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1.
Biochem Pharmacol ; 210: 115490, 2023 04.
Article in English | MEDLINE | ID: mdl-36893816

ABSTRACT

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.


Subject(s)
Folic Acid , Maternal Exposure , Polychlorinated Dibenzodioxins , Prenatal Exposure Delayed Effects , Sex Characteristics , Sexual Development , Thioctic Acid , Animals , Female , Male , Pregnancy , Rats , Fetus/drug effects , Fetus/metabolism , Folic Acid/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Maternal Exposure/adverse effects , Polychlorinated Dibenzodioxins/toxicity , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/prevention & control , S-Adenosylmethionine/metabolism , Sexual Development/drug effects , Thioctic Acid/administration & dosage , Thioctic Acid/pharmacology , Thioctic Acid/therapeutic use , Reproduction/drug effects
2.
Gan To Kagaku Ryoho ; 43(9): 1117-9, 2016 Sep.
Article in Japanese | MEDLINE | ID: mdl-27628556

ABSTRACT

A 74-year-old man with advanced gastric cancer was admitted to our hospital. His liver function was impaired(total bilirubin 1.6mg/dL)with multiple liver metastases. He was treated with chemotherapy of S-1 plus cisplatin but it was discon- tinued due to severe diarrhea(CTCAE Grade 3)on day 6 and his liver dysfunction progressed(total bilirubin 10.3mg/dL). After his diarrhea improved, he was treated with capecitabine plus oxaliplatin(capecitabine 3,600mg/day on day 1-14, oxaliplatin 130mg/m2 on day 1, q3 weeks). His severe jaundice and general condition improved without severe non-hematological toxicity, and he was ultimately discharged. He achieved a partial response(RECIST v1.1)after capecitabine plus oxaliplatin treatment, and this therapy has been continued for 15 months. This case suggests that capecitabine plus oxaliplatin may be beneficial even in advanced gastric cancer patients with impaired liver function from multiple liver metastases.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Jaundice/etiology , Liver Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Aged , Capecitabine/administration & dosage , Humans , Liver Neoplasms/secondary , Male , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Stomach Neoplasms/pathology , Treatment Outcome
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