Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat.

Published on Aug 12, 2021in Environmental Health Perspectives8.382
· DOI :10.1289/EHP8795
David Lopez-Rodriguez2
Estimated H-index: 2
(University of Liège),
Carlos F. Aylwin5
Estimated H-index: 5
(Oregon National Primate Research Center)
+ 10 AuthorsEzio Tirelli23
Estimated H-index: 23
(University of Liège)
BACKGROUND The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. OBJECTIVES We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. METHODS Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. RESULTS Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. DISCUSSION Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations.
#1Neruja LoganathanH-Index: 5
#2Emma K. McIlwraithH-Index: 5
Last. Denise D. BelshamH-Index: 47
view all 3 authors...
BACKGROUND Bisphenol A is a ubiquitous endocrine disrupting chemical and obesogen. Although limited evidence exists of the effects of BPA on hypothalamic agouti-related peptide (AgRP) levels, the mechanisms underlying these effects remain unknown. Given that AgRP is a potent orexigenic neuropeptide, determining the mechanism by which BPA increases AgRP is critical to preventing the progression to metabolic disease. METHODS Using quantitative reverse-transcriptase PCR (qRT-PCR), we investigated t...
4 CitationsSource
#1David Lopez-Rodriguez (University of Liège)H-Index: 2
#2Delphine Franssen (University of Liège)H-Index: 11
Last. Anne-Simone Parent (University of Liège)H-Index: 25
view all 5 authors...
The onset of puberty and the female ovulatory cycle are important developmental milestones of the reproductive system. These processes are controlled by a tightly organized network of neurotransmitters and neuropeptides, as well as genetic, epigenetic and hormonal factors, which ultimately drive the pulsatile secretion of gonadotropin-releasing hormone. They also strongly depend on organizational processes that take place during fetal and early postnatal life. Therefore, exposure to environmenta...
8 CitationsSource
Last. Sakina Mhaouty-Kodja (CNRS: Centre national de la recherche scientifique)H-Index: 3
view all 3 authors...
BACKGROUND We have previously shown that adult male mice exposure to low doses of an ubiquitous endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP), alters courtship behavior. OBJECTIVE The effects of adult exposure to low doses of DEHP alone or in an environmental phthalate mixture on estrous cyclicity, reproductive behavior, and underlying neural structures were analyzed in female mice. METHODS Two-month-old C57BL/6J females were exposed orally for 6 wk to DEHP alone (0, 5 or 50μg/kg/d) or ...
2 CitationsSource
#1Aline Murawski (EA: Environment Agency)H-Index: 7
#2Maria I.H. Schmied-Tobies (EA: Environment Agency)H-Index: 3
Last. Marike Kolossa-Gehring (EA: Environment Agency)H-Index: 35
view all 12 authors...
Abstract The UV filter 4-methylbenzylidene camphor (4-MBC), used in cosmetics, the antioxidant butylated hydroxytoluene (BHT), used inter alia as a food additive and in cosmetics, and the plasticizer tris(2-ethylhexyl) trimellitate (TOTM), used mainly in medical devices as substitute for di-(2-ethylhexyl) phthalate (DEHP), are suspected to have endocrine disrupting effects. Human biomonitoring methods that allow for assessing the internal exposure of the general population to these substances we...
6 CitationsSource
#1Žiga TkalecH-Index: 1
#2Tina KosjekH-Index: 30
Last. Milena HorvatH-Index: 64
view all 8 authors...
Chemicals such as bisphenols, parabens and triclosan are endocrine disrupting chemicals. They are used in a wide variety of consumer products, making human exposure to those chemicals widespread. In the present study, levels of three bisphenols (bisphenol A, F and S), 7 parabens (methyl-, ethyl-, isopropyl-, propyl-, isobutyl-, butyl-, benzyl paraben) and triclosan were measured in first morning void from 246 Slovenian children and adolescents, aged 6-9 and 11-15 years and living in a rural regi...
4 CitationsSource
#1Yunhui Xia (NU: Nanjing University)H-Index: 1
#2Tan Ma (NU: Nanjing University)H-Index: 4
Last. Dongmei Li (NU: Nanjing University)H-Index: 16
view all 9 authors...
Abstract Di-n-butyl phthalate (DBP), the most commonly used plasticizer and typical endocrine disrupting chemicals (EDCs), has shown its characteristics of causing reproductive and developmental toxicity in males, while the neuroendocrine toxicity induced by DBP exposure in utero and the mechanism beneath still remain unclear. Here, the pregnant mice were treated with corn oil (control) or DBP at three different doses by oral gavage during gestational days (GD) 12.5–21.5. The results showed that...
4 CitationsSource
#1Na Li (HMU: Hainan Medical University)H-Index: 16
#2Liting Zhou (JLU: Jilin University)H-Index: 9
Last. Lin Ye (JLU: Jilin University)H-Index: 12
view all 5 authors...
Abstract Plasticiser di-(2-ethylhexyl) phthalate (DEHP) is associated with female reproductive endocrine toxicity. Our previous study found that mono-(2-ethylhexyl) phthalate (MEHP), the metabolite of DEHP, can interfere with ovarian function via dysregulation of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro. The aim of this study was to verify this hypothesis in vivo. The present study tested the hypothesis that subacute exposure to DEHP induced ovarian dysfunction by dysregulating 17β-HS...
8 CitationsSource
Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitous in the environment and has been proposed to lead to reproductive disruption. In this study, we systematically investigated the effects of different doses of DEHP exposure on female hypothalamic–pituitary–gonadal axis development. Female Sprague–Dawley rats were gavaged with vehicle (corn oil) or DEHP (5 or 500mgkg–1 day–1) during postnatal Days (PNDs) 22–28 or PNDs 22–70. Results demonstrated that the low and high doses of DEHP exerted opposite ef...
4 CitationsSource
#1Yuanyuan Wei (Agricultural University of Hebei)H-Index: 5
#2Chao Han (Agricultural University of Hebei)H-Index: 6
Last. Wanyu Shi (Agricultural University of Hebei)H-Index: 7
view all 6 authors...
Abstracts This study was conducted to investigate the effects of maternal exposure bisphenol A (BPA) on ovaries development of F1 female mice. The BPA exposure model of pregnant mice was prepared by intragastric administration of BPA at the doses of 0, 2.5, 5, 10, 20, 40 mg kg−1 d−1 at gestation day (GD) 0.5–17.5. The ovarian index of the offspring mice was calculated at postnatal day (PND) 21 and PND 56. The results showed that BPA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg significantly incre...
10 CitationsSource
#1David Lopez-Rodriguez (University of Liège)H-Index: 2
#2Delphine Franssen (University of Liège)H-Index: 11
Last. Anne-Simone Parent (University of Liège)H-Index: 25
view all 8 authors...
: Exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical (EDC), is known to produce variable effects on female puberty and ovulation. This variability of effects is possibly due to differences in dose and period of exposure. Little is known about the effects of adult exposure to environmentally relevant doses of this EDC and the differences in effect after neonatal exposure. This study sought to compare the effects of neonatal vs adult exposure to a very low dose or a high dos...
11 CitationsSource
Cited By1