size was estimated on adult DG thickness following AAP exposure, the estimated 95% CIs around the differences of the means reveal no significant effect. Hence, larger sample sizes are warranted to clarify if neonatal AAP exposure affects adult DG thickness in mice.

A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis.

δ9-tetrahydrocannabinol (THC) is one of the most used drugs during pregnancy and lactation and efficiently crosses the placental and blood-brain barriers. Despite the recent legalization initiatives worldwide, the adverse outcome pathway (AOP) of THC following exposure during brain development is incompletely understood. We have previously reported that a single injection of THC on postnatal day (PND) 10 altered adult spontaneous behavior and habituation rates in adult mice. Similar behavioral alterations have been reported following PND 10 exposure to the commonly used over-the-counter analgesic acetaminophen (AAP; also known as paracetamol); as both THC and AAP interact with the endocannabinoid system, we hypothesize that this system might be involved in the AOP of both these pharmaceuticals/drugs. Here, we report that a single THC dose on PND 10 decreased transcript levels of tropomyosin receptor kinase b (Trkb) 24 h after exposure in both the frontal and parietal cortex, and in the hippocampus in mice. An increase in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) ratio were also found in both the parietal cortex and hippocampus following neonatal exposure to THC. In addition, THC exposure increased transcript levels of cannabinoid receptor type 1 (Cb1r) in the parietal cortex and increased the apoptosis regulator BAX in the frontal cortex. This study is important for mainly 3 reasons: 1) we are starting to get information on the developmental neurotoxic AOP of PND 10 exposure to THC, where we suggest that transcriptional changes of the neurotrophic receptor Trkb are central, 2) our PND 10 exposure model provides information relevant to human exposure and 3) since PND 10 exposure to AAP also decreased Trkb transcript levels, we suggest THC and AAP may share key events in their respective AOP through endocannabinoid-mediated alterations of the brain-derived neurotrophic factor (BDNF)-TRKB signaling pathway.

A Cannabinoid Receptor Type 1 (CB1R) Agonist Enhances the Developmental Neurotoxicity of Acetaminophen (Paracetamol).

Acetaminophen (AAP; also known as paracetamol) is the most used and only recommended analgesic and antipyretic among pregnant women and young children. However, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and adverse neurobehavioral effects later in life. We hypothesized that the cannabinoid receptor type 1 (CB1R) may be involved in the developmental neurotoxicity of AAP, owing to its interaction with the endocannabinoid system. Here we test if CB1R agonist WIN 55 212-2 (WIN) and AAP can interact when exposure occurs during a neurodevelopmental stage known for increased growth rate and for its vulnerability to AAP exposure. We exposed male NMRI mice on postnatal day 10 to different combinations of AAP and WIN. Adult mice, neonatally co-exposed to AAP and WIN, displayed a significant lack of habituation in the spontaneous behavior test, when compared with controls and single agent exposed mice. These adult adverse effects may at least in part be explained by a reduction of transcript levels of hippocampal synaptophysin (Syp) and tropomyosin receptor kinase B (Trkb), and cerebral cortical fatty acid amide hydroxylase (Faah), 24 h after exposure. These findings are consistent with our hypothesis that AAP and WIN can interact when exposure occurs during early postnatal brain development in mice. Assuming our results are relevant for humans, they raise concerns on AAP safety because it is the only recommended analgesic and antipyretic during pregnancy and early life.

Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period.

Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg-1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice. Copyright © 2017 John Wiley & Sons, Ltd.

Short-term exposure and long-term consequences of neonatal exposure to Δ(9)-tetrahydrocannabinol (THC) and ibuprofen in mice.

Both Δ(9)-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 months of age, the mice were subjected to a spontaneous behavior test, consisting of a 60min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC.

Postnatal exposure to PFOS, but not PBDE 99, disturb dopaminergic gene transcription in the mouse CNS.

The CNS of breast feeding infants and toddlers may be exposed to persistent organic pollutants via lactational transfer. Here, 10 days old mice were exposed to single oral doses of either PFOS, PBDE99 or vehicle control and were examined for changes in dopaminergic gene transcription in CNS tissue collected at 24h or 2 months post exposure.qPCR analyses of brain tissue from mice euthanized 24h post exposure revealed that PFOS affected transcription of Dopamine receptor-D5 (DRD5) in cerebral cortex and Tyrosine hydroxylase (TH) in the hippocampus. At 2 months of age, mice neonatally exposed to PFOS displayed decreased transcription of Dopamine receptor-D2 (DRD2) and TH in hippocampus. No significant changes in any of the tested genes were observed in PBDE99 exposed mice. This indicates that PFOS, but not PBDE99, affects the developing cerebral dopaminergic system at gene transcriptional level in cortex and hippocampus, which may account for some of the mechanistic effects behind the aetiology of neuropsychiatric disorders.

Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl.

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 5mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0mg/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.

More signs of neurotoxicity of surfactants and flame retardants - Neonatal PFOS and PBDE 99 cause transcriptional alterations in cholinergic genes in the mouse CNS.

