OR15-05 Transmission of environmental health risks across generations and the impact on age at menarche

Abstract Disclosure: X. Hu: None. P. Cirillo: None. N. Krigbaum: None. B. Minasenko: None. V. Tran: None. M.M. Nellis: None. D. Wang: None. Y. Go: None. D.P. Jones: None. B. Cohn: None. Girls are entering puberty at increasingly younger ages. The average age at menarche, a tightly regulated milestone in pubertal development, is decreasing from generation to generation. While experimental studies suggest an environmental contribution, the underlying links in population have not been elucidated. We examined how parental and grandparental environmental exposures affect the age at menarche across generations in Child Health and Development Studies (CHDS). Using high-resolution metabolomics, we analyzed serum samples collected from 250 F0 pairs of male and female between 1959-1967 and assessed associations with age at menarche in their daughters (F1, n=247, median birth year 1963) and granddaughters (F2, n=139, median birth year 1990). Results showed that while the median age at menarche was stable between F0 and F1, it dropped by a full year from F1 to F2. Linear regression models identified distinct metabolic contributions from paternal and maternal lines, with interactive effects suggesting strong impact from both (grand)parents’ metabolic status. Notably, more associations with F1/F2 age at menarche were observed in couples with similar chemical exposure profiles, indicating a reinforcing health risk from the male line. We also found that F0 male phenoxyethanol levels were inversely associated with age at menarche in both generations from couples with similar exposures. We observed key metabolic interactions between the male and female lines in predicting F1 and F2 age at menarche, particularly involving tryptophan, tyrosine, taurine (and its bile acid conjugates), as well as citric acid cycle intermediates, and the interactions were more pronounced for F2 than for F1. For example, F0 male tryptophan levels were inversely associated with age at menarche in F1 and F2 when F0 female tryptophan levels were low, and the association was stronger in F2 than F1. Similarly, associations between age at menarche in F2, but not F1, and levels of fumarate and succinate—metabolites known for their roles in epigenetic regulation—varied depending on the spouse’s levels, demonstrating a stronger molecular interaction in F2 than F1. These findings underscore the importance of the male line in influencing age at menarche, with stronger generational effects seen in F2 than F1, supporting a role for epigenetic inheritance. Paternal exposure to environmental chemicals may play an unrecognized but critical role in shaping offspring endocrine health. Presentation: Sunday, July 13, 2025