ARTICLE | doi:10.20944/preprints202211.0355.v1
Subject: Life Sciences, Other Keywords: testosterone; estrogen; cyprotenone acetate; masculinizing; feminizing; cytochrome P450; sex-specific genes
Online: 18 November 2022 (10:10:00 CET)
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.
REVIEW | doi:10.20944/preprints202211.0206.v1
Subject: Life Sciences, Other Keywords: new approach methodologies (NAMs); adverse outcome pathways (AOPs); endocrine disruptors; animal replacement; OECD TG 414
Online: 11 November 2022 (02:00:48 CET)
Developmental toxicity testing urgently requires the implementation of human relevant new approach methodologies (NAMs) that better recapitulate the peculiar nature of human physiology during pregnancy, especially the placenta and the maternal/fetal interface, which represent a key stage for the human lifelong health. Fit-for-purpose NAMs for the placental-fetal interface are desirable to improve the biological knowledge of environmental exposure at molecular level and to reduce the high cost, time and ethical impact of animal studies. This article reviews the state of the art on the available in vitro (placental, fetal and amniotic cell-based systems) and in silico NAMs of human relevance for developmental toxicity testing purposes, as well as of the available Adverse Outcome Pathways related to developmental toxicity. The OECD TG 414 for the identification and assessment of deleterious effects of prenatal exposure to chemicals on developing organisms will be discussed to delineate the regulatory context and to better debate what is missing and needed in the context of the developmental origins of health and disease hypothesis to significantly improve this sector. Starting from this analysis, the development of a novel human feto-placental organ-on-chip platform will be introduced as an innovative alternative tool for developmental toxicity testing, considering possible implementation and validation strategies to overcome the limitation of the current animal studies and NAMs available in regulatory toxicology and in the biomedical field.