Does consumption of a high-fructose diet during pregnancy and lactation exacerbate the effects of maternal exposure to cadmium on development and metabolic function of mouse offspring?
Exposures to pollutants rarely occur in isolation, and often exist concurrently with other adverse conditions in one’s environment such as dietary stressors (e.g., over- and/or under-nutrition). The impacts of such exposures may be particularly insidious if it occurs during early life-stages. This study evaluated the effects of maternal exposure to cadmium (Cd) and consumption of a high-fructose diet (HFrD) on development of the offspring. Female CD-1 mice were given 0.5 or 5 ppm Cd in drinking water with or without a ~60% HFrD for 3 weeks before mating with untreated males; controls received deionized water and calorie-matched diet. Dams were maintained on the same diets until postnatal day (PND) 16. Cd concentrations in maternal, fetal, and neonatal liver increased in a dose-dependent manner; HFrD did not alter the hepatic bioaccumulation of this metal. Approximately 55% of Cd was cleared from livers of offspring by 6 months of age. Cd did not alter maternal weight gain or pregnancy outcomes, but HFrD produced a significant reduction in weight gain. Similarly, Cd alone did not alter neonatal growth at preweaning age. Significant post-weaning growth deficits were observed in Cd (5 ppm) and HFrD groups that persisted into adulthood, although a significant interaction between Cd and HFrD was not detected. Neither Cd nor HFrD exposure altered the age of eye-opening in the neonates. Maternal exposure of Cd alone or HFrD alone led to an early onset of puberty in male offspring. Cd alone also advanced onset of puberty in the females and HFrD masked the Cd effects. Maternal exposure to Cd (5 ppm) alone produced a decrease of body fat at adolescence, which recovered by adulthood; in contrast, HFrD led to a persistent reduction of body fat in the adult offspring. Similarly, maternal exposure to 5 ppm Cd alone or HFrD alone led to significant improvement of glucose tolerance in the adult offspring. Interestingly, maternal exposure to either stressor did not significantly alter the liver triglyceride levels in the adult offspring. Mechanistic evaluations of the neonatal and adult livers by transcriptomic and gene methylation analysis largely confirmed the phenotypic findings. Minimal differentially expressed hepatic genes (DEGs) were detected in the Cd and/or HFrD exposure groups. The few changes in gene expression involved cellular matrix, growth, inflammation, metabolism, and insulin regulatory pathways. DNA methylation changes in offspring liver were more robust at PND3, with minimal impact after cessation of maternal Cd and/or HFrD exposures. These alterations involved cell regulatory response pathways with maternal Cd exposure, metabolic and insulin regulatory pathways with HFrD, and inflammatory processes with Cd+HFrD. In summary, maternal exposure to Cd with or without HFrD altered growth and development, body composition, and glucose tolerance of the offspring that persisted into young adulthood. Generally, significantly exaggerated adverse outcomes due to interactions between these chemical and non-chemical stressors were not consistently apparent with the endpoints examined herein.