Page 716 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

PCBs, PBBs, Dioxin, PCDDs Chapter | 51 681

VetBooks.ir mink, and monkey. The time period during which expo- clefting; thus, the urinary tract is more sensitive to TCDD
than is the secondary palate (Birnbaum et al., 1989;
sure of the embryo/fetus to TCDD occurs is just as impor-
Couture et al., 1990). In addition, while palatal sensitivity
tant as the dose of TCDD administered in terms of
prenatal mortality. In most laboratory mammals, gesta- to TCDD increases with gestational age at days 6 12 in
tional exposure to TCDD produces a characteristic pattern the C57BL/6N mouse, the urinary tract appears to be
of fetotoxic responses that consist of thymic hypoplasia, equally sensitive throughout the major period of organo-
subcutaneous edema, decreased fetal growth, and prenatal genesis (Couture et al., 1990).
mortality, as well as other effects of TCDD that are Cleft palate in mice has been studied extensively
highly species-specific. In the mouse, hydronephrosis is (Abbott and Birnbaum, 1991; Abbott et al., 1992;
the sensitive sign of prenatal toxicity, followed by cleft Moriguchi et al., 2003). TCDD-exposed murine palatal
palate formation and atrophy of the thymus at higher shelves grow and make contact, but the subsequent pro-
doses, and by subcutaneous edema and mortality at mater- cess of epithelial-to-mesenchyme transformation does not
nally toxic doses. In the rat, TCDD prenatal toxicity is occur. Therefore, a cleft is formed as the palatal shelves
characterized by intestinal hemorrhage, subcutaneous continue to grow without fusing (Bock and Ko ¨hle, 2006).
edema, decreased fetal growth, and mortality. Structural Human embryonic palatal shelves are similarly affected,
abnormalities occur in the rat only at relatively large but at a much higher TCDD concentration (Abbott and
doses. In the hamster fetus, hydronephrosis and renal Birnbaum, 1991). The observation that humans are less
congestion are the most sensitive effects, followed by sensitive than mice is supported by studies with AhR-
subcutaneous edema and mortality. In the rabbit, an transgenic “humanized” mice (Moriguchi et al., 2003).
increased incidence of extra ribs and prenatal mortality is
found, whereas in the guinea pig and rhesus monkey, pre- Neuroendocrine Effects
natal mortality is seen (Dickson and Buzik, 1993;
Peterson et al., 1993). PCBs are the most studied class of endocrine-disrupting
Studies characterizing the developmental cardiovascular chemicals, yet the neuroendocrine effects of PCBs have
toxicity of TCDD in mammalian species have focused on not enjoyed the same attention. The reproductive and thy-
mice. Since fetal exposure to TCDD in mice does not roid axes are organized with hierarchical control at hypo-
cause overt toxicity and mortality when exposure occurs thalamic, pituitary, and organ levels. Neuroendocrine
after the fusion of the palate, studies assessing the develop- systems within the hypothalamus depend on a relatively
mental effects of TCDD on the heart have conducted expo- more porous blood brain barrier at the hypothalamic-
sures on GD 14.5, a developmental window of pituitary interface, and are subject to negative feedback
cardiomyocyte proliferation (Kopf and Walker, 2009). from peripheral hormones. Therefore, it is likely that PCBs
Fetal heart-to-body weight ratio is decreased on GD 17.5, produce part of their actions via neuroendocrine disruption.
with a reduction in myocyte proliferation. This decreased Early-life PCB exposure results in long-term changes in
heart-to-body weight ratio persisted, with a trend in PND 7 reproductive capacity. There is mounting evidence that
pups. However, PND 21 pups from TCDD-treated litters PCBs impact reproductive function via neurotoxic actions
exhibited a significant increase in heart-to-body weight on multiple aspects of hypothalamic neuroendocrine cir-
ratios, decreased basal heart rate, and a concomitant cuitry. In combination, the evidence suggests that neuro-
increase in mRNA expression of atrial natriuretic factor, an transmitters, neurotrophic factors, steroid hormone
indicator of cardiac stress and hypertrophy (Thackaberry receptors, and metabolic factors involved in the control of
et al., 2005; Kopf and Walker, 2009). Expression of extra- gonadotropin-releasing hormone (GnRH) activity are
cellular matrix remodeling and cardiac hypertrophy genes altered by PCB exposure (Bell, 2014).
were dysregulated in both fetal (GD 17.5) and adult PCBs can increase the responsiveness of the pituitary
(3 months) hearts, suggestive of cardiac remodeling that gland to GnRH in female sheep. In utero and lactational
persists into adulthood. Additionally, adult mice exposed exposure to PCB 153 can significantly enhance LH secre-
to TCDD in utero had increased left ventricle weight, tion induced by GnRH in PND60 offspring (Kraugerud
mild hydronephrosis, and decreased plasma volume et al., 2012). These effects may result from interactions
(Aragon et al., 2008). with developmental processes, with adult functions, or a
The teratogenic responses induced by TCDD-like che- combination of both. Estrogenic PCBs can also suppress
micals are species- and strain-specific. The induction of LH levels on proestrus, the day of the preovulatory
terata is one of the most sensitive indicators of TCDD GnRH/gonadotropin surge in F2 female Sprague-Dawley
toxicity in mice, as hydronephrosis and cleft palate are rats. These profound transgenerational effects of PCBs on
induced at doses below those resulting in either maternal the reproductive axis of female rats may represent epige-
or embryo/fetal toxicity (Couture et al., 1990). netic reprogramming actions of their estrogenic activity
Hydronephrosis is induced in the absence of palatal (Steinberg et al., 2008).