The neonatal period is characterised in many mammalian species by rapid growth and development of the brain. This is a period when a number of fundamental changes occur. During this period, several of the signalling systems of the brain develop, and the mammalian brain can begin to process new information from the senses and translate this into adequate behaviour.
In humans, this brain growth spurt begins during the third trimester of pregnancy and continues during the first two years of life, while in our usual experimental animals such as mice and rats it occurs after birth and extends over the first 3-4 weeks. In mice, we have identified a limited critical period of brain growth spurt when the brain is especially sensitive to low doses of toxic compounds. The presence of toxic compounds during a limited phase of this developmental period can induce permanent damage to brain function.
In our modern environment we are constantly exposed to different chemicals. The question is whether different chemicals can interact and produce enhanced neurological and behavioural defects.
Faroes and Seychelles
Epidemiological investigations show that children on the Faroes have reduced neurological development, while children in the Seychelles do not, although both groups had been exposed to methylmercury. The difference is that on the Faroes the children were also exposed to PCB.
In the animal model we have developed, interaction and synergistic effects between chemicals, and interaction between early and late exposure, can be studied under controlled conditions. In the project we have studied whether PCBs, PBDEs (flame retardants), DDT, methylmercury and gamma radiation can interact and produce enhanced developmental neurotoxic effects.
PCB and mercury interact
We have also studied whether substances, which have a direct effect on the cholinergic transmitter system (nicotine and substances that inhibit acetylcholine esterase) and which are given during a critical phase of the neonatal period, can alter adult susceptibility to chemicals.
The results from this project show that PCBs and methylmercury can interact and give rise to enhanced developmental neurotoxicological effects. Interaction occurs at low doses where the substances, on their own, produce no effects. In the project we have also shown that PBDE + methylmercury, gamma radiation + methylmercury, PCB + PBDE, and DDT + PBDE, can interact and give rise to developmental neurotoxic defects.
Decreased learning ability
These interaction effects were observed as persistent changes in spontaneous behaviour, including hyperactive behaviour. The interaction effects were also seen to result in decreased learning and memory ability and to give rise to changes in the cholinergic transmitter system, a system that is involved in learning, memory and cognitive functions. The synergistic effects are mostly initiated when the toxic agent or ionising radiation on its own gives rise to no persistent effect.
Exposure to nicotine, which affects the cholinergic transmitter system during the neonatal period, results in increased adult susceptibility to an organophosphate (paraoxon) and also to donepezil, a drug used in treating patients with Alzheimer's disease, manifested as changes in spontaneous behaviour.
Differences in adult susceptibility are therefore not necessarily an inherited condition, but may have been acquired early in life through exposure to low doses of toxic agents. Possibly also through co-exposure to environmental toxicants in low doses, each of which on their own do not produce any toxic effects but which can interact and produce persistent behavioural changes and altered adult susceptibility to environmental toxicants and/or pharmaceuticals.
Author
:
Per Eriksson
is PhD and Professor at Department of Physiology and Developmental Biology, Ecotoxicology, Uppsala University, Norbyvägen 18A, 752 36 Uppsala.
E-mail:
per.eriksson@ebc.uu.se