Page 717 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

682 SECTION | IX Gases, Solvents and Other Industrial Toxicants

VetBooks.ir been reported, suggesting complex interaction between first trimester of pregnancy (Hisada et al., 2014). Several
Hypothyroid and hyperthyroid actions of PCBs have
other studies showed no changes in TSH even though free
PCBs and the thyroid axis. For example, low-chlorinated
and total T4 and T3 concentrations were suppressed
PCB exposure during late gestation and lactation may sig- (Morse et al., 1996; Khan et al., 2002). The varied out-
nificantly decrease total triiodothyronine (T3) levels in 3- comes of these studies is likely due to differences in the
week-old children (Darnerud et al., 2010). In contrast, PCB mixtures and doses used, length and time of expo-
exaggerated circulating T3 has been shown in adolescent sure, and gender differences. It is unclear if altered TSH
children belonging to baby-mother pairs to be associated levels resulting after PCB exposure is due, in part, to a
with high body burdens of dioxin like-PCBs in the reduction of neuroendocrine stimulation by TRH, or from
Netherlands from 1987 to 1991 (Leijs et al., 2012). The an increase in the peripheral metabolism of THs through
latter finding suggests that developmental effects of PCBs induction of hepatic microsomal enzymes or by other
on thyroid function may continue to impact physiology in mechanisms.
adolescence. Studies on experimental animals suggest that PCBs appear to have direct agonist action on TH
inhibitory and stimulatory actions of PCBs arise due to receptors. Gestational exposure to Aroclor 1254 (1 and
reduction in circulating thyroid hormone (TH) levels, 4 mg/kg/day) produced stimulatory actions on TH-
reducing pituitary sensitivity to thyrotropin-releasing hor- responsive genes (RC3/neurogranin, Oct-1) in the fetal
mone (TRH) and/or TH receptor agonism, respectively cortex of GD 16 rat embryos (Gauger et al., 2004). These
(Bansal and Zoeller, 2008). effects are contradictory to those seen in exposed preg-
PCBs share a striking structural similarity with THs, nant dams (reduced T3 and T4), suggesting that PCBs can
making it likely that PCBs interfere with biosynthesis have direct stimulatory actions on the fetus aside from
and metabolism, transport of THs, and/or action at TH inhibitory actions produced via maternal hypothyroidism.
receptors. Chlorinated hydrocarbons, such as PCBs, Exposure to PCBs and related compounds causes a
result in T3 reduction and a compensatory increase in reduction in THs in developing and adult animals
thyroid-stimulating hormone (TSH) secretion, as well as (Kodavanti et al., 1998; Kodavanti and Curras-Collazo,
thyroid hypertrophy and increased incidence of tumors 2010). Several mechanisms have been summarized
(Capen, 1994). In contrast, acute oral exposure of adult (Kashiwagi et al., 2009; Kodavanti and Loganathan,
male Sprague-Dawley rats to PCB 126 (75 and 275 μg/kg 2014) to explain how PCBs and related chemicals alter
body weight) increased serum TSH and reduced serum thyroid function. Since these chemicals are structurally
thyroxine (T4) and T3 (Fisher et al., 2006). similar to THs, PCBs, especially those that are nondioxin-
Administration of 2,3,6,2 ,5 -pentachlorinated biphenyl like bind to transthyretin (TTR) and displace T4
0
0
(PCB 95; 32 mg/kg/day, i.p) to early-weaned male rats on (Chauhan et al., 2000). This free T4 in serum is subjected
PND 15 and 16 reduced serum concentrations of T4, T3 to hepatic metabolism and elimination. PCBs that are
and increased serum concentration of TSH at PND 17 and bound to TTR will be transported to the target sites,
18 compared to controls. This negative correlation where it can bind to TH receptors to elicit a physiological
between organohalogens and serum T4 has also been response. Dioxin-like PCBs act through the AhR. These
demonstrated in a North American human cohort (Makey PCBs can bind to the AhR in the liver and induce hepatic
et al., 2016b). This hypothyroid state was correlated with uridine diphosphate glucuronyl transferases, leading to
higher serum concentrations of leptin, adiponectin, and biliary excretion and elimination of T4. Consistent with
lower serum concentrations of insulin compared with these multiple modes of action of PCBs on the thyroid
the control group, pointing to a possible link between axis and the importance of thyroid status during
PCB-induced hypothyroidism and metabolic disease neural development, functional studies have also demon-
(Ahmed, 2013). strated delayed hippocampal and cerebellar development
Fetal and neonatal neurons express TH receptors and altered dendritogenesis after neonatal exposure to
before the fetal thyroid is functional, suggesting a role for Aroclor 1254 (Lein et al., 2007; Royland et al., 2008;
maternal THs. An important question is whether develop- Yang et al., 2008). Disruption of dendritic growth by
mental exposure to PCBs interferes with TH signaling PCBs could explain, in part, the impairment in learning
indirectly by producing maternal hypothyroidism or and memory after perinatal exposure (Yang et al., 2008;
directly by disrupting the hypothalamic-pituitary-thyroid Parent et al., 2011).
axis (HPT) of the offspring. Nevertheless, maternal expo-
sure to PCBs is associated with lower TSH during preg-
Neurobehavioral Effects
nancy, warning of adverse consequences for maternal
health and fetal development (Lv et al., 2015). In the case In humans as well as wildlife, laboratory along with epi-
of hydroxylated PCB isomers, neonatal TSH has been demiological studies have shown that exposure to TCDD-
positively associated with maternal exposure during the like compounds can impair cognitive functions, motor