Unraveling Hypothalamus-Pituitary dysregulation: Hypergonadotropism in F1 progeny due to prenatal exposure to hexavalent chromium.

The endocrine disruptor hexavalent chromium [Cr(VI)] is a proven reproductive toxicant. We recently demonstrated that prenatal Cr(VI) exposure causes testicular resistance to gonadotropins, resulting in hypergonadotropic hypoandrogenism in F1 rats. However, the mechanism driving hypergonadotropism in F1 rats exposed to Cr(VI) prenatally remains an enigma. Therefore, we hypothesized that 'Prenatal Cr(VI) exposure may disrupt steroid hormones-mediated negative feedback regulation of the hypothalamic GnRH, and its receptor in the pituitary of F1 rats, leading to hypergonadotropism.' We administered potassium dichromate (50, 100, or 200 mg/L) to pregnant rats through drinking water between days 9 and 14, and their male F1 offspring were euthanized at 60 days of age. Prenatal Cr(VI) exposure in F1 rats resulted in the accumulation of Cr in the hypothalamus and pituitary. Western blot detected decreased hypothalamic GnRH, Kisspeptin1, and its receptor GPR54, along with diminished ERα, AR, aromatase, and 5α reductase, and GnRH regulatory transcription factors Pit-1 and GATA-4 proteins. Immunohistochemical studies revealed increased immunopositivity of GnRH receptor, AR, 5α reductase, ERα, ERß, and aromatase proteins in the pituitary, whereas decreased Kisspeptin1, GPR54, and inhibin ß. Our findings imply that Cr(VI) exposure during the prenatal period disrupts the hypothalamic Kisspeptin-GPR54-Pit-1/GATA4-GnRH network, boosting the pituitary GnRH receptor. We conclude that prenatal exposure to Cr(VI) alters GnRH expression in the hypothalamus and its receptor in the pituitary of F1 progeny through interfering with the negative feedback effect of androgens and estrogens.

Indole Propionic Acid Increases T Regulatory Cells and Decreases T Helper 17 Cells and Blood Pressure in Mice with Salt-Sensitive Hypertension.

Hypertension affects over a billion adults worldwide and is a major risk factor for cardiovascular disease. Studies have reported that the microbiota and its metabolites regulate hypertension pathophysiology. Recently, tryptophan metabolites have been identified to contribute to and inhibit the progression of metabolic disorders and cardiovascular diseases, including hypertension. Indole propionic acid (IPA) is a tryptophan metabolite with reported protective effects in neurodegenerative and cardiovascular diseases; however, its involvement in renal immunomodulation and sodium handling in hypertension is unknown. In the current study, targeted metabolomic analysis revealed decreased serum and fecal IPA levels in mice with L-arginine methyl ester hydrochloride (L-NAME)/high salt diet-induced hypertension (LSHTN) compared to normotensive control mice. Additionally, kidneys from LSHTN mice had increased T helper 17 (Th17) cells and decreased T regulatory (Treg) cells. Dietary IPA supplementation in LSHTN mice for 3 weeks resulted in decreased systolic blood pressure, along with increased total 24 h and fractional sodium excretion. Kidney immunophenotyping demonstrated decreased Th17 cells and a trend toward increased Treg cells in IPA-supplemented LSHTN mice. In vitro, naïve T cells from control mice were skewed into Th17 or Treg cells. The presence of IPA decreased Th17 cells and increased Treg cells after 3 days. These results identify a direct role for IPA in attenuating renal Th17 cells and increasing Treg cells, leading to improved sodium handling and decreased blood pressure. IPA may be a potential metabolite-based therapeutic option for hypertension.