Page 735 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

700 Section |IX Gases, Solvents and Other Industrial Toxicants

VetBooks.ir as well as changes in both male and female reproductive et al., 2013). Recent work found 5 days of 250 mg/kg
TBBPA in Wistar Han adult rats induced significant
end points (Kodavanti et al., 2010). Further studies
decreases in serum T4, altered nuclear receptor gene
using the same cohort of animals focused on proteomic
analysis indicated that energy metabolism and processes expression in liver and uterine samples, and caused a strik-
related to neuroplasticity and growth may be ing increase in uterine CYP1B1, UGT1A1, and IGF-1,
involved in the developmental neurotoxicity of PBDEs with corresponding decreases in liver SULT 2A1 and 1E1,
(Kodavanti et al., 2015). solidifying its role as an endocrine disruptor (Sanders
In addition to the effects on TH, there is evidence that et al., 2016). In prior studies, neither persistence nor accu-
PBDEs affect the cholinergic neurotransmitter system mulation of 14 C-labeled TBBPA was observed in uterine
(Viberg et al., 2003a,b), which is involved in memory and tissue following repeated oral administration to adult
motor function, among others. Several PBDE congeners female Wistar Han rats (Knudsen et al., 2014), suggesting
have been compared to PCBs with regard to their ability to metabolic/endocrine disrupting effects as primary modes of
affect intracellular signaling in a cerebellar (brain) culture action.
system (Kodavanti and Ward, 2005; Kodavanti et al.,
2005; Fan et al., 2010). The Ca/protein kinase C signaling Perfluorinated Compounds
pathways are also proposed as mechanisms of neurotoxic-
ity for a number of chemicals, including PCBs and PBDEs. Table 52.4 summarizes PFC concentrations in farm and
The order of potency for their effects on intracellular sig- pet/captive animals. Detectable levels of PFCs were found
naling was DE-71 (a commercial mixture of tetra-, penta-, in serum samples from chicken, pigs, cattle (Jack Black),
and hexaBDEs) .PBDE-47 . PBDE-100. PBDE-99. On horses, dogs, and goats from Japan (Guruge et al., 2008).
a molar basis, DE-71 was equipotent with Aroclor 1254; Among several PFCs measured, PFOS and PFOA concen-
the most widely used commercial PCB mixture. A trations were consistently higher in almost all samples.
Swedish study found that PBDE-99 and PCB-52 produced The serum PFOS and PFOA concentrations ranged from
effects on behavior when given together but not at the 0.57 to 4.9 ng/g wet weight and from less than 0.05 to
same dose given alone (Eriksson et al., 2006). These results 2.5 ng/g wet weight, respectively (Table 52.4). Serum
suggest that there may be little difference in neurotoxic samples of Amur tigers, giant pandas, and red pandas
potency between PBDEs and PCBs, and that effects of from China also contained detectable concentrations of
PCBs and PBDEs are additive. This implies that body bur- PFCs (Dai et al., 2006; Li et al., 2008). As observed in
dens of PCBs and PBDEs in humans may need to be added farm animals, Amur tiger and panda serum samples had
when assessing risk. comparatively higher concentrations of PFOS than other
The NTP published results of the 2-year bioassay on PFCs, including PFOA. Animal tissue samples from
the reportedly nonpersistent BFR, TBBPA, and found a remote locations, such as polar bear liver samples from
significant treatment-related increase in uterine carcinoma Svalbard and serum samples from bottlenose dolphin
incidence in Wistar Han rats (NTP, 2014). In fact, using from Bermuda, also showed relatively high concentrations
longitudinal and transverse sections of the female repro- of PFOS compared to other PFCs (Table 52.4). Polar bear
ductive tract, Malignant Mixed Mu ¨llerian Tumors were liver contained 1290 ng/g wet weight of PFOS and
diagnosed and were found to have a 76% metastatic rate 2940 ng/g wet weight of PFHxS (Kannan et al., 2005b).
(MR) compared to those rats diagnosed with endometrial Perfluorinated chemicals (PFCs), especially PFOS and
adenocarcinoma alone (MR 5 24%) (Dunnick et al., 2015). PFOA, were associated with liver enlargement and hepa-
There was an overall dose related increase in endometrial tocellular adenomas in rats (Lau et al., 2007). Lau and
adenocarcinoma in the study (n 5 50/grp); 0 (12%), 250 coworkers suggested that agonism of the peroxisome
(22%), 500 (32%), and 1000 (38%) mg/kg TBBPA. Other proliferator-activated receptor-α (PPAR-α) may be
sites demonstrating TBBPA-enhanced tumor risk in the rat involved in tumor (primarily liver) induction by a number
were the testis, and in the B6C3F1 mice, large intestine of nongenotoxic carcinogens in the rodents. Following
(males), liver, and vascular system. Although the mecha- this, a number of studies were conducted to determine
nism for these tumors is not well understood, there was a whether the PPAR-α agonistic mode of action is involved
significant correlation of increased Her2 expression and in the liver toxicity and hepatocellular adenomas observed
Tp53 mutation in the tumors; markers of aggressive endo- in rats treated with PFOS and PFOA. Several short-term
metrial cancer in women (Harvey et al., 2015). Other stud- studies in rats and mice have revealed that PFOS and
ies have assessed the effects of TBBPA on estrogenic PFOA are capable of inducing peroxisome proliferation,
outcomes and have found no effect on ERα or ERβ activ- and the first key event in this mode of action is activation
ity (Molina-Molina et al., 2013; Dorosh et al., 2011), but of PPAR-α (Ikeda et al., 1987; Berthiaume and Wallace,
report interactions with the thyroid receptor and PPARγ 2002; 3M Company, 2004; Vanden Huevel et al., 2006).
(Kitamura et al., 2002; Riu et al., 2011; Molina-Molina Because several PFCs can activate PPAR-α, these