Potentially Increased Sensitivity of Pregnant and Lactating Female Rats to Immunotoxic Agents

Menke, Aswin; Wolterbeek, André; Snel, Cor J.; Bruijntjes, J.P.; Groot, Didima de; Oostrum, Lidy van; Waalkens, Ine; Kuper, C. Frieke

doi:10.1177/0192623311428476

Cited by 10 publications

(5 citation statements)

References 17 publications

(16 reference statements)

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“…25 Reduction in lymphoid cellularity and alterations in the corticomedullary ratio, had been regarded as deleterious effect of xenobiotics on the thymus, and is considered as a highly sensitive indicator of immunotoxicant exposure. 26 The reduction in the lymphoid cellularity in spleen of CY treated rats is in agreement with previous studies that observed depletion of T lymphocytes in mice treated with a single dose of 4 mg, 27 and 200 mg/kg of CY, 28 and decreased cellularity in the spleen in rats treated daily with 10mg/kg CY for 30 days. 19 Several studies have reported that naturally extracted remedies that possess high antioxidant property showed protective effects on CY-induced myelosuppression and cytotoxicity in lymphoid tissues.…”

Section: Discussionsupporting

confidence: 92%

Protective Effect of Virgin Coconut Oil on Cyclophosphamide-induced Histological Changes in Lymphoid Tissues

Senin¹,

Al-Ani²,

Mahmud³

et al. 2020

imjm

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Introduction: Virgin coconut oil (VCO) is known for its health and therapeutic benefits. However, the immunomodulatory effects of VCO have not been extensively investigated. Objective: The present study was devoted to examining the effects of VCO on cyclophosphamide (CY)-induced toxicity of lymphoid tissues. Methods: Thirty healthy male Wistar rats were sorted into 5 groups of 6 animals. The first control (NC) group was given distilled water via gavage at 5 ml/kg once daily. The second (CY) group received CY orally at 10 mg/kg/day for 4 weeks. Rats in the other three groups (CV5, CV10, and CV15) were given 10 mg/kg/day CY for 4 weeks, 5 m/kg/day, 10 ml/kg/day and 15 ml/kg/day VCO for 6 weeks, respectively. Rats were sacrificed at the end of 6th week; blood sample from the animals was collected for full blood count and biochemical analysis. The thymus and spleen of each animal was processed for histological examination. Results: The thymus and spleen showed marked reduction in lymphoid cellularity following daily administration of CY. The thymus also showed a marked reduction in the size of the medulla, and the white pulp areas of spleen had reduction in the follicle number and size. Supplementation with 10 ml/kg and 15 ml/kg VCO showed evidence of restoration of both the thymus and splenic lymphoid architecture. The total white cell counts, absolute lymphocyte counts and plasma globulin levels of the VCO groups were significantly increased compared to CY group. Conclusion: VCO displayed potential protective effects on CYinduced histological changes in lymphoid tissues.

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Section: Discussionsupporting

confidence: 92%

Protective Effect of Virgin Coconut Oil on Cyclophosphamide-induced Histological Changes in Lymphoid Tissues

Senin¹,

Al-Ani²,

Mahmud³

et al. 2020

imjm

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“…Relative thymus weight of untreated pregnant and lactating female rats was 46% of age‐matched dioctyltin dichloride (DOTC)‐treated nonpregnant and nonlactating females. By postnatal Day 56, thymus weight and immune function had recovered (Menke et al, 2012). Certain butyltin substances were also shown to cause developmental effects.…”

Section: Introductionmentioning

confidence: 99%

Simulated gastric hydrolysis and developmental toxicity of dibutyltin bis(2‐ethylhexyl thioglycolate) in rats

