Gender difference and BMDL exploration of developmental immunotoxicity induced by early-life low-dose exposure to 4-nonylphenol in Wistar rats

Background: Nonylphenol (NP) is a widespread environmental endocrine disruptor with potential developmental immunotoxicity. The present study aimed to investigate the gender-specific developmental immunotoxic effects of early-life exposure to low doses of 4-nonylphenol (4-NP) on Wistar rats and the corresponding thresholds. Methods: Pregnant rats (F0 generation) were exposed to low doses of 4-NP from gestational day 6 (GD6) to postnatal day 90 (PND90), and F1 offspring continued to be exposed until the maturation of the immune system on PND42. We assessed immune organ development, immune responses, lymphocyte subset composition, cytokine secretion, and the Th17/Treg cell balance as endpoints for developmental immunotoxicity. Benchmark Dose analysis was conducted to explore the thresholds. Results: Early-life exposure to 4-NP led to significant gender-specific differences in the immune response. Female pups exhibited greater sensitivity to 4-NP, with reduced thymus and spleen weights, suppressed humoral immune function, decreased natural killer (NK) cell activity, and an imbalance in the Th17/Treg cell ratio. Male pups showed inhibition of NK cell activity but no significant changes in humoral immune function. Levels of phosphorylated STAT3, STAT5, and JAK3 proteins increased in the spleens of exposed pups of both gender. The lowest benchmark dose lower limit (BMDL) value of developmental immunotoxicity was lower in female rats (based on the thymus weight) than in male rats (based on the NK cell activity). Conclusion: Early-life exposure to 4-NP has been shown to induce gender-specific developmental immunotoxicity in rats, with female pups exhibiting greater sensitivity. And developmental immunotoxicity may serve as a more sensitive indicator for the risk assessment of 4-NP. Th17/Treg balance may be interrupted through JNK/STAT pathway by 4-NP exposure, which needs to be further investigated.