Polychlorinated Biphenyls and Polybrominated Biphenyls - Organic Pollutants: An Ecotoxicological Perspective - page 145

Normal

Transthyretin

Retinol (r) (TTR)

RBP RBPr TTR-RBPr

T 4

In presence of TCB

MO

3, 3', 4, 4'-TCB TCBOH TTR-TCBOH

Retinol (r)

RBP RBPr

TTR RBPr

T 4

T 4

I

NH 3 +

3

Cl Cl Cl

3 3 5'

CHCH 2

O

4' 4'

Cl Cl Cl OH

COO -

5 4 4

I

I

3'

3'

3'

Cl Cl

5'

I OH

3, 3', 4, 4'-TCB 4'-OH-3, 4, 3', 5'-TCB (TCBOH)

L-yroxine (T 4 )

fIgure 6.5 Thyroxine antagonism. Mechanism of toxicity of a polychlorinated biphenyl.
Retinol (r) binds to retinol-binding protein (RBP), which is then attached to transthyretin
(TTR). Thyroxine (T 4 ) binds to TTR and is transported via the blood in this form. The
coplanar PCB, 3,3′,4,4′-tetrachlorobiphenyl (3,3′,4,4′-PCB), is converted into hydroxyme-
tabolites by the inducible cytochrome P450 called P4501A1. The metabolite 4′-OH-3,3′,4,5′-
tetrachlorobiphenyl (TCBOH) is structurally similar to thyroxine and strongly competes for
thyroxine binding sites. The consequences are loss of thyroxine from TTR, the fragmenta-
tion of the TTR-RBP complex, and loss of both thyroxine and retinol from blood (after
Brouwer 1991).

effects were found when pregnant rats were exposed to Aroclor 1254, where relatively
high levels of 4 OH, 2,3,3′,4′,5 pentachlorobiphenyl were detected in fetal plasma and
brain (Morse et al. 1995). Similar effects have also been demonstrated in pregnant
mice fed 3,3′,4,4′-TCB (Darnerud et al. 1996). Changes in fetal and neonatal levels
of thyroid hormones caused by PCBs may have a number of harmful consequences,
including effects on brain development and behavior.
The functional form of thyroxine (T3) is generated by the deiodination of T4, and
PCBs can influence the tissue levels of this form by disturbing metabolism, as well as
by reducing the binding of T4. PCBs have been shown to inhibit the sulfation of thy-
roid hormones and the deiodination of T4 to T3. They can also induce the glucuronyl
transferase that conjugates T4 (Brouwer et al. 1998).
There is considerable evidence that PCB mixtures and higher chlorinated conge-
ners act as immunosuppressants in mammals (Environmental Health Criteria 140).
Apart from a number of studies showing effects on gross measures of immunologi-
cal function (e.g., spleen and thymus weights, lymphocyte counts, and histology of
lymphoid tissue), functional alterations in humoral and cell-mediated immunity have
also been demonstrated. Immunosuppression has been reported in seals fed fish diets
rich in higher chlorinated PCBs (see de Voogt 1996). In a study with the harbor seal