Maternally and lactionally transferred persistent organic pollutants may interfere with CNS development. Here, 10-day-old male mice were exposed to single oral doses of PFOS (perflourooctanosulphonate) or PBDE 99 (2,2',4,4',5-penta-bromodiphenyl ether), and examined for changes in cholinergic gene transcription in the CNS 24h and 7 weeks later. 24h after exposure qPCR analyses revealed decreased transcription of nAChR-ß2 and AChE in cortex, and increased mAChR-5 in hippocampus of PFOS treated mice. Neonatal PFOS treatment altered spontaneous behaviour at 2 months of age but did not affect gene transcription in adults. At 2 months of age neonatally PBDE 99 treated mice had altered spontaneous behaviour, and cortical transcription of AChE, nAChR-α4, nAChR-ß2 and mAChR-5 were elevated. Our results indicate that PFOS and PBDE 99 affects the developing central cholinergic system by altering gene transcription in cortex and hippocampus, which may in part account for mechanisms causing changes in spontaneous behaviour.

Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin.

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.

Effects of neonatal exposure to the flame retardant tetrabromobisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term potentiation and synaptic protein levels in mice.

Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17-19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment.

Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice.

Medical use of ionizing radiation (IR) has great benefits for treatment and diagnostic imaging, but procedures as computerized tomography (CT) may deliver a significant radiation dose to the patient. Recently, awareness has been raised about possible non-cancer consequences from low dose exposure to IR during critical phases of perinatal and/or neonatal brain development. In the present study neonatal NMRI mice were whole body irradiated with a single dose of gamma radiation (0; 350 and 500 mGy) on postnatal day 10 (PND 10). At 2 and 4 months of age, mice of both sexes were observed for spontaneous behaviour in a novel home environment. The neuroproteins CaMKII, GAP-43, synaptophysin and total tau in male mouse cerebral cortex and hippocampus were analysed 24h post-irradiation and in adults at 6 months of age exposed to 0 or 500 mGy on PND 10. A significantly dose-response related deranged spontaneous behaviour in 2- and 4-month-old mice was observed, where both males and females displayed a modified habituation, indicating reduced cognitive function. The dose of 350 mGy seems to be a tentative threshold. Six-month-old male mice showed a significantly increased level of total tau in cerebral cortex after irradiation to 500 mGy compared to controls. This demonstrates that a single moderate dose of IR, given during a defined critical period of brain development, is sufficient to cause persistently reduced cognitive function. Moreover, an elevation of tau protein was observed in male mice displaying reduced cognitive function.

Developmental exposure to the polybrominated diphenyl ether PBDE 209: Neurobehavioural and neuroprotein analysis in adult male and female mice.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants in polymer products, are reported to cause developmental neurotoxic effects in mammals. The present study have investigated neurotoxic effects arising from neonatal exposure to PBDE 209, including alterations in sex differences, spontaneous behaviour, learning and memory, neuroproteins and altered susceptibility of the cholinergic system in adults. Three-day-old NMRI mice, of both sexes, were exposed to PBDE 209 (2,2',3,3',4,4',5,5',6,6'-decaBDE at 0, 1.4, 6.0 and 14.0µmol/kg b.w.). At adult age (2-7 months) a similar developmental neurotoxic effects in both male and female mice were seen, including lack of or reduced habituation to a novel home environment, learning and memory defects, modified response to the cholinergic agent's paraoxon (males) and nicotine (females) indicating increased susceptibility of the cholinergic system. The behavioural defects were dose-response related and persistent. In mice of both sexes and showing behavioural defects, neuroprotein tau was increased.

Paracetamol (acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice.

Paracetamol (acetaminophen) is one of the most commonly used drugs for the treatment of pain and fever in children, both at home and in the clinic, and is now also found in the environment. Paracetamol is known to act on the endocannabinoid system, involved in normal development of the brain. We examined if neonatal paracetamol exposure could affect the development of the brain, manifested as adult behavior and cognitive deficits, as well as changes in the response to paracetamol. Ten-day-old mice were administered a single dose of paracetamol (30 mg/kg body weight) or repeated doses of paracetamol (30 + 30 mg/kg body weight, 4h apart). Concentrations of paracetamol and brain-derived neurotrophic factor (BDNF) were measured in the neonatal brain, and behavioral testing was done when animals reached adulthood. This study shows that acute neonatal exposure to paracetamol (2 × 30 mg) results in altered locomotor activity on exposure to a novel home cage arena and a failure to acquire spatial learning in adulthood, without affecting thermal nociceptive responding or anxiety-related behavior. However, mice neonatally exposed to paracetamol (2 × 30 mg) fail to exhibit paracetamol-induced antinociceptive and anxiogenic-like behavior in adulthood. Behavioral alterations in adulthood may, in part, be due to paracetamol-induced changes in BDNF levels in key brain regions at a critical time during development. This indicates that exposure to and presence of paracetamol during a critical period of brain development can induce long-lasting effects on cognitive function and alter the adult response to paracetamol in mice.

