Supplement

The first six papers are candidates for the ASRM Scientific Congress
Prize Paper Awards. Six additional candidates will be presented during
the Prize Paper Candidates’ session on Tuesday.
SCIENTIFIC CONGRESS PRIZE PAPER SESSION 1
O-1 Monday, October 17, 2016 11:15 AM
MATERNAL AND PATERNAL PRECONCEPTION PHTHALATE
EXPOSURE AND BIRTHWEIGHT OF IVF
SINGLETONS. C. Messerlian, a J. M. Braun, b L. Minguez-Alarcon, a
P. Williams, c J. B. Ford, a A. Calafat, d R. Hauser. a a Environmental Health,
Harvard T. H. Chan School of Public Health, Boston, MA; b Epidemiology,
Brown University School of Public Health, Providence, RI; c Biostatistics
and Epidemiology, Harvard T. H. Chan School of Public Health, Boston,
MA; d CDC, Atlanta, GA.
OBJECTIVE: Several phthalates are developmental and reproductive toxicants
and reduce fetal weight in experimental animal studies. We examined
the association between maternal and paternal urinary phthalate metabolite
concentrations and birthweight among singleton infants conceived by in-vitro
fertilization (IVF).
DESIGN: A prospective preconception cohort study.
MATERIALS AND METHODS: We collected the birthweight of 159 singletons
born after IVF from 159 mothers and 97 fathers (97 couples) from the
Massachusetts General Hospital Fertility Center. We estimated mean preconception
and prenatal exposures by averaging natural log-phthalate metabolite
concentrations in multiple paternal preconception (n¼258), maternal preconception
(n¼730), and maternal prenatal (n¼380) urine samples. Birthweight
was abstracted from delivery records by trained study staff. We estimated the
association of 11 individual phthalate metabolites and a summary measure of
di-(2-ethylhexyl) phthalate (DEHP) metabolites with birthweight using
linear regression, and adjusted for a priori covariates, including maternal
and paternal age, BMI and smoking status, maternal education, and infertility
diagnosis.
RESULTS: Father’s preconception urinary concentrations of mono-n-butyl
phthalate (MBP) and the molar sum of 4 DEHP metabolites ( P DEHP) were
associated with a significant decrease in birthweight. Each log e -unit increase
in paternal preconception MBP and P DEHP concentrations was associated
with a 127 (95%CI: -231, -24) and 128 (95%CI: -228, -28) gram decrease in
birthweight, respectively. Additional adjustment for respective maternal prenatal
phthalate metabolite concentrations strengthened associations for DEHP
metabolites and moderately attenuated the association for MBP. Although
some maternal prenatal phthalate metabolite concentrations were also associated
with birthweight, after adjustment for paternal preconception concentrations
these associations were no longer present. None of the 11 maternal
preconception phthalate metabolites were associated with birthweight.
CONCLUSIONS: Paternal preconception urinary concentrations of MBP
and P DEHP were associated with a significant decrease in birthweight
among IVF conceived singletons.
Supported by: NIH grants R01 ES009718 and R01 ES024381 from the
NIEHS. CM was supported by a fellowship from the Canadian Institutes
of Health Research.
DESIGN: Laboratory research studies using Eker rat fibroid model: myometrium
tissues as well as rat MSCs.
MATERIALS AND METHODS: Female newborn rats were treated S.C.
with vehicle (VEH) or 1 mg/kg of diethylstilbestrol (DES, a tool compound
of environmental EDCs) on postnatal days 10-12, a key period of uterine
development. MSCs were isolated from adult endometrium-free myometrium
tissue (N¼5 for each group) using Stro-1 and CD44 surface markers.
To identify targets of epigenomic reprogramming in MSCs, whole genome
RNA-sequencing and ChIP-sequencing (with an anti-H3K4me3 antibody)
was performed in DES- and VEH-MSCs. In addition, Fisher’s exact test
was used to examine the correlation between RNA expression and
H3K4me3 enrichment of reprogrammed genes (estrogen responsive genes;
ERGs). Finally, epigallocatechin gallate (EGCG, green tea extract) was
used to determine whether the observed disease-causing reprogramming of
ERGs can be reversed.
RESULTS: By RNA-sequencing, we identified 68 ERGs that were dysregulated
in DES-MSCs compared to VEH-MSCs. Among them, 49 ERGs
were markedly upregulated in DES-MSCs compared to VEH controls. We
performed gene set enrichment analysis on the ChIP-sequencing data and
identified enrichment of H3K4me3 (an active mark for gene transcription)
at the promoters of 82 ERGs in DES-MSCs as compared to VEH-MSCs.
Furthermore, the increased expression of ERGs was positively correlated
with the elevated H3K4me3 mark (p