Page 715 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

680 SECTION | IX Gases, Solvents and Other Industrial Toxicants

VetBooks.ir been associated with significantly increased rates of dis- about the association between body burden of TCDD and
PCBs and the incidence of endometriosis (Bruner-Tran
omy in male sperm (Perry et al., 2016). The DEHP/PCB
and Osteen, 2010). TCDD-induced ovarian toxicity
mixture reduced testis weight more than DEHP or PCB
alone, while all treatments significantly lowered intratesti- appears to be strain-dependent and can lead to infertility.
cular testosterone levels similarly. DEHP or PCB expo- Long-Evans rats exposed to 1 μg TCDD/kg body weight
sure reduced the number of Leydig cells and reduced the on GD 8 had reduced ovarian weight, a decline in fertility
ratio of Group 1 2 seminiferous tubules. DEHP or PCB and persistent vaginal estrous. Recently, Baldridge et al.
reduced sperm viability, epididymal sperm count, or daily (2015) reported that TCDD at femtomolar levels signifi-
sperm production. When testing sperm cells from treated cantly decreases E2 (estradiol-17β) production by human
and control mice offspring, the predominant effect luteinizing granulose cells obtained from women stimu-
reported was an 80% 90 % reduction by DEHP in the lated for in vitro fertilization. It has been suggested that
ability of embryos to reach the blastocyst stage, indicating in utero exposure to TCDD results in placental hypoxia.
predominant effects on development capacity of semen Li et al. (2015) reported that TCDD suppresses prolifera-
(Fiandanese et al., 2016). tion and migration of human umbilical cord vein and
artery endothelial cells and inhibits fetoplacental angio-
genesis, leading to negative pregnancy outcomes.
Female Reproductive Effects
Fenton et al. (2002) reported that in utero and lac-
TCDD and approximate stereoisomers have been shown tational exposure of Long-Evans rats to TCDD (1 μg/kg
to affect female reproductive endpoints in a variety of body weight) on GD 15 (but not GD 20) delayed matura-
animal studies. Among the effects reported are a decrease tion of the mammary gland and could increase the inci-
in the number of females mated in rats, mink, and mon- dence of breast cancer due to increased susceptibility of
keys, fewer completed pregnancies in rats, mink, and the gland to carcinogens. Brown et al., (1998) treated
monkeys, lower maternal weight gain during pregnancy Sprague-Dawley rats prenatally with 1 μg TCDD/kg body
in rats, rabbits, and monkeys, decreased litter size in rats, weight, which resulted in more of the less-mature termi-
rabbits, mink, and swine, effects on female gonads in nal end buds and less lobules II in mammary gland at
guinea pigs and mice, and altered estrous and menstrual postnatal day (PND) 50 compared to controls. This may
cycles in mice, rats, and monkeys. explain the increased propensity for developing mammary
Consumption of PCB-contaminated fish from Lake adenocarcinomas after prenatal TCDD exposure is fol-
Ontario by women of reproductive age has been associ- lowed by exposure to chemical carcinogens like dimethyl-
ated with reduced fecundity and menstrual cycle length benzanthracene (Brown et al., 1998). Prenatal exposure to
(Mendola et al., 1997; Buck et al., 2000). Irregular non-ortho PCB congeners also results in similar effects
menstrual cycle length and abnormal menstrual bleeding (Muto et al., 2002).
has been associated with consumption of rice oil contam- The mammary gland is also susceptible to exposure to
inated with PCBs and PCDFs in Yucheng, Taiwan, TCDD-like chemicals during pregnancy as the gland pre-
between 1978 and 1979 (Yu et al., 2000) and with greater pares for lactation (Fenton, 2006). Vorderstrasse et al.
placental toxic-equivalency PCDD/PCDF concentrations (2004) reported that pregnant C57B1/6 mice exposed to
in Taiwanese women (Chao et al., 2007). In utero expo- 5 μg TCDD/kg body weight had stunted gland growth,
sure to PCBs and PCDFs during the Yucheng incident decreased branching, and poor formation of lobular alveo-
and serum dioxin levels in women from Seveso, Italy, lar structures. In addition, expression of a specific milk
are associated with a dose-related reduced fertility and/or protein in the gland was suppressed, and all pups born to
prolonged time to pregnancy (Yang et al., 2008; TCDD-treated dams died within 24 h of birth. TCDD has
Eskenazi et al., 2010). A recent study using the human been implicated in impaired mammary differentiation and
choriocarcinoma cell line JAR and the human endome- lactation since TCDD directly blocks lactogenesis in iso-
trial cell line lshikawa in vitro model for human embryo lated mammary epithelial cells of mouse. The study sug-
implantation, has shown that PCBs impair the endome- gested a model in which aryl hydrocarbon receptor
trial receptivity. Environmental-relevant concentrations repressor (AhRR) induction by TCDD promotes forma-
of the PCB mixture Aroclor 1254 (2.5, 12.5, and tion of AhRR/AhR nuclear translocator (ARNT) heterodi-
62.5 mM) dose-dependently reduced the adhesion of JAR mers, which transcriptionally inhibits β-casein production
spheroid attachment and increased the spheroid out- (Basham et al., 2015).
growth (Cai et al., 2016).
Rier et al. (1993) were the first to report an association Developmental and Teratogenic Effects
between chronic exposure to TCDD-like chemicals and
endometriosis in rhesus monkeys. Findings from subse- Exposure to TCDD during pregnancy causes prenatal
quent human epidemiological studies are inconclusive mortality in the mouse, rat, guinea pig, hamster, rabbit,