Lasting biological effects of early environmental influences. II. Lasting depression of weight caused by neonatal contamination.

Certain specific-pathogen-free (SPF) mice bred and maintained under semiprotected conditions have an intestinal flora which is qualitatively simpler (although not quantitatively smaller) than that of mice of the same genetic stock produced under ordinary conditions. They are also heavier at weaning time, grow at a faster rate, and reach a greater adult weight than ordinary mice. When SPF mice are contaminated per os shortly after birth with certain bacterial cultures isolated from the intestinal contents of adult ordinary mice, these bacteria multiply extensively throughout the gastrointestinal tract and persist at extremely high levels until weaning time. Such bacterial infections do not affect significantly either weaning weight, growth rate, or maximum adult weight. In contrast, weight depression could be consistently brought about by contaminating newborn SPF mice per os with bacteria-free filtrates of homogenates of intestines from ordinary mice. The weight-depressing agent passed through Millipore discs of 0.45 and 0.22 micro porosity, but was held back at 0.10 micro porosity. The depression of weight caused by either intestine homogenate or filtrates thereof could be detected within a few days after contamination (of 2 day old mice) and persisted throughout the adult life of the contaminated animals. When intestine homogenate of the SPF mice used in this study were introduced per os into newborn SPF mice, they did not affect their growth rate or adult weight. On several occasions, but not consistently, bacteria-free filtrates capable of depressing the weight curve of SPF mice produced alterations in the appearance of tissue cultures of BHK-21 and mouse embryo cells. When tissue cultures so infected were introduced into newborn SPF mice, the weight of these animals was depressed early and lastingly. An agent exhibiting weight-depressing activity has been transferred from mouse to mouse over many passages by contaminating newborn SPF animals per os. Weight depression was achieved with extremely small doses of material (10(-5) ml of intestine homogenate of 10(-4) of mouse embryo culture). Under these conditions, none of the animals showed obvious signs of disease except reduced weight. Only very young SPF mice (preferably less than 3 days old) proved susceptible to the weight-depressing effect of the filtrates of intestine homogenates or of infected tissue cultures prepared therefrom. After oral contamination, it took approximately 1 wk before the intestinal homogenate obtained from contaminated animals exhibited a high level of weight-depressing activity. The growth-depressing effect could be transmitted from one generation to the next by mating SPF mice that had been contaminated shortly after birth and that were consequently smaller than control SPF animals.