# Melengestrol acetate dysregulates HPP, HPT, and HPI axes, affecting the metamorphosis of Xenopus (Silurana) tropicalis

## TL;DR

Melengestrol acetate disrupts tadpole metamorphosis by affecting multiple hormone systems, leading to developmental issues like delayed limb growth.

## Contribution

The study reveals MGA's impact on the HPP, HPT, and HPI axes during amphibian metamorphosis.

## Key findings

- MGA exposure caused asynchronous metamorphosis and blocked forelimb emergence in tadpoles.
- MGA altered gene expression of prl, crh, dio2, dio3, and trβ, and reduced circulating corticosterone levels.
- RU486 partially reversed MGA's effects, suggesting a role for progesterone and glucocorticoid receptors.

## Abstract

Tadpole development involves several morphological, biochemical, and behavioral transformations regulated by endocrine networks, primarily the hypothalamic–pituitary–thyroid (HPT) and hypothalamic–pituitary–interrenal (HPI) axes. Exposure to melengestrol acetate (MGA), a progesterone-like compound, disrupts these processes, resulting in asynchronous metamorphosis characterized by narrower heads, skin abnormalities, and absence of forelimb emergence (FLE). To examine endocrinal alterations associated with these effects, Xenopus (Silurana) tropicalis tadpoles were exposed to 1.7 μg/L MGA, and combinations of MGA with 24.9 μg/L metyrapone (MTP, a 21-hydroxylase inhibitor that inhibits endogenous corticosterone synthesis) or 43 μg/L mifepristone (RU486, a dual antiprogestogen and antiglucocorticoid). MGA and MGA + MTP treatments induced asynchronous metamorphosis and blocked FLE, while MGA + RU486 attenuated MGA-associated phenotypic effects. Histological analysis revealed that FLE obstruction in MGA and MGA + MTP groups was associated with changes in the epithelium layer surrounding the forelimb. Gene expression analysis showed upregulated prl and downregulated crh, dio2, dio3, and trβ in MGA and MGA + RU486 groups. Circulating corticosterone was significantly reduced by MGA exposure and partially modulated in presence of RU486 co-treatment, without fully restoring control-like endocrine profiles. Together, these findings reveal that MGA disrupts tadpole metamorphosis through coordinated alterations across multiple endocrine axes, including the HPT, HPI, and hypothalamic–pituitary–prolactin (HPP) axes, highlighting the integrative nature of endocrine regulation during amphibian development.