Mycotoxins are toxic fungal metabolites

[Guest guest]

V. Sava et al. 3

INTRODUCTION

http://stinet.dtic.mil/cgi-bin/GetTRDoc?

AD=A452374 & Location=U2 & doc=GetTRDoc.pdf

Mycotoxins are toxic fungal metabolites which are structurally

diverse, common

contaminants of the ingredients of animal feed and human food. These

fungal products

exhibit a range of pharmacological activities that have been

utilized in development of

mycotoxins or mycotoxin derivatives as antibiotics, growth

promoters, and other kinds of

drugs; still others have been developed as biological and chemical

warfare agents [1]. Bombs

and ballistic missiles laden with biological agents including

aflatoxin were believed to be

deployed by Iraq during Operation Desert Storm[2]. In light of the

excess incidence of

amyotrophic lateral sclerosis in young Gulf War veterans [3], it is

important not to forget the

potential neurotoxic effects of low doses of mycotoxins. Although

much is known about the

lethal effects of the aflatoxins, little is known about the acute

and long-term effects of less

potent mycotoxins, such as Rubratoxin B (RB), on adult nervous

system.

Rubratoxin B (RB) is a metabolite of the molds Penicillum rubrum and

Penicillum

purpurogenum. These molds commonly contaminate cereals, foodstuffs

and grow on damp

tents and fabrics. RB is not known to produce a serious health

hazard in this naturally

occurring form, but pure RB is a bisanhydride lactone with

hepatotoxic [4] and teratogenic

properties [5, 6, 7]. Investigation of the effects of acute and

chronic exposure to RB on the

nervous system has been scarce, even though neuronal tissue appears

to be very susceptible to

the deleterious effect of RB in teratogenic studies [8].

RB has numerous biochemical actions including the inhibition of (Na+-

K+)-ATPase

[9], inhibition of the hepatic cytochrome P-450-dependent

monooxygenase system[10],

reduction of hepatic and renal nonprotein sulfhydryl content [11]

and inhibition of gap

junctional intercellular communication [12]. It was found that RB

caused shifts in the

V. Sava et al. 4

ultraviolet absorption spectra of DNA and RNA [13]. The observed

binding properties of RB

can disrupt the integrity of DNA and RNA. RB has been shown to

induce apoptosis [14, 15]

and internucleosomal fragmentation of DNA [14].

Studies with isolated mouse liver mitochondria revealed that RB

disrupted

mitochondrial respiration and depressed oxygen consumption[8]. The

principal site of action

of RB in the mitochondrial electron transport system was found to be

between cytochrome C1

and the termination of electron flow [8]. Ochratoxin, a related

mycotoxin, has been

reported to alter mitochondrial respiration and oxidative

phosphorylation through impairment

of the mitochondrial membrane and inhibition of the succinate-

dependent electron transfer

activities of the respiratory chain [16].

The overall objective was to study RB neurotoxicity in the context

of oxidative stress

induced by inhibition of mitochondrial electron transport in brain

tissues. Inhibition of

oxidative phosphorylation would be expected to result in increased

generation of oxyradicals

and decreased production of ATP[17]. We hypothesized that RB-

induced alteration of

oxidative processes would not be homogeneous across all brain

regions but would reflect the

capacity of distinct brain regions to upregulate anti-oxidative

mechanisms and repair

processes. Parameters of oxidative stress measured included lipid

peroxidation

(thiobarbituric acid-reactive substances or TBARS), SOD activity,

oxidative DNA damage

and repair in each of six brain regions cerebellum (CB), cortex

(CX), hippocampus (HP),

midbrain (MB), caudate/putamen (CP) and pons/medulla (PM).

Accumulation of 8-oxodG

was chosen as an indicator of DNA damage and activity of DNA

glycosylase was used as an

index of DNA repair.