Nephrotoxicity induced by N‐(3,5‐dichlorophenyl)‐3‐hydroxysuccinamic acid in male and female Fischer 344 rats

Abstract

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is a more potent nephrotoxicant in female rats than in males. Similarly, nephrotoxicant NDPS metabolites studied to date in male and female rats have also demonstrated gender differences, being twice as potent as nephrotoxicants in females as in males. The purpose of this study was to examine the nephrotoxic potential of N-(3,5-dichlorophenyl)-3-hydroxysuccinimide (3-NDHSA) in male and female Fisher 344 rats to determine if gender differences in nephrotoxic potential also exist for this metabolite. Rats (four per group) were administered a single intraperitoneal (i.p.) injection of 3-NDHSA (0.1, 0.2 or 0.4 mmol kg(-1)) or vehicle, and renal function was monitored at 24 and 48 h. 3-NDHSA 0.1 mmol kg(-1) did not induce nephrotoxicity in male or female rats. In male rats, 3-NDHSA 0.2 mmol kg(-1) induced mild nephrotoxicity seen as diuresis and transient, mild proteinuria. However, 3-NDHSA 0.4 mmol kg(-1) induced marked nephrotoxicity. In female rats, 3-NDHSA 0.2 mmol kg(-1) induced mild nephrotoxicity, as evidenced by transient diuresis and proteinuria. As in males, 3-NDHSA 0.4 mmol kg(-1) induced marked nephrotoxicity. These results indicate that, unlike NDPS and other nephrotoxic NDPS metabolites, 3-NDHSA does not exhibit gender differences in nephrotoxic potential. In addition, in comparison with NDPS and other nephrotoxic NDPS metabolites, 3-NDHSA is a less potent nephrotoxicant that NDHS or 2-NDHSA and similar to NDPS in nephrotoxic potential in male rats.

Chemo‐Selective Single‐Cell Metabolomics Reveals the Spatiotemporal Behavior of Exogenous Pollutants During Xenopus Laevis Embryogenesis

“…Furthermore, to explore how they were transformed in vivo, enzyme enrichment analysis was adopted (Figure 6B), and it showed the accumulation of cis diols in vertebrates could be attributed to 2,4 dihydroxy nitrophenol exchange, 4-nitrophenol sulfotransferase, 4-nitrophenyl sulfate exchange, and cytochrome P450 2E1. By comparing and analyzing the above enzyme enrichment analysis results with reported papers, [44,45] we found 1-(3,5-dichlorophenyl)pyrrole-2,3,5-triol could be converted from dimethachlon, a pesticide used for water and plant sterilization, by P450 in vivo (Figure 6C). To the best of our knowledge, although it has been revealed that dimethachlon is toxic to rats because it may lead to kidney tubular necrosis and polyuria, [46] how it influences metabolic pathways of early embryo development has not been reported.…”

Sex-related differences in renal toxicodynamics in rodents

“…N-(3,5-dichlorophenyl)succinimide (NDPS) is an agricultural fungicide and is a more potent nephrotoxicant in female Fischer 344 rats than in males [150]. In general, the NDPS metabolites also show sex differences in nephrotoxicity [151], but not N-(3,5-dichlorophenyl)-3-hydroxysuccinic acid that is, among NDPS metabolites the least nephrotoxic [152]. The kidney probably accumulates toxic sulphate conjugates of NDPS metabolites rather than forming the conjugates.…”

“…As well stated by Gochfeld [6], sex is a basic biological variable, not a confounder factor. In toxicology, the gender issue has been recently emerged, given the growing requirement of information about the toxicokinetics and toxicodynamics of xenobiotics in PER Rat F344 M > F Related to TCVG formation [123] 1,3D Rat renal cortical slices M > F Differences in oxidative and conjugative metabolism [125] TFE Rat AP derived M = F [128] HCBD Rat W M > F Role of CYP3A1/2 with sex-specific sulfoxidation [135] Rat W M > F Formation of N-ac-PCBC sulfoxide in male rats, an alternative, -lyase-independent bioactivation pathway [43] Rat F344, AP derived, W F > M Differences in hepatic and renal enzymes Female rat kidney shows marked dose-related decrease in nonprotein sulfhydryl content [137] [137, 138,140] Mice AP Swiss derived M = F TBZ Mice ICR M > F Androgen-mediated [145] HCB Rat SD M only HD formation [146] EQ Rat F344 M > F [148] PFOA Rat W M > F Androgen-mediated [149] NDPS Rat F344 F > M Different renal accumulation of sulphate conjugates [150][151][152][153] FeNTA Mice ddY M > F Faster glutathione turnover [154][155][156] EG Rats SF M > F Promotion of calcium oxalate stone formation by testosterone [158] DCB: P-dichlorobenzene; EG: Ethylene glycol; EQ: Ethoxiquin; F: Females; F344: Fischer 344 rats; FeNTA: Ferric nitrilotriacetate; HCB: Hexachlorobenzene; M: Males; NDPS: N-(3,5-dichlorophenyl)succinimide; PFOA: Perfluorooctanoic acid; SD: Sprague-Dawley rats; TBZ: Thiobendazole; W: Wistar rats.…”