Risk Assessment of Transgender People: Development of Rodent Models Mimicking Gender-Affirming Hormone Therapies and Identification of Sex-Dimorphic Liver Genes as Novel Biomarkers of Sex Transition

Transgender (TG) describes individuals whose gender identity differs from the social norms. Some TG people undergo gender-affirming hormone therapy (HT) and may be considered as a sub-group of population susceptible to environmental contaminants for their targets and modes of action. Aim of the work is to set appropriate HT doses and identify specific biomarkers to implement TG animal models. Four adult rats/group/sex are subcutaneously exposed to 3 doses of HT (plus control) selected starting from available data. Demasculinizing-feminizing model (dMF): β-estradiol plus cyproterone acetate: 0.09+0.33, 0.09+0.93 and 0.18+0.33 mg, 5 times/week. Defeminizing-masculinizing model (dFM): testosterone 0.45, 0.95 and 2.05 mg, 2 times/week. Clitoral gain and sperm count, histophatological analysis of reproductive organs and liver, hormone serum levels and gene expression of sex-dimorphic CYP450 are evaluated. In dMF model, the selected doses, leading to T serum levels at the range of the corresponding cisgender, induced strong general toxicity and cannot be used in long-term studies. In dFM model, 0.45 mg of testosterone represents the correct dose. In addition, the endpoints selected are considered suitable and reliable to implement the animal model. The sex-specific CYP expression is a suita-ble biomarker to set proper (de)masculinizing/(de)feminizing HT and to implement TG animal models.