ABSTRACT

This PhD dissertation was carried out at the Department of Chemical Work Environment at the National Institute of Occupational Health, Copenhagen, Denmark.

The aim of the project was to investigate the susceptibility of the foetal nervous system to maternal stress during pregnancy, also in a situation of concomitant exposure to a developmental neurotoxicant, in an animal model.

Four different models of chronic stress were applied during the two last weeks of gestation in rats: 1) Enriched environment. 2) Repeated reversal of the light/dark cycle ("shift work"). 3) An unpredictable schedule of moderate level noise. 4) Chronic Mild Stress (CMS - an unpredictable schedule of varying milder stressors, e.g. damp bedding, small cage etc.). Subsequently, gestational exposure to CMS was combined with exposure to the organic solvent toluene. Investigations in dams included basal plasma corticosterone, in offspring cognitive function as well as anxiety, reactivity, and the stress response were studied.

Enriched environment was associated with increased thymic weight in female offspring. Female offspring prenatally exposed to light/dark reversal exhibited increased body weight in adulthood. Small behavioural changes in the offspring indicated prenatal exposure to unpredictable noise led to increased coping ability in stressful situations. CMS decreased plasma corticosterone in pregnant dams, and the offspring exhibited decreased thymic weight and increased reactivity (acoustic startle response). Prenatal stress has been hypothesized to elevate baseline ASR. Possibly, the increased reactivity in CMS-offspring may represent an increased perception of the experimental situation as fearful.

In the combined exposure situation, early lactational weight was lower in the combined exposure group. No statistically significant interactions were observed between CMS and Ttluene, but cognitive function appeared differentially affected by prenatal exposure to CMS (improvement) and toluene (impairment). In conclusion, there was no indication of a potentating effect of prenatal stress on the nervous insults induced by toluene.

Future studies ought to investigate whether the increased reactivity (acoustic startle reflex) in prenatally stressed offspring occurred due to a general increase in sensitivity towards imprinting by life experiences, as well as if the decreased weight of thymus in prenatally stressed offspring have consequences for immune function later in life. Finally, the potential of the CMS model for development of an animal model of hypocortisolism deserves further attention.