Hearing loss following exposure during development to polychlorinated biphenyls: A cochlear site of action

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Abstract

Maternal exposure to polyhalogenated hydrocarbons results in early postnatal hypothyroxenemia and a low-frequency hearing loss in adult offspring (Goldey et al., 1995a. Toxicol. Appl. Pharmacol. 135, 67–76; Herr et al., 1996. Fundam. Appl. Toxicol. 33, 120–128). The purpose of the present work was to determine whether the site-of-action of this auditory impairment was within the cochlea. Primiparous Long–Evans rats were given daily oral doses of corn oil (control) or 8 mg/kg of the commercial PCB mixture Aroclor 1254 (A1254) from gestation day (GD) 6 through postnatal day (PND) 21. Auditory thresholds for 1-, 4-, 16-, and 40-kHz tones were assessed using reflex modification audiometry in young adult offspring on postnatal days (PND) 92–110. Approximately 6 weeks after auditory assessments, a subset of animals (n=4 per group) were killed for histological assessment of the cochlea. Surface preparations of the organ of Corti were prepared from one cochlea per animal and modiolar sections were prepared from the opposite cochlea. Consistent with previous findings, auditory thresholds for 1-kHz tones were elevated by approximately 25 dB in the A1254-exposed animals. Thresholds for all higher frequencies were not different compared to controls. Surface preparations of the organ of Corti revealed a mild to moderate loss of outer hair cells in the upper-middle and apical turns. Inner hair cells were not affected. Modiolar sections failed to reveal alterations in any other cochlear structures. There was also no apparent loss of ganglion cells. These data clearly link the loss of low-frequency hearing caused by exposure during development to A1254 to a loss of outer hair cells in the organ of Corti. The mechanism that underlies this developmental ototoxicity remains to be determined. These data provide the first evidence of a structural deficit in the nervous system of adult animals exposed to PCBs during development.

Introduction

Polyhalogenated aromatic hydrocarbons are a chemical class that includes dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs). These chemicals are a pervasive and persistent environmental problem. Due to their historically widespread use, improper disposal, and chemical characteristics, PCBs are among the most widely detected organic contaminants in environmental and biological samples (for review, see Safe, 1994). PCBs have been shown to affect a number of organ systems in mature and developing animals (for review, see WHO, 1993), and there is particular interest in the effects of PCBs on endocrine function (e.g. Colborn et al., 1993). The thyroid axis appears to be particularly vulnerable to disruption by PCBs (Meserve et al., 1992, Ness et al., 1993, Morse et al., 1993, Morse et al., 1996, Goldey et al., 1995a, Seo et al., 1995, Darnerud et al., 1996, Corey et al., 1996) and PCB metabolites (Sinjari, 1997). Related environmental contaminants, such as dioxin, hexachlorobenzene, polybrominated biphenyls, and chlorinated diphenyl ethers, also cause a reduction in circulating thyroxine (T4) concentrations following developmental exposure (Collins and Capen, 1980, Meserve et al., 1992, Seo et al., 1995, Goldey et al., 1995a, Rosiak et al., 1997, Zhou et al., 1999). Interestingly, exposure to these compounds during development results mainly in hypothyroxenemia, a decrease in T4 with no concomitant increase in TSH (cf. Goldey et al., 1995a). This is quite different from the classic hypothyroidism characterized by decreased thyroid hormones and subsequent activation of the hypothalamic–pituitary feedback loop with increased release of thyroid-stimulating hormone (TSH) from the pituitary (Sarne and Refetoff, 1995). In addition, studies of mothers and their offspring demonstrate that humans are also sensitive to changes in thyroid hormone homeostasis caused by PCBs and dioxins (Koopman-Esseboom et al., 1994, Pluim et al., 1993, Ilsen et al., 1996, Nagayama et al., 1997, Fiolet et al., 1997).

We previously reported that perinatal exposure of pregnant rats to a commercial PCB mixture, Aroclor 1254 (A1254) results in a low-frequency hearing loss in adult offspring (Goldey et al., 1995a, Herr et al., 1996). We have hypothesized that this ototoxicity results from A1254-induced hypothyroxenemia during a critical period of auditory development. Evidence for this hypothesis includes: a correlation between the severity of functional auditory impairment and the degree of thyroid hormone depletion (Goldey et al., 1995b), and amelioration of the hearing loss following postnatal thyroxine replacement (Goldey and Crofton, 1998).

