Neurotoxic Effects Assessment Of Offspring Developmental Co-Exposure To Low Doses Of PBDEs And Methylmercury

Polybrominated diphenyl ether (PBDEs) and methylmercury (MeHg) are two of the most ubiquitous environmental contaminants, and both are known to cause neurotoxic effects. Exposure to PBDEs and MeHg can occur simultaneously since the two contaminants are found in the same food sources, especially fish, seafood, marine mammals and milk. The most commonly found PBDEs congener in human milk and cord blood is 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and 2,2′,4,4′,5- pentabrominatediphenyl ether (BDE-99). A number of experimental studies have been conducted in mice and rats, in order to evaluate the potential noxious effects of developmental exposure to MeHg, BDE-99 or BDE-47 alone on developing and adult organisms. However, there is still a paucity of information on the potential additive or synergistic interactions between MeHg and BDE-99 or BDE-47.In order to assess the neurotoxic effects of offspring developmental co-exposure to low doses of PBDEs and methylmercury, female rats were exposed to BDE-47, BDE-99, MeHg, MeHg+∑PBDEs and MeHg+ BDE-99 from the period of PND 7-13 or GD 6 - PND 21. Righting reflex, cliff avoidance and negative geotaxis were used to assess the pre-weaning neurobehavioural development. The rotarod test and the Morris water maze were used to assess the post-weaning neurobehavioural development. Assessment of biochemical effects was used to study the oxidative damage induced by developmental co-exposure to low doses of PBDEs and methylmercury in offspring.The results showed that:1. ICR mice were exposed to the low dose of BDE-47 (1802 ng/kg/d) and MeHg (2577ng/kg/d) +∑PBDEs (BDE-47 244 ng/kg/d, BDE-99 45 ng/kg/d, BDE-153 148 ng/kg/d) from PND 7 to PND 14. The body weight of the exposed mice had no significant differences compared with the control. The ability of memory and learning had no significant differences between the exposed and control groups. The present study showed that the low-dose exposure of BDE-47 to the development of mice brain has not yet induced injury seriously. Brain indexes analysis during the period from PND 14 to PND 28 revealed that brain indexes decreased significantly on PND 14 after co-exposure to MeHg+∑PBDEs compared with the control. At the dose used, MeHg+∑PBDEs did not affect significantly the ability of memory and learning. However, the content of NO, the vigor of SOD and the content of GSH in brains had significant difference compared with the controls, which indicated a marked decrease of antioxidant capacity in brain tissue after co-exposure.2. Sprague-Dawley rats were exposed to the low dose of BDE-99 (2 mg/kg/day) from GD 6 to PND 21 except for PND 0 when dams were left undisturbed. The results showed that: The cliff drop and negative geotaxis reflexes were delayed significantly in exposed offspring relative to controls. The rats developmental exposure to BDE-99 showed significantly longer latencies in locating the platform on the second and third day of the acquisition period, compared to the control group. The present study has demonstrated that developmental BDE-99 exposure causes oxidative stress in hippocampus of rat offspring by altering the activities of different antioxidant enzymes and giving rise to free radicals. The studies have demonstrated adverse effects following developmental exposure to BDE-99 associated with tissue concentrations very close to the current human body burden of this persistent and bioaccumulative compound.3. Sprague-Dawley rats were exposed to the low dose of MeHg(2.0μg/mL)+BDE-99(0.2 mg/kg/day) from GD 6 to PND 21 except for PND 0 when dams were left undisturbed. Dams in all exposure groups had gestational lengths, gestational weight gains, litter sizes, percent male pups, and percent live births similar to controls. Pup body weight analysis during the period from PND 1 to 33 revealed that there were no significant differences between exposed groups and controls. The cliff drop and righting reflex did not differ among groups. However, for MeHg+BDE-99 exposed group, a delay in negative geotaxis reflexe maturation was observed. In particular, on PND17, pups treated with MeHg+BDE-99 did not reach the criterion, while all other groups did at that time point. There were no differences among control, MeHg and BDE-99 groups in coordination and balance on the rotarod. However, the offspring given MeHg+BDE-99 were significantly less success rate compared to the controls. The common finding to offspring developmental co-exposure to MeHg and BDE-99 caused significant changes in SOD, GSH-Px, GSH, LPO, H₂O₂, NO levels and ESR signal intensity in the cerebellum, when compared with the controls. However, rats given either MeHg or BDE-99 showed no significant differences in these biochemical parameters in cerebellum, when compared to controls.4. The present study shows that developmental co-exposure to low dose of MeHg and BDE-99 can enhance developmental neurotoxic effects. The neurotoxicity of low dose MeHg can be exacerbated by the presence of low dose of BDE-99. The cerebellum appeared to be the most sensitive areas to combined low dose of MeHg and BDE-99 when compared to the hippocampus and cerebral cortex.It could be concluded that:1. The ability of learning and memory of offsprings were impacted significantly after exposure to PBDEs. It could be concluded that the target tissue of PBDEs is hippocampus.2. The present study shows that developmental co-exposure to low dose of MeHg and BDE-99 can enhance developmental neurotoxic effects.3. Significant oxidative stress has occurred in the cerebellum of offsprings after co-exposure to MeHg and BDE-99; however, there were no significant differences in hippocampus compared with the control group, which indicated that the neurotoxicity of low dose MeHg can be exacerbated by the presence of low dose of BDE-99.4. The results showed adverse effects following developmental co-exposure to MeHg and BDE-99, associated with tissue concentrations very close to the current human body burden of this persistent bioaccumulative compound.