Prenatal exposure to PFOS or PFOA alters motor function in mice in a sex-related manner.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are organic surfactants widely used in various industrial and consumer applications. Due to their chemical properties, these perfluorinated compounds (PFCs) have also become persistent contaminants. The risk of possible intrauterine and lactational exposure to these chemicals poses a significant health concern for potential developmental effects. In the present study we have found that dietary exposure of mice to 0.3 mg/kg of PFOS or PFOA throughout pregnancy results in different distribution pattern in the offspring brain and liver. In particular, exposure to PFOS led to four times higher accumulation of the chemical in the brains of newborn mice than PFOA. We have used a battery of behavioral tests to evaluate motor function, circadian activity, and emotion-related behavior in the exposed offspring. Exposure to PFOS resulted in decreased locomotion in a novel environment and reduced muscle strength only in male offspring. Prenatal exposure to PFOA was associated with changes in exploratory behavior in male and female offspring, as well as with increased global activity in males in their home cage. The neurobehavioral outcome of prenatal exposure to PFCs in mice is characterized by mild alterations in motor function and it appears to be sex-related.

Interaction of gamma-radiation and methyl mercury during a critical phase of neonatal brain development in mice exacerbates developmental neurobehavioural effects.

In our environment, mammals (including humans) are exposed to various types of ionizing radiation and both persistent and non-persistent toxic chemicals. It is known that ionizing radiation, as well as methyl mercury, can induce neurotoxicological and neurobehavioural effects in mammals. These developmental neurotoxic effects can be seen following exposure during gestation. There is a lack of knowledge concerning the effects and consequences of low-dose exposure during critical phases of perinatal and/or neonatal brain development, and of the combination of ionizing radiation and environmental chemicals. A recent study has indicated that low doses of ionizing radiation to the human brain during infancy influence cognitive ability in adulthood. In the present study, 10-day old neonatal male NMRI mice were exposed to a single oral dose of MeHg (0.40 or 4.0 mg/kg bw). Four hours after the MeHg exposure the mice were subjected to (60)Co gamma-radiation on one occasion at doses of 0.2 and 0.5 Gy. The animals were then subjected to a spontaneous behaviour test at 2 and 4 months, and a water maze test at the age of 5 months. Neither the single dose of MeHg (0.4 mg/kg bw) nor the radiation dose of 0.2 Gy affected their spontaneous behaviour, whereas the co-exposure to external gamma-radiation and MeHg caused developmental neurotoxic effects. The study shows that gamma-radiation and MeHg can interact and significantly exacerbate developmental neurotoxic effects, as manifested by disrupted spontaneous behaviour, lack of habituation, and impaired learning and memory functions.

Neonatal co-exposure to low doses of an ortho-PCB (PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice.

Epidemiological studies have shown a discrepancy between children in the Faeroe Islands and children in the Seychelles with regard to neuropsychological defects during early development. Both populations have a high consumption of MeHg-contaminated fish. The defective neuropsychological differences seen in children from the Faeroe Islands could be attributed to PCBs via the mother's dietary consumption of whale meat and blubber in addition to MeHg. We have previously reported that certain persistent environmental toxicants like PCBs, DDT and PBDEs can induce permanent developmental neurotoxic effects in mice when these agents are present during a critical period of the neonatal brain development. The present study investigates whether PCB 153 (an ortho-substituted PCB) can interact with MeHg to enhance developmental neurotoxic effects on spontaneous behavior and habituation. Neonatal NMRI male mice were exposed at 10 days of age to a single oral dose of one of the following doses: PCB 153 (1.4micromol/kg body weight), MeHg (0.08, 0.40, or 4.0mg/kg body weight), PCB 153 plus MeHg, or a vehicle (20% fat emulsion). Spontaneous behavior, habituation, and cognitive function were observed in 2- and 4-month-old mice. The present study demonstrates that an interaction from co-exposure to low doses of PCB 153 and MeHg enhances developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, lack of habituation, and reduced cognitive functions. These effects occur at doses within the same order of magnitude as reported for exposed children.