Developmental exposure of rats to A1254 will also increase the latency and amplitude of the early peaks of the brainstem-auditory evoked potential (BAER) for low-frequency stimuli (Herr et al., 1996). The previous research demonstrating a moderate (i.e. 25–30 dB) auditory impairment (Goldey et al., 1995a, Goldey and Crofton, 1998), coupled with the decreased amplitude in the early BAER peaks (Herr et al., 1996) led to the hypothesis that the PCB-induced hypothyroxinemia could result in a loss of outer hair cells in the low-frequency region of the cochlea. The current research tested this hypothesis by using behavioral thresholds to confirm the auditory impairment in adult offspring of dams exposed during gestation and lactation, followed by a light microscopic histological survey of the cochlea.

Section snippets

Animals

Forty primiparous Long–Evans rats arrived from Charles River (Raleigh, NC) on gestation day (GD) 2 (the day of insemination was GD 0). Rats were housed individually, in standard plastic hanging cages (45 ×24×20 cm) with sterilized pine shavings as bedding, in an AAALAC-approved animal facility. All experiments were approved in advance by the National Health and Environmental Effects Research Laboratory Animal Care Committee of the US Environmental Protection Agency. Animal rooms were maintained

Results

Auditory threshold data demonstrate a low-frequency auditory impairment in the A1254-exposed group compared to controls (Fig. 1). The magnitude of effect of A1254 on low-frequency hearing was independent of gender (data not shown). The group mean threshold for 1 kHz in the A1254 group was approximately 26 dB higher than the control mean. There were no significant treatment related effects on thresholds for any of the higher frequencies (Fig. 1). These findings were supported by an overall

Discussion

The present work demonstrates that developmental exposure to a commercial PCB mixture results in loss of hair cells in the upper turns of the cochlea. These findings are the first to clearly demonstrate an effect of developmental PCB exposure on the structure of the nervous system. Furthermore, the structural damage correlates well with a functional deficit. The current study also replicated previous work demonstrating loss of low-frequency hearing produced by A1254 exposure (Goldey et al.,

Acknowledgements

The authors would like to thank Keith Tarpley for assistance with the graphics and photomicrographs.

References (54)

  • G. Meza et al.

    Development of vestibular and auditory function: effects of hypothyroidism and thyroxine replacement therapy on nystagmus and auditory evoked potentials in the pigmented rat

    Int. J. Dev. Neurosci.

    (1996)
  • D.C. Morse et al.

    Interference of polyclorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats

    Toxicol. Appl. Pharmacol.

    (1993)
  • D.C. Morse et al.

    Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254)

    Toxicol. Appl. Pharmacol.

    (1996)
  • D.K. Ness et al.

    Effects of perinatal exposure to specific PCB congeners on thyroid hormone concentrations and thyroid histology in the rat

    Toxicol. Lett.

    (1993)
  • B.W. O’Malley et al.

    Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt/hyt) mouse

    Hear. Res.

    (1995)
  • B.-W. Seo et al.

    Effects of gestational and lactational exposure to coplanar polychlorinated biphenyl (PCB) congeners or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thyroid hormone concentrations in weanling rats

    Toxicol. Lett.

    (1995)
  • A. Uziel et al.

    The effect of hypothyroidism on the onset of cochlear potentials in developing rats

    Brain Res.

    (1980)
  • A. Uziel et al.

    Maturational and degenerative processes in the organ of Corti after neonatal hypothyroidism

    Hear. Res.

    (1983)
  • A. Uziel et al.

    Corrective effects of thyroxine on cochlear abnormalities induced by congenital hypothyroidism in the rat. I. Morphological study

    Dev. Brain Res.

    (1985)
  • A. Uziel et al.

    Corrective effects of thyroxine on cochlear abnormalities induced by congenital hypothyroidism in the rat. II. Electrophysiological study

    Dev. Brain Res.

    (1985)
  • D.J. Bradley et al.

    Alpha and beta thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo

    Proc. Natl. Acad. Sci. USA

    (1994)
  • A.O. Cheek et al.

    Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin

    Environ. Health Perspect.

    (1999)
  • T. Colborn et al.

    Developmental effects of endocrine-disrupting chemicals in wildlife and humans

    Environ. Health Perspect.

    (1993)
  • W.T. Collins et al.

    Fine structural lesions and hormonal alterations in thyroid glands of perinatal rats exposed in utero and by the milk to polychlorinated biphenyls

    Am. J. Pathol.

    (1980)
  • D.A. Corey et al.

    Effects of exposure to polychlorinated biphenyl (PCB) from conception on growth, and development of endocrine, neurochemical, and cognitive measures in 60 day old rats

    Growth Dev. Aging

    (1996)
  • Crofton, K.M., 1992. Reflex modification and the assessment of sensory dysfunction. In: Tilson, H., Mitchell, C....
  • Crofton, K.M., Kodavanti, P.R.S., Derr-Yellin, E.C., Nace, C.G., Bush, B., 1997. Thyroid hormones and ototoxicity in...
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    This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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