Elsevier

Reproductive Toxicology

Volume 102, June 2021, Pages 109-127
Reproductive Toxicology

Endocrine, metabolic and apical effects of in utero and lactational exposure to non-dioxin-like 2,2′,3,4,4′,5,5′-heptachlorobiphenyl (PCB 180): A postnatal follow-up study in rats

https://doi.org/10.1016/j.reprotox.2021.04.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • PCB 180 reduced progressively serum testosterone and fT3 levels in offspring.

  • PCB 180 IUL exposure altered the retinoid system in offspring.

  • Enzyme induction after IUL exposure suggests activation via CAR, PXR and AHR.

  • Current human exposure does not exceed the estimated tolerable PCB 180 level.

  • This study provides new knowledge for improved risk assessment of NDL-PCBs.

Abstract

PCB 180 is a persistent and abundant non-dioxin-like PCB (NDL-PCB). We determined the developmental toxicity profile of ultrapure PCB 180 in developing offspring following in utero and lactational exposure with the focus on endocrine, metabolic and retinoid system alterations. Pregnant rats were given total doses of 0, 10, 30, 100, 300 or 1000 mg PCB 180/kg bw on gestational days 7−10 by oral gavage, and the offspring were sampled on postnatal days (PND) 7, 35 and 84. Decreased serum testosterone and triiodothyronine concentrations on PND 84, altered liver retinoid levels, increased liver weights and induced 7-pentoxyresorufin O-dealkylase (PROD) activity were the sensitive effects used for margin of exposure (MoE) calculations. Liver weights were increased together with induction of the metabolizing enzymes cytochrome P450 (CYP) 2B1, CYP3A1, and CYP1A1. Less sensitive effects included decreased serum estradiol and increased luteinizing hormone levels in females, decreased prostate and seminal vesicle weight and increased pituitary weight in males, increased cortical bone area and thickness of tibial diaphysis in females and decreased cortical bone mineral density in males. Developmental toxicity profiles were partly different in male and female offspring, males being more sensitive to increased liver weight, PROD induction and decreased thyroxine concentrations. MoE assessment indicated that the 95th percentile of current maternal PCB 180 concentrations do not exceed the estimated tolerable human lipid-based PCB 180 concentration. Although PCB 180 is much less potent than dioxin-like compounds, it shares several toxicological targets suggesting a potential for interactions.

Abbreviations

AHR
aryl hydrocarbon receptor
ANOVA
one-way analysis of variance
AR
androgen receptor
BMD
benchmark dose
BMDL
lower bound of the 90 % confidence interval of the BMD
BMR
benchmark dose response
bw
body weight
CAR
constitutive androstane receptor
CED
critical effect dose = benchmark dose
CES
critical effect size = benchmark dose response
CV
coefficients of variation
CYP
cytochrome P450
DL
dioxin-like
EFSA
European Food Safety Authority
Emax
maximum efficacy
ER
estrogen receptor
EROD
7-ethoxyresorufin O-deethylase
FSH
follicle stimulating hormone
fT3
free triiodothyronine
fT4
free thyroxine
GD
gestational day
GLP
Good Laboratory Practice
IUL
in utero and lactational
JECFA
Joint FAO/WHO Expert Committee on Food Additives
LH
luteinizing hormone
LOD
limit of detection
MoE
margin of exposure
NDL
non-dioxin-like
NOAEL
no-observable-adverse-effect level
PCB
polychlorinated biphenyl
PCDD/Fs
polychlorinated dibenzo-p-dioxins and furans
PND
postnatal day
PROD
7-pentoxyresorufin O-dealkylase
PXR
pregnane-X receptor
RAR
retinoic acid receptor
RXR
retinoid X receptor
TBG
thyroid-binding globulin
TCDD
2,3,7,8-tetrachlorodibenzo-p-dioxin
TR
thyroid hormone receptor
TRIR
total RNA isolation reagent
TTR
transthyretin
UF
uncertainty factor
UGT
UDP glucuronosyltransferase

Keywords

PCB 180
Non-dioxin-like PCBs
Testosterone
Thyroid hormones
Retinoid
Endocrine disruption
Liver

Cited by (0)

1

Equal contribution.

2

Current address: Labor and Mine Inspection, Ministry of Work, Grand-Duchy of Luxembourg.

3

Current address: Office for Medicine and Pharmacy, BMC, Uppsala University, SE-751 23 Uppsala, Sweden.