Coexposure of neonatal mice to a flame retardant PBDE 99 (2,2',4,4',5-pentabromodiphenyl ether) and methyl mercury enhances developmental neurotoxic defects.

Epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development. The interaction between environmental pollutants is suggested as one reason for the observed defective neurological development in children from the Faeroe Islands as compared to children from the Seychelles. We have previously seen in mice that polychlorinated biphenyls (PCBs) can interact together with methyl mercury (MeHg), as well as PCB together with polybrominated diphenyl ether (PBDE 99) to exacerbate developmental neurotoxic effects when present during a critical period of neonatal brain development. PBDEs are a new class of global environmental contaminants. The present study shows that neonatal coexposure to PBDE 99 (0.8 mg/kg body weight) and MeHg (0.4 or 4.0 mg/kg body weight) can exacerbate developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, reduced habituation, and impaired learning/memory abilities. This is seen in the low dose range, where the sole compounds do no give rise to developmental neurotoxic effects. The effects seen are more than just additive. Furthermore, a significant effect of interaction was seen on the cholinergic nicotinic receptors in the cerebral cortex and hippocampus. This suggests that a mechanism for the observed cognitive defects is via the cholinergic system. Furthermore, PBDE can interact with MeHg causing developmental neurotoxic effects similar to those we previously have observed between PCB 153 + MeHg and PCB 52 + PBDE 99. This is of vital importance, as the levels of PBDEs are increasing in mother's milk and in the environment generally.

Polybrominated diphenyl ethers, a group of brominated flame retardants, can interact with polychlorinated biphenyls in enhancing developmental neurobehavioral defects.

The present study shows that polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can interact and enhance developmental neurobehavioral defects when the exposure occurs during a critical stage of neonatal brain development. PBDEs are used in large quantities as flame-retardant additives in polymers, especially in the manufacture of a great variety of electrical appliances, and textiles. In contrast to the well-known persistent compounds PCBs and DDT, the PBDEs have been found to increase in the environment and in human mother's milk. We have previously shown that low-dose exposure to environmental toxic agents such as PCB can cause developmental neurotoxic effects when present during a critical stage of neonatal brain development. Epidemiological studies indicate the adverse neurobehavioral impact of PCBs. Recently, we reported that neonatal exposure to PBDEs causes developmental neurotoxic effects. In the present study, 10-day-old Naval Medical Research Institute male mice were given one single oral dose of PCB 52 (1.4 micromol/kg body weight [bw]) + PBDE 99 (1.4 micromol), PCB 52 (1.4 micromol or 14 micromol), or PBDE 99 (1.4 micromol or 14 micromol). Controls received a vehicle (20% fat emulsion). Animals exposed to the combined dose of PCB 52 (1.4 micromol) + PBDE 99 (1.4 micromol) and the high dose of PCB 52 (14 micromol) or PBDE 99 (14 micromol) showed significantly impaired spontaneous motor behavior and habituation capability at the age of 4 and 6 months. The neurobehavioral defects were also seen to worsen with age in mice neonatally exposed to PCB 52 + PBDE 99.

Proteomic evaluation of neonatal exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether.

Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.

Impaired behaviour, learning and memory, in adult mice neonatally exposed to hexabromocyclododecane (HBCDD).

Brominated flame-retardants (BFRs) are a diverse group of global environmental pollutants. In the present study, we show that neonatal exposure to hexabromocyclododecane (HBCDD) can cause developmental behavioural defects that are similar to those recently reported for PBDEs and certain PCBs. Furthermore, HBCDD appears to be as potent as PBDEs in inducing developmental neurotoxic effects in mice. In this study, neonatal NMRI mouse pups were given either a single oral dose of 0.9mg HBCDD/kg body weight, 13.5mg HBCDD/kg body weight, or a 20% fat emulsion vehicle on postnatal day 10. At the age of 3 months, the mice were observed regarding spontaneous behaviour and concerning learning and memory capability. Mice exposed to 0.9mg HBCDD or to 13.5mg HBCDD/kg body weight showed a significantly altered spontaneous behaviour, manifested as a hyperactive condition and reduced habituation. Learning and memory, as observed in a Morris water maze, was also significantly affected in mice given the higher dose of HBCDD.