PCB Related Pattern of Elevated CYP1A1 and Thyroid Hormone Receptor Targets Observed in Term Placentas

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 338-354-Physiological Impacts of Endocrine Disrupting Chemicals
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-352
Katherine Geromini1, Judy McKinley Brewer1, Nadia Abdelouahab2, Thomas Wadzinski*3, Ruby Bansal1, Larissa Takser2 and R Thomas Zoeller1
1Univ of Massachusetts, Amherst, MA, 2University of Sherbrooke, Sherbrooke, QC, Canada, 3Baystate Medical Center, Springfield, MA
Introduction: Prenatal exposure to polychlorinated biphenyls (PCBs) is associated with cognitive deficits including lower global IQ.(1) PCBs could affect the fetal environment in two ways. First there is a dominant theory that PCBs directly interfere with thyroid hormone (TH) action in the prenatal brain during development.(2) Second, PCBs could act directly on the placenta’s TH receptors (THRs) to change levels of placental growth hormone V (GH) and placental lactogen (PL), changing the fetal environment.

PCB activation of THRs appears to have a unique signature within a particular tissue. First, CYP1A1 enzyme is upregulated with dioxin-like chemicals including some PCBs.(3) Second, THR target genes (ie GH and PL in the placenta) are upregulated without increased TH by PCB metabolites that are converted to THR agonists by CYP1A1.(3,4) The upregulation of both CYP1A1 and THR targets with no association to serum TH is suggestive of the action of an endocrine disruptor and potentially PCBs in particular.

We hypothesized that if this scenario is occurring in the placenta, CYP1A1 expression would be associated with PL and GH expression with no correlation to serum TH. To test this hypothesis we measure expression levels in 138 placental samples obtained from a Canadian prospective birth cohort study GESTE aiming to study low dose environmental toxins including PCBs and their health effects.

Methods:Pregnant women (n=397) without thyroid related diagnoses were enrolled for this study in early pregnancy (<20 weeks gestation) with a protocol approved by the Ethics Committee at Sherbrooke University Hospital (CHUS). At delivery, fresh placenta samples were collected and immediately frozen at -80C. RNA was isolated from a convenience sample of 172 samples.  qPCR was used to quantitate mRNA levels of CYP1A1, PL, and GH, which were normalized with control genes (beta-actin and 18S). 34 samples did not have detectable levels of CYP1A1 and were taken out of further analysis, leaving 138 placental samples studied. Maternal and cord blood serum TH levels were tested at CHUS. Pearson’s correlation test and linear regression were used to test the strength of association of these measures.

Results: CYP1A1 mRNA had a 4-fold range of expression across the 138 placental samples. CYP1A1 mRNA was significantly and positively correlated with PL (r2=0.39; p<0.0001) and GH (r2=0.36, p<0.0001) mRNA. PL and GH mRNA were positively correlated with eachother (r2=0.88, p<0.0001) suggesting a common stimulus. CYP1A1, PL and GH mRNA level were not predicted by maternal or cord blood free T4 or total T4 (r2<0.05). CYP1A1 mRNA levels were not significantly different between mothers reporting or denying smoking.

Conclusions: The correlated upregulation of CYP1A1 with THR target genes unrelated to serum TH levels does exist in these human placental samples. This is consistent with PCBs affecting the human placenta.

(1) Stewart PW et al., Environmental health perspectives 2008; 116:1416. (2) Bansal R et al., Developmental brain research 2005; 156:13. (3) Giera S et al., Endocrinology 2011; 152:2909. (4) Gauger KJ et al., Environmental health perspectives 2007; 115:1623.

Nothing to Disclose: KG, JMB, NA, TW, RB, LT, RTZ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH R01 Grant #ES010026, CIHR Grant #MOP-84551, Grant from the Passport Foundation