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Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains.

ABSTRACT: We previously reported that mouse strains with lower circulating insulin-like growth factor 1 (IGF1) level at 6 mo have significantly extended longevity. Here we report that strains with lower IGF1 have significantly delayed age of female sexual maturation, measured by vaginal patency (VP). Among strains with normal lifespans (mean lifespan >600 d), delayed age of VP associated with greater longevity (P = 0.015), suggesting a genetically regulated tradeoff at least partly mediated by IGF1. Supporting this hypothesis, C57BL/6J females had 9% lower IGF1, 6% delayed age of VP, and 24% extended lifespan compared with C57BL/6J.C3H/HeJ-Igf1, which carries a C3H/HeJ allele on chromosome (Chr) 10 that increases IGF1. To identify genetic loci/genes that regulate female sexual maturation, including loci that mediate lifespan tradeoffs, we performed haplotype association mapping for age of VP and identified significant loci on Chrs 4 (Vpq1) and 16 (Vpq2 and 3). At each locus, wild-derived strains share a unique haplotype that associates with delayed VP. Substitution of Chr 16 of C57BL/6J with Chr 16 from a wild-derived strain significantly reduced IGF1 and delayed VP. Strains with a wild-derived allele at Vpq3 have significantly extended longevity compared with strains with other alleles. Bioinformatic analysis identified Nrip1 at Vpq3 as a candidate gene. Nrip1(-/-) females have significantly reduced IGF1 and delayed age of VP compared with Nrip1(+/+) females. We conclude that IGF1 may coregulate female sexual maturation and longevity; wild-derived strains carry specific alleles that delay sexual maturation; and Nrip1 is involved in regulating sexual maturation and may affect longevity by regulating IGF1 level.

SUBMITTER: Yuan R

PROVIDER: S-EPMC3361401 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains.

Yuan Rong R Meng Qingying Q Nautiyal Jaya J Flurkey Kevin K Tsaih Shirng-Wern SW Krier Rebecca R Parker Malcolm G MG Harrison David E DE Paigen Beverly B

Proceedings of the National Academy of Sciences of the United States of America 20120507 21

We previously reported that mouse strains with lower circulating insulin-like growth factor 1 (IGF1) level at 6 mo have significantly extended longevity. Here we report that strains with lower IGF1 have significantly delayed age of female sexual maturation, measured by vaginal patency (VP). Among strains with normal lifespans (mean lifespan >600 d), delayed age of VP associated with greater longevity (P = 0.015), suggesting a genetically regulated tradeoff at least partly mediated by IGF1. Suppo ...[more]

PMID: 22566614

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Project description:The age of pubertal onset for girls has declined over past decades. Research suggests that endocrine disrupting chemicals (EDCs) may play a role but exposure at multiple stages of development has not been considered. We examined in utero and peripubertal exposure to bisphenol-A (BPA) and phthalates in relation to serum hormones and sexual maturation among females in a Mexico City birth cohort. We measured phthalate metabolite and BPA concentrations in urine collected from mothers during their third trimester (n=116) and from their female children at ages 8-13 years (n=129). Among girls, we measured concurrent serum hormone concentrations, Tanner stages for breast and pubic hair development, and collected information on menarche onset. We used linear and logistic regression to model associations between in utero and peripubertal measures of exposure with hormones and sexual maturation, respectively, controlling for covariates. An interquartile range (IQR) increase in in utero urinary mono-2-ethylhexyl phthalate (MEHP) was positively associated with 29% (95% CI: 9.2-52.6%) higher dehydroepiandrosterone sulfate (DHEA-S), an early indicator of adrenarche, and 5.3 (95% CI: 1.13-24.9) times higher odds of a Tanner stage >1 for pubic hair development. Similar relationships were observed with other in utero but not peripubertal di-2-ethylhexyl phthalate (DEHP) metabolites. IQR increases in in utero monobenzyl phthalate (MBzP) and monoethyl phthalate (MEP) were associated with 29% and 25% higher serum testosterone concentrations (95% CI: 4.3-59.3; 2.1-54.1), respectively. In addition, we observed suggestive associations between in utero and peripubertal MEP concentrations and increased odds of having undergone menarche, and between peripubertal MnBP concentrations and increased odds of having a Tanner stage >1 for both breast and pubic hair development. BPA was not associated with in utero or peripubertal serum hormones or sexual maturation. Our findings suggest in utero phthalate exposure may impact hormone concentrations during peripubescence and timing of sexual maturation. Efforts to control phthalate exposure during pregnancy should be of high priority.

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Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains.

Publications

Genetic coregulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains.

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