Costlow¹,

Nasshan²,

Frenkel³

et al. 2021

J of Applied Toxicology

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Previously, dibutyltin dichloride (DBTC) was the putative toxophore for dibutyltin bis‐alkyl and bis‐thio esters. Recent chemical and toxicological data on dioctyltin bis(2‐ethylhexyl thioglycolate) suggest the thioglycolate esters of alkyltins do not generate the dichloride toxophore. Our results, using 119Sn‐nuclear magnetic resonance (NMR) spectroscopy, demonstrated that dibutyltin bis(2‐ethylhexyl thioglycolate) (DBTE) is hydrolyzed to dibutyltin chloro‐(2‐ethylhexyl thioglycolate) (DBTEC) under simulated gastric conditions. No DBTC was detected. DBTE was administered orally to presumed‐pregnant Sprague–Dawley rats in a corn oil vehicle at 2.5, 8.5, and 25.0 mg/kg/day (Gestation Day 5 [GD5] through GD19). There were no maternal deaths, no treatment‐related statistically significant reductions in feed consumption, maternal body weight or weight gain, or adverse gestational outcomes. Maternal thymus weight was significantly reduced in rats at 25 mg/kg. There were no effects on fetal growth, no dose‐dependent pattern of external, visceral, or skeletal malformations, and no increase in anatomical variations. Based on the obtained experimental data, it is concluded here that DBTE forms DBTEC, not DBTC, in the stomach, and DBTE was not teratogenic nor fetotoxic in rats, a species sensitive to DBTC. The maternal no‐observed‐adverse‐effect level (NOAEL) was 8.5 mg/kg/day, and the developmental NOAEL was 25 mg/kg/day, the high dose. The maternal LOAEL was 25 mg/kg/day based on reduced maternal thymus weight.

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“…Indeed, organotin (IV) compounds when applied as anti-cancer metallodrugs, have efficacy comparable to the platinum-based cisplatin (Attanzio et al, 2020). DMTC is associated with neurotoxicity, trimethyltin chloride and dioctyltin dichloride (DOTC) are associated with thymic toxicity which is dose dependent and reversible (Menke et al, 2012). Under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and the legal framework for classification and labelling in the EU (CLP Regulation) DMTC is classified as Reprotoxicant of Category 2 (H361d) as it induced developmental toxicity in experimental fertilized animals (ECHA, 2012).…”

Section: Introductionmentioning

confidence: 99%

Simulated gastric hydrolysis and developmental toxicity of dimethyltin bis(2-ethylhexylthioglycolate) in rats

Kirf¹,

Costlow²,

Nasshan³

et al. 2023

Front. Toxicol.

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Dimethyltin dichloride is used as the putative toxophore for dimethyltin bis-alkylthio esters in a read-across approach. Recent chemical and toxicological investigations challenges this read across as data on dioctyltin bis(2-ethylhexyl thioglycolate) and dibutyltin bis(2-ethylhexyl thioglycolate) showed the dialkyltin thioglycolates do not generate dialkyltin dichloride. Results obtained by 119Sn-NMR spectroscopy demonstrated that dimethyltin bis(2-ethylhexyl thioglycolate), the smallest commercially manufactured dialkyltin thioester molecule of this kind, hydrolyzed to dimethyltin chloro-(2-ethylhexyl) thioglycolate under simulated gastric conditions. These studies did not detect dimethyltin dichloride. Dimethyltin bis(2-ethylhexyl thioglycolate) was administered orally to timed-pregnant Wistar-Han rats in an Arachis oil vehicle at 5, 10, and 25 mg/kg/day [Gestation Day 6 (GD6) through GD20] with no maternal deaths observed. At 25 mg/kg/day treatment statistically significant reductions occurred in feed consumption (−9%), maternal body weight (−2.4%) and adjusted maternal weight gain (−68%). There were no adverse gestational findings. Maternal thymus weight was significantly reduced in rats at 25 mg/kg in the absence of changes in hormone levels of T3, T4 or TSH. There were no effects on fetal growth, no dose-dependent pattern of external, visceral, or skeletal malformations and no toxicologically relevant increase in anatomical variations at any dose group. Based on the obtained experimental data it is concluded that dimethyltin bis(2-ethylhexyl thioglycolate) forms dimethyltin chloro-(2-ethylhexyl thioglycolate), not dimethyltin dichloride, in the stomach environment at pH 1.2, and dimethyltin bis(2-ethylhexyl thioglycolate) was not teratogenic nor fetotoxic in rats. The maternal NOAEL was 10 mg/kg/day, and the developmental NOAEL was 25 mg/kg/day, the high dose. The maternal LOAEL was 25 mg/kg/day based on decreased food consumption, lower adjusted mean body weight gain and reduced maternal thymus weight.

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Potentially Increased Sensitivity of Pregnant and Lactating Female Rats to Immunotoxic Agents

Cited by 10 publications

References 17 publications

Protective Effect of Virgin Coconut Oil on Cyclophosphamide-induced Histological Changes in Lymphoid Tissues

Protective Effect of Virgin Coconut Oil on Cyclophosphamide-induced Histological Changes in Lymphoid Tissues

Simulated gastric hydrolysis and developmental toxicity of dibutyltin bis(2‐ethylhexyl thioglycolate) in rats

Simulated gastric hydrolysis and developmental toxicity of dimethyltin bis(2-ethylhexylthioglycolate) in rats

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