A single neonatal exposure to perfluorohexane sulfonate (PFHxS) affects the levels of important neuroproteins in the developing mouse brain.

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.

Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose.

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.

A single exposure to bisphenol A alters the levels of important neuroproteins in adult male and female mice.

Bisphenol A (BPA) is widely used in polymer products in food and beverage containers, baby bottles, dental sealants and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that a single neonatal exposure to bisphenol A can induce persistent aberrations in spontaneous behavior, in a dose-dependent manner, and affect the adult response to the cholinergic agent nicotine. Furthermore, other recent reports indicate that pre- and perinatal exposure to bisphenol A can induce neurotoxic effects. The present study indicates that a single neonatal exposure to bisphenol A, on postnatal day 10, during the peak of the brain growth spurt, can alter the adult levels of proteins important for normal brain development (CaMKII and synaptophysin). These alterations are induced in both male and female mice and effects are seen in both hippocampus and cerebral cortex. These results further support our recent study showing that neonatal exposure to bisphenol A can act as a developmental neurotoxicant and the effects are similar to effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.

Dose-dependent behavioral disturbances after a single neonatal Bisphenol A dose.

Bisphenol A is widely used in polymer products for food and beverage packaging, baby bottles, dental sealants, and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that neonatal exposure to other environmental pollutants can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. Furthermore, recent reports indicate that pre- and perinatal exposure to Bisphenol A can induce neurotoxic effects. The present study indicates that a single exposure to Bisphenol A on postnatal day 10 can alter adult spontaneous behavior and cognitive function in mice, effects that are both dose-response related and long-lasting/irreversible. Earlier studies on neonatal exposure to persistent organic pollutants (POPs) have shown the cholinergic system to be a target of neurotoxicity, but here only minor effects on the nicotine-induced behavior was seen. Furthermore, Morris swim-maze and the elevated plus-maze did not reveal any effects on spatial learning and anxiety-like behaviors. The present findings show similarities with effects earlier reported after pre- and perinatal exposure to Bisphenol A, and also with effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.

Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice.

Flame retardants such as polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A are used as flame retardants and detected in the environmental, wildlife species and human tissues. Exposure to PBDEs during the neonatal development of the brain has been shown to affect behavior and learning and memory in adult mice, while neonatal exposure to TBBPA (another brominated flame retardant) did not affect behavioral variables in the adult. In this study, we hypothesized that the effects of these compounds could be reflected by changes in biochemical substrates and cholinergic receptors and have examined the levels of four proteins involved in maturation of the brain, neuronal growth and synaptogenesis and the densities of both muscarinic and nicotinic cholinergic receptors. We measured the levels of radioactivity in the brain after administration of (14)C-labelled TBBPA at different time points and saw that levels of TBBA peaked earlier and decreased faster than the earlier reported levels of PBDE 99. The protein analysis in the neonatal brain showed changes in the levels of calcium/calmodulin-dependent protein kinase II (CaMKII), growth associated protein-43 (GAP-43) and synaptophysin following neonatal exposure to PBDE 99 (21 µmol/kg body weight), but not following exposure TBBPA. Furthermore, neonatal exposure to PBDE 99 and TBBPA caused a decrease in binding sites of the nicotinic ligand cytisine in frontal cortex. These results confirm earlier reported data that PBDE 99 can act as a developmental neurotoxicant, possibly due to its different uptake and retention in the brain compared to TBBPA. In addition, the changes in protein levels are interesting leads in the search for mechanisms behind the developmental neonatal neurotoxicity of PBDEs in general and PBDE 99 in particular, since also other compounds inducing similar adult behavioral disturbances as PBDE 99, affect these proteins during the period of rapid brain development.

Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain.

Animal studies have shown that neonatal anaesthesia is associated with acute signs of neurodegeneration and later behavioural changes in adult animals. The anaesthetic effect of propofol is thought to be mediated by γ-amino butyric acid (GABA)(A) receptors. The present study investigated the effects on proteins important for normal neonatal brain development (i.e. BDNF, CaMKII, GAP-43, synaptophysin and tau), and adult spontaneous motor and anxiety-like behaviours in response to diazepam, after neonatal exposure to propofol. Ten-day-old mice were exposed to 0, 10 or 60 mg/kg bodyweight propofol. Neonatal propofol exposure changed the levels of BDNF in the brain, 24h after exposure, but did not alter any of the other proteins. Neonatal propofol exposure significantly changed the adult response to the GABA-mimetic drug diazepam, manifest as no change in spontaneous motor activity and/or reduced sedative effect and an extinguished effect on the reduction of anxiety-like behaviours in an elevated plus maze. Although no adult spontaneous behavioural changes were detected after neonatal propofol exposure, the exposure caused an adult dose-dependent decrease in the response to the GABA-mimetic drug diazepam. These changes may be due to neonatal alterations in BDNF levels.