Steroid 5α-reductase type 1 as a neurodevelopmental toxicological target: Hydrophobicity governs environmental inhibition within, but not across, chemical classes.

Abstract

Steroid 5α-reductase type 1 (SRD5A1) catalyzes the rate-limiting reduction of progesterone to 5α-dihydroprogesterone, the committed step toward allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid type A (GABAA) receptors. Its clinical relevance is shown by allopregnanolone therapeutics for postpartum depression and by finasteride's neuropsychiatric effects. Between 2017 through 2026, 14 structurally unrelated classes of environmental and naturally occurring chemicals were reported to inhibit human SRD5A1, forming an unusually uniform data set: mostly one human enzyme, testosterone substrate, NADPH cofactor. As an exploratory synthesis we ask whether a single physicochemical descriptor predicts potency across classes. Pooling 46 compounds, which fall into 14 classes and so are not independent, we find no cross-class correlation between potency and hydrophobicity (R² ≈ 0), whereas within individual classes hydrophobicity is often a strong determinant. The most potent inhibitors are not the most lipophilic: dithiocarbamates and aldehydes are potent at low LogP, reflecting metal chelation and covalent chemistry rather than partitioning. Potency is thus set by scaffold and mechanism, with hydrophobicity tuning it only within a scaffold, so cross-class read-across is not justified. We place these findings in an adverse outcome pathway linking SRD5A1 inhibition to reduced allopregnanolone synthesis, impaired GABAA modulation, and disrupted neurodevelopment. Two limitations temper their weight: reliance on a surrogate substrate and few laboratories, and a wide gap between micromolar in vitro potencies and nanomolar exposures that narrows only for a few chemicals, such as perfluorooctane sulfonate, organotins, and pentabromophenol. We recommend progesterone-based human SRD5A1 assays, rather than the testosterone surrogate, before these chemicals enter developmental neurotoxicity screening.