Critical analysis of potential body temperature confounders on neurochemical endpoints caused by direct dosing and maternal separation in neonatal mice: a study of bioallethrin and deltamethrin interactions with temperature on brain muscarinic receptors

• Published in: Journal of applied toxicology Vol. 23; no. 1; pp. 9 - 18
• Main Authors: Pauluhn, Jürgen, Schmuck, Gabriele
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2003; Wiley
• Subjects: Administration, Oral; Allethrin - administration & dosage; Allethrin - toxicity; Animals; Animals, Newborn; Behavior, Animal - drug effects; Biological and medical sciences; Body Temperature - drug effects; Body Temperature Regulation - drug effects; Body Temperature Regulation - physiology; Body Weight - drug effects; Brain - drug effects; Brain - metabolism; Brain - pathology; brain development; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; developmental toxicity; direct dosing of neonatal pups; Female; homeothermy; Male; Maternal Behavior - drug effects; Maternal Behavior - physiology; Medical sciences; Mice; Mice, Inbred Strains; muscarinic receptors; Nitriles; Organ Size; Pesticides, fertilizers and other agrochemicals toxicology; poikilothermy; Pyrethrins - administration & dosage; Pyrethrins - toxicity; pyrethroid; Receptors, Muscarinic - metabolism; Respiratory Mechanics - drug effects; Respiratory Mechanics - physiology; route-to-route extrapolation; Temperature; thermolability; Toxicology; Insecticide; Toxicity; Body temperature; Rodentia; Pesticides; Central nervous system; Pyrethroids; Postnatal development; Homeothermy; Vertebrata; Mammalia; Mouse; Newborn animal; Muscarinic receptor; Poikilothermia; Deltamethrin; Brain (vertebrata)
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.873

The present investigation was conducted to understand better possible confounding factors caused by direct dosing of neonatal mice during the pre‐weaning developmental period. By direct dosing, pups might encounter thermal challenges when temporarily removed from their ‘natural habitat’. Typically, this leads to a cold environment and food deprivation (impaired lactation) and modulation of the toxic potency of the substance administered. Growth retardation as a consequence of such behavioural changes in pups makes it increasingly difficult to differentiate specific from non‐specific mechanisms. Neonatal NMRI mice were dosed daily by gavage (0.7 mg kg−1 body wt.) from postnatal day (PND) 10–16 with S‐bioallethrin, deltamethrin or the vehicle. Then the pups, including their non‐treated foster dams, were subjected temporarily for 6 h day to a hypo‐, normo‐ or hyperthermic environment, which was followed by normal housing. The measured temperatures in the environmental chambers were ca. 21, 25 and 30°C, respectively. Thus, temperatures in the hypo‐ and normothermic groups are comparable to the temperatures commonly present in testing laboratories, whereas the hyperthermic condition is that temperature typically present in the ‘natural habitat’ of pups. A deviation from the normal behaviour of both pups and dams was observed in the hypo‐ and normothermic groups. In these groups the rectal temperatures of pups were markedly decreased, especially in the early phase of the study (PND 10–12). Neonates that received either test substance displayed changes in body weights and brain weights at terminal sacrifice (PND 17) when subjected temporarily to a non‐physiological environment. An enormous influence of environmental temperature on the density of muscarinic receptors in the crude synaptosomal fraction of the cerebral cortex was ascertained. In summary, these results demonstrate that the direct dosing of thermolabile neonatal mice by gavage is subject to significant artefacts that render the interpretation of findings from such studies difficult. It appears that if direct dosing of neonatal pups is mandated, and inhalation is a relevant route of exposure, the combined inhalation exposure of dams with their litters is an alternative procedure that does not cause disruption of the ‘natural habitat’ of pups. However, owing to their higher ventilation, under such conditions the pups may receive dosages at least double those of the dams. Copyright © 2003 John Wiley & Sons, Ltd.