Lactational retrorsine exposure changes maternal milk components and disturbs metabolism homeostasis of offspring rats

Pyrrolizidine alkaloids (PAs) are a type of plant-derived environmental toxins, which pose a health hazard to human and livestock via contaminating soil, water, plants and food. In this study, we aimed to investigate the effect of lactational retrorsine (RTS, a typical toxic PA) exposure on breastmilk components and glucose-lipid metabolism of offspring rats. Dams were intragastrically administered with 5 mg/(kg & BULL;d) RTS during lactation. After metabolomic analyses, 114 differential constituents were identified in breastmilk between control and RTS groups, featured by reduction of lipids and lipid-like molecules, while presence of abundant RTS and its derivative in RTS-exposed milk. RTS exposure induced liver injury in pups, but the leakage of transaminases in serum recovered in their adulthood. Serum glucose levels were lower in pups but higher in male adult offspring from RTS group. RTS exposure also induced hypertriglyceridemia, hepatic steatosis and decreased glycogen content in both pups and adult offspring. Additionally, suppression of PPARa-FGF21 axis persisted in offspring liver after RTS exposure. These data indicated that inhibition of PPARa-FGF21 axis induced by milk deficient in lipid contents, together with hepatotoxic injury caused by RTS in breastmilk, may disrupt glucose and lipid metabolism of pups, and the persistent suppression of PPARa-FGF21 axis may program metabolic disorder of glucose and lipid in adult offspring.

Automated summary

This study aimed to investigate the impact of lactational exposure to lactational synthetic oxo determinant (RTS), a common toxic pyrrolizidine alkaloid, on breast milk components and glucose-lipid metabolism in offspring rats. The results revealed a significant reduction in lipids and lipid-like molecules, as well as an accumulation of RTS and its derivatives in breast milk following RTS exposure. Pups exposed to RTS exhibited liver injury, while transaminase leakage in their serum returned to normal levels in adulthood. Furthermore, RTS exposure led to lower serum glucose levels in pups and higher levels in adult male offspring. It also induced hypertriglyceridemia, hepatic steatosis, and decreased glycogen content in both pups and adult offspring. Importantly, the inhibition of the PPARa-FGF21 axis persisted in the offspring's liver after RTS exposure, which may contribute to the metabolic disorders observed in glucose and lipid metabolism in adult offspring.