Role of steroid hormone differentiation during adolescence in metabolism and cardiometabolic health

• Applicants: Dr. Carla Harris; Marie Standl, Ph.D.
• Subject Area: Nutritional Sciences ; Epidemiology and Medical Biometry/Statistics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467855870

There is compelling evidence tracing the life-long risk for chronic diseases to sensitive developmental periods of life, which include developmental changes regulated by steroid hormones. Metabolic disorders often begin to manifest with sex-specific trajectories in adolescence. Regulatory effects of steroid hormones may represent a potential underlying mechanism, given that these are elevated for the first time in adolescence following a long period of quiescence since early infancy. We aim to address the following specific hypotheses 1) early-life factors known to be associated with long-term disease, such as lack of or short breastfeeding, and accelerated postnatal growth, act via a maladaptation of the stress response, manifesting in adolescence as sex-specific, inter-individual differences in steroid hormone levels; 2) metabolites associated with steroid hormone levels in adolescence indicate sex-specific biological pathways influenced by steroid hormones; 3) inter-individual differences in steroid hormone levels in adolescence are associated with differences in cardiometabolic outcomes, pointing towards possible mechanisms underlying disease development and sex-specific disease trajectories. In this context, a secondary hypothesis is that differences in steroid hormone levels also underlie sexually dimorphic phenotypes of mental health problems, a common comorbidity of cardiovascular diseases also emerging in adolescence.We will make use of two comprehensively assessed prospective birth cohort studies, GINIplus and LISA. These cohorts offer the necessary data in early life (breastfeeding, early growth) and adolescent outcomes (targeted metabolomics, metabolic and mental health outcomes) to address the proposed project goals. Plasma samples collected at age 15 years are available in around 450 subjects for the measurement of steroid hormones. These will be considered as dependent variables in prospective regression analyses evaluating the effect of early life factors, and as independent variables in cross-sectional analyses at age 15 years, assessing associations with metabolomic profiles, cardiometabolic health markers (anthropometry, body composition, blood lipids, glucose and insulin levels, low-grade inflammation) and mental health (mental health problems, depression). All analyses will be performed stratified by sex.The proposed combination of studies will provide a comprehensive and integrated vision of steroid hormones and their role in pathways underlying metabolic disorders, as well as their link to early risk factors. Analyses will underscore sex-specific mechanisms determining sexually dimorphic disease trajectories arising in adolescence.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Berthold V. Koletzko; Professor Dr. Martin Reincke