Gestational exposure to haloxyfop-R-methyl drives maternal and embryonic residue burden and hepatic biochemical injury in Wistar rats.

Abstract

Haloxyfop-R-methyl is a grass-selective aryloxyphenoxypropionate herbicide whose gestational exposure is toxicologically important because maternal xenobiotic burden can coincide with fetal organogenesis, placental transfer, and hepatic metabolic stress. The present investigation evaluated organ-specific accumulation of haloxyfop-R-methyl in pregnant Wistar rats and their fetuses following exposure on GD3, GD13, or GD17. It also assessed the corrective efficacy of narcissin and sophoroflavonoside (SFL) against pesticide-induced alterations in maternal hepatic biomarkers. Pregnant rats received haloxyfop-R-methyl orally at a sublethal dose equivalent to 1/10 LD₅₀ on gestational day (GD) 3, 13, or 17. Maternal and fetal liver, lung, spleen, and brain were collected on GD20-GD21 for LC-MS-based residue quantification. A parallel experiment measured maternal plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin. These biomarkers were assessed after haloxyfop-R-methyl exposure alone or combined with narcissin or SFL. LC-MS calibration showed strong linearity, with slopes of 93,384.20 and 97,181.37 and uncentered R² values of 0.99993 and 0.99978. Haloxyfop-R-methyl was absent from controls but was detected in all examined maternal and fetal tissues. Residue concentrations differed among exposure-timing groups at terminal sampling. Maternal liver and lung showed the highest concentrations in the GD17-dosed group, reaching 0.619 ± 0.050 and 0.529 ± 0.041 µg g⁻¹, respectively. Fetal liver and lung also showed the highest concentrations in the GD17-dosed group, reaching 0.419 ± 0.035 and 0.405 ± 0.020 µg g⁻¹. Fetal-to-maternal residue ratios were highest in several organs in the GD17-dosed group, particularly lung, liver, and brain. Haloxyfop-R-methyl increased maternal ALT, AST, and total bilirubin across all exposure windows. The highest values occurred in the GD17-dosed group at terminal sampling. However, all groups were sampled on GD20-GD21, resulting in different intervals between dosing and sampling. Therefore, the observed differences cannot distinguish gestational stage effects from effects of time elapsed since exposure. Narcissin and SFL reduced pesticide-induced biochemical alterations. SFL showed greater protective efficacy across most endpoints, particularly bilirubin on GD3 and AST on GD13. Standardized effect-size analysis confirmed large haloxyfop-R-methyl-associated effects and measurable biochemical correction following flavonoid treatment. The integrated residue-biomarker framework characterizes exposure window-associated maternal-fetal residue distribution and flavonoid-mediated biochemical correction during pregnancy.