Transgenerational effects of polychlorinated biphenyls: 1. Development and physiology across 3 generations of rats

Abstract

BackgroundPolychlorinated biphenyls (PCBs) are persistent organic environmental contaminants and known endocrine-disrupting chemicals (EDCs). Previous studies demonstrated that developmental exposure to the weakly estrogenic PCB mixture Aroclor 1221 (A1221) in Sprague-Dawley rats altered sexual development, adult reproductive physiology and body weight. The current study tested the hypothesis that prenatal A1221 exposure not only disrupts these endpoints within an exposed individual’s (F1 generation) lifespan, but may also affect subsequent generations (F2-F3).MethodsWe treated pregnant female rats on embryonic days (E) 16 and E18 with A1221 (1 mg/kg), estradiol benzoate (50 μg/kg, positive estrogenic control), or vehicle (3% DMSO in sesame oil, negative control). Endpoints related to sexually dimorphic developmental trajectories of reproductive and developmental physiology were measured, and as adults, reproductive endocrine status was assessed, in the F1, F2, and F3 generations.ResultsSignificant effects of transgenerational EDCs were found for body weight and serum hormones. The A1221 descendants had significantly higher body weight in the F2-maternal lineage throughout postnatal development, and in F3-maternal lineage animals after weaning. In females, generation- and lineage-specific effects of exposure were found for serum progesterone and estradiol. Specifically, serum progesterone concentrations were lower in F2-A1221 females, and higher in F3-A1221 females, compared to their respective F2- and F3-vehicle counterparts. Serum estradiol concentrations were higher in F3-A1221 than F3-vehicle females. Reproductive and adrenal organ weights, birth outcomes, sex ratio, and estrous cycles, were unaffected. It is notable that effects of A1221 were only sometimes mirrored by the estrogenic control, EB, indicating that the mechanism of action of A1221 was likely via non-estrogenic pathways.ConclusionsPCBs caused body weight and hormonal effects in rats that were not observed in the directly exposed F1 offspring, but emerged in F2 and F3 generations. Furthermore, most effects were in the maternal lineage; this may relate to the timing of exposure of the F1 fetuses at E16 and 18, when germline (the future F2 generation) epigenetic changes diverge in the sexes. These results showing transgenerational effects of EDCs have implications for humans, as we are now in the 3rd generation since the Chemical Revolution of the mid-twentieth century, and even banned chemicals such as PCBs have a persistent imprint on the health of our descendants.Electronic supplementary materialThe online version of this article (10.1186/s12940-018-0362-5) contains supplementary material, which is available to authorized users.

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm

“…Since then, other EDCs, especially bisphenol A [22], tributyltin [29] and phthalates [30] have also been demonstrated to have adverse transgenerational phenotypes. Limited evidence from our lab also showed transgenerational effects of PCBs [7,31,32]. The current study extended prior work substantially by utilizing more realistic exposures to VIN (1 mg/kg in the current study, vs. 50-100 mg/kg in other studies), the inclusion of PCBs, and epigenetic endpoints in F1 and F3 sperm and brain.…”

“…These F3 individuals also showed altered anxiety, social, and sexual behavior [4,5], and had changes in gene expression and metabolic activity in specific brain nuclei [5,6]. An endocrine-disrupting mixture of weakly estrogenic polychlorinated biphenyls (PCBs), Aroclor 1221 (A1221), also caused phenotypic changes through the F3 generation [7].…”

Environmental neglect: endocrine disruptors as underappreciated but potentially modifiable diabetes risk factors

“…These data fit within a broadening context of multigenerational and transgenerational effects of multiple EDC classes on various endocrine and metabolic tissues [7,[26][27][28][29]. Recently, studies have demonstrated that changes in the expression and methylation of imprinted genes in the brain persist across three generations after BPA exposure in mice [30].…”

The developmental basis of disease: Update on environmental exposures and animal models

“…As reviewed in Ref. , there are data for transgenerational inheritance of diseases/dysfunctions including reproduction, obesity, psychiatric disorders from a variety of environmental stressors including vinclozolin, bisphenol A, atrazine bisphenol A plus phthalates (DEHP and DBP), permethrin plus DEET, methoxychlor, Jet fuel 8, phthalate (DEHP),dioxin, DDT, PCBs, tributyltin, nicotine, alcohol, calorie restriction, high‐fat diets, folate and stress. Mechanisms currently focus on a variety of epigenetic changes including DNA methylation, histone changes and non‐coding RNAs .…”