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A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice

Michelle C. Cora, William Gwinn, Ralph Wilson, Debra King, Suramya Waidyanatha, Grace E. Kissling, Sukhdev S. Brar, Dorian Olivera, Chad Blystone, and Greg Travlos.
Toxicologic Pathology (2017) DOI: https://doi.org/10.1177/0192623317714343 PMID: 28618975


Publication


Abstract

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Figures


Figure 1. Mean number of Howell–Jolly bodies observed per 10 high-power fields.

Mean number of Howell–Jolly bodies observed per 10 high-power fields on the peripheral blood smears of control mice and mice treated daily with 1,000 mg/kg black cohosh extract for 92 days. Each bar represents mean ± SE. *p < .0001.

Figure 2. Howell–Jolly (HJ) bodies were significantly increased in mice.

Howell–Jolly (HJ) bodies were significantly increased in mice treated daily with 1,000 mg/kg black cohosh extract for 92 days. HJ bodies are present within 3 individual erythrocytes (arrows). Wright–Giemsa stain.

Figure 3. Basophilic stippling was occasionally observed on the blood smears of mice.

Basophilic stippling was occasionally observed on the blood smears of mice treated daily with 1,000 mg/kg black cohosh extract for 92 days. (A and B) Erythrocytes with basophilic stippling (arrows) observed on 2 different peripheral blood smears. Wright–Giemsa stain.

Figure 4. Principal components of folate and cobalamin metabolism.

Principal components of folate and cobalamin metabolism as it relates to DNA synthesis, methylations, and the production of methionine from homocysteine. DHFR = dihydrofolate reductase; THF = tetrahydrofolate; TS = thymidylate synthase; dUMP = deoxyuridine monophosphate; dUMT = deoxythymidine monophosphate; MTHFR = methylene tetrahydrofolate reductase; MS = methionine synthase; SAM = S-adenosylmethionine (also AdoMet); SAH = S-adenosylhomocysteine (also AdoHcy).

Figure 5. The role of cobalamin in the metabolism of methylmalonic acid (MMA).

MCM = methylmalonyl-coenzyme A (CoA) mutase; MCH = methylmalonyl-CoA hydrolase.

Tables


Table 1. Hematology Parameters of B6C3F1/N Female Mice.

Table 1. Hematology Parameters of B6C3F1/N Female Mice after Gavage Treatment with Vehicle or 1,000 mg/kg Black Cohosh Extract for 92 Days.

Table 2. Clinical Chemistry Parameters of B6C3F1/N Female Mice.

Clinical Chemistry Parameters of B6C3F1/N Female Mice after Gavage Treatment with Vehicle or 1,000 mg/kg Black Cohosh Extract for 92 Days.

Table 3. Liver and Kidney Tissue Folate Concentrations of B6C3F1/N Female Mice.

Liver and Kidney Tissue Folate Concentrations of B6C3F1/N Female Mice after Gavage Treatment with Vehicle or 1,000 mg/kg Black Cohosh Extract for 92